ELSEVIER SAUNDERS The Curtis Center 170S. Independence Mall W 300E Philadelphia, Pennsylvania 19106
ENTERAL AND TUBE FEEDING
ISBN 0-7216-0379-3
Copyright © 2005, Elsevier Inc. (USA). Ail rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier's Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 2152387869, fax: (+1) 2152382239, e-mail:
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NOTICE Medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the author assumesany liability for any injury and/or damage to persons or property arising from this publication. The Publisher
Previous editions copyrighted 1997, 1990, 1984
Clinical nutrition: enteral and tube feeding / editor-in-chief, Rolando H. Rolandelli ; associate editors, Robin Bankhead, Joseph 1. Boullata, Charlene W. Compher.-4th ed. p. ;cm. Includes bibliographical references and index. ISBN 0-7216-0379-3 1. Enteral feeding. 2. Tube feeding. 1. Rolandelli, Rolando. [DNLM: 1. Enteral Nutrition. 2. Food, Formulated. 3. Intubation, Gastrointestinal. 4. Nutrition. WB 410 C64152004) RM225.C565 2005 615.8'55-dc22 2004049197
Printed in the United Statesof America
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DEDICATION This book is dedicated to my wife Mercedes and my children Patrick, Florencia, and Victoria for their continued love and support.
Contributors
Satoshi Aiko. MD. PhD Professor of Surgery Department of Surgery II National Defense Medical College Tokorozawa, Japan jorge Albina. MD Professor of Surgery, Brown Medical School Directorof Surgical Research Department of Surgery, Rhode Island Hospital Director of Nutritional Support Service Departmentof Surgery, Rhode Island Hospital Providence, Rhode Island Abhinandana Anantharaju. MD Fellow in Gastroenterology Loyola University Maywood, Illinois Olga Antonopoulos. MS. RD Clinical Dietitian Clinical Nutrition Support Service University of Pennsylvania Medical Center Philadelphia, Pennsylvania Vincent Arment], MD. PhD Professor of Surgery Department Kidney Transplantation Abdominal Organ Transplant Surgery Temple University Hospital Philadelphia, Pennsylvania juan Pablo Arnoletti. MD Assistant Professor Surgery University of Alabama at Birmingham Birmingham, Alabama
Stig Bengmark. MD. PhD Emeritus Professorof Surgery Lund University, Sweden Honorary Visiting Professor Departments of Hepatology and Surgery University College, London London MedicalSchool London, England Mette M. Berger. MD. PhD Medecin adjoint (staffphysician) Service de Soins Intensifs Chirurgicaux & Centre des Bniles Lausanne, France Carolyn D. Berdanier. PhD ProfessorEmerita Nutrition and Cell Biology University of Georgia Athens, Georgia Michele Bishop. MD Assistant Professorof Medicine Directorof Pancreas Interest Group Division of Gastroenterology and Hepatology Mayo Clinic Jacksonville, Florida joseph I. Boullata. PharmD. BCNSP Professor of Pharmacy Practice Nutrition Support and Critical Care Temple University School of Pharmacy Philadelphia, Pennsylvania
Robin Bankhead. CRNP. MS. CNSN Coordinator, Nutrition Support Service Clinical Nurse Specialist Temple University Philadelphia, Pennsylvania
Todd W. Canada. PharmD. BCNSP Critical Care/Nutrition Support Pharmacist The University of Texas M.D. Anderson Cancer Center Division of Pharmacy Houston, Texas Clinical Assistant Professor The University of Texas At Austin College of Pharmacy Austin, Texas
Adrian Barbul. MD Chairman, Department of Surgery Sinai Hospital of Baltimore Professor, Johns Hopkins Medical Institutions Baltimore, Maryland
Pamela Charney. MS. RD/LD. CNSD PhDStudent School of Health Related Professional University of Medicine and Dentistry Dayton, Ohio
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Contributors
Connie Brewer, RPh, BCNSP
Mark DeLegge, MD
Nutrition Support Pharmacist Pharmacy Mount Carmel Medical Center Columbus, Ohio
Associate Professor of Medicine Director, Section of Nutrition Digestive Disease Center Medical University of South Carolina Charleston, South Carolina
Rene L. Chiolero, MD Head Surgical ICU & Burn Center University Hospital (CHUV) Lausanne, Switzerland
David Ciccolella, MD Associate Professor of Medicine Director, Asthma Center Medical Director, Respiratory Therapy Associate Director, Airways Disease Center Pulmonary and Critical Care Division Temple University School of Medicine Philadelphia, Pennsylvania
Greg van Citters, PhD Research Fellow Gonda Diabetes Research Center Department of Gene Regulation & Drug Discovery Division of Molecular Medicine City of Hope National Medical Center/Beckman Research Institute Duarte, California
Melanie Berg, MS, RD Directory of Nutritional Services Hazelwood Center Louisville, Kentucky
Sheila Clohessy, RD, LD, CNSD Clinical Dietitian Loyola University Medical Center Maywood, Illinois
Charlene Compher, PhD, RD, CNSD Assistant Professor in Nutrition Science University of Pennsylvania School of Nursing Philadelphia, Pennsylvania
Tracy Crane, RD Research Specialist Senior University of Arizona Department of Nutritional Sciences Tucson, Arizona
Edwin Deitch, MD
Clifford S. Deutschman, MS, MD, FCCM Professor of Anesthesia and Surgery Hospital of the University of Pennsylvania Philadelphia, Pennsylvania
Rupinder Dhaliwal, RD Nutrition Research Associate Departent of Medicine Queens University Kingston, Canada
Wilfred Druml, MD Professor of Nephrology University of Vienna Vienna General Hospital Vienna, Austria
Nancy Evans-Stoner, MSN, RN Clinical Nurse Specialist Clinical Nutrition Support Service University of Pennsylvania Medical Center Philadelphia, Pennsylvania
Ivone M. Ferreira, MD, MSc, PhD International Specialist Physician University of Toronto and University of Western Ontario Ontario, Canada
Lisa Freeman, PhD, DVM Associate Professor, Department of Clinical Sciences Tufts University School of Veterinary Medicine North Grafton, Massachusetts
Jan Willem M. Greve, MD, PhD Professor of Surgery University Hospital Maastricht Maastricht, The Netherlands
Peggi Guenter, PhD, RN, CNSN
Chairman and Professor of Surgery Department of Surgery University of Medicine and Dentistry of New Jersey Newark, New Jersey
Managing Editor for Special Projects American Society for Parenteral and Enteral Nutrition Havertown, Pennsylvania
Cornelis H.C. Dejong, MD, PhD
Research Fellow Cardiac and Thoracic Surgery Temple University School of Medicine Philadelphia, Pennsylvania
Consultant Surgeon Academic Hospital Maastricht Maastricht, The Netherlands
Dipin Gupta, MD
Contributors
Myeongsik Han, MD, PhD Associate Professor Department of Surgery University of Ulsan College of Medicine Seoul, Korea Theresa Han-Markey, MS, RD Didactic Program Director, Adjunct Lecturer University of Michigan School of Public Health Program in Human Nutrition Ann Arbor, Michigan jeanette Hasse, PhD, RD Transplant Nutrition Specialist Baylor Regional Transplant Institute Baylor University Medical Center Dallas, Texas jimmi Hatton, PharmD, BCNSP Associate Professor Pharmacy and Neurosurgery University of Kentucky College of Pharmacy Lexington, Kentucky Daren Keith Heyland, MD, FRCPC, MSC Associate Professor Departmentof Medicine Queens University Kingston, Canada Mary Hise, PhD, RD Assistant Professor, Dietetics and Nutrition University of Kansas Medical Center Kansas City, Kansas Daniel L. Hurley, MD, FACE Assistant Professor of Medicine Mayo Medical School Consultant Division of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine Mayo Clinic and Mayo Foundation Rochester, Minnesota Gabriel lonescu, MD First YearFellow St. Luke's-Roosevelt Hospital Center New York, NewYork Gordon jensen, MD, PhD Director of VanderbiltCenter for Human Nutrition Vanderbilt Medical Center Nashville, Tennessee Donald Kotler, MD Chief, Division of Gastroenterology St. Luke's-Roosevelt Hospital Center Professor of Medicine Columbia University College of Physiciansand Surgeons New York, NewYork
Debra S. Kovacevich, RN, MPH Coordinator of Nursing, Nutrition & Patient Care Services HomeMed University of Michigan Hospitals and Health Centers Clinical Assistant Professor, College of Pharmacy University of Michigan Ann Arbor, Michigan Lori Kowalski, MS, RD, CNSD Clinical Dietitian Clinical Nutrition/Nutrition Support Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania Polly Lenssen, MS, RD, CD, FADA Manager Clinical Nutrition Children's Hospital and Regional Medical Center Dietitian Seattle Cancer Care Alliance Seattle, Washington Henry Lin, MD Associate Professorof Medicine Division of Gastrointestinal and Liver Diseases KeckSchool of Medicine University of Southern California Los Angeles, California Linda Lord, NP, MSN Nurse Practitioner Nutrition Support Service University of Rochester Medical Center Rochester, NewYork Louis j. Magnotti, MD Assistant Professorof Surgery Department of Trauma University of Medicine and Dentistry of NewJersey Newark, NewJersey Ainsley Malone, MS, RD Nutrition Support Dietitian Pharmacy Mount Carmel West Hospital Columbus, Ohio Paul E. Marik, MD, FCCM, FCCP ProfessorCritical Care Medicine Department of Critical Care Medicine University of Pittsburgh Pittsburgh, Pennsylvania Karen McDoniel, RD, LD, CNSD Nutrition Support Specialist Barnes-Jewish Hospital, St. Louis, MO
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Contributors
M. Molly McMahon, MD, FACE
Kathy Prelack, PhD, RD
Associate Professor of Medicine Mayo Medical School Consultant Division of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine Mayo Clinic and Mayo Foundation Rochester, Minnesota
Clinical Nutrition Manager Nutrition Support Service Shriners Hospital for Children Boston, Massachusetts
Margaret M. McQuiggan, MS, RD, CNSD Clinical Dietitian Specialist Herman Hospital Houston, Texas
Kathryn Michel, DVM, MS, DACVN Assistant Professor of Nutrition School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania
William E. Mitch, M.D. President, American Society of Nephrology Edward Randall Professor of Medicine Chairman, Department of Medicine University of Texas Medical Branch Galveston, Texas
Sohrab Mobarhan, MD Professor of Medicine Loyola University Maywood, Illinois
Frederick A. Moore, MD Medical Director, Trauma Services Professor and Vice Chairman University of Texas Medical School Department of Surgery Houston, Texas
Patrick Neligan, MA, MB, BcH, FCARCSI Assistant Professor of Anesthesia Hospital of the University of Pennsylvania Philadelphia, Pennsylvania
Massimo Raimondo, MD Assistant Professor of Medicine Division of Gastroenterology & Hepatology Mayo Clinic Jacksonville, Florida
jorge Reyes, MD Professor of Surgery University of Pittsburgh Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania
Carol Rollins, MS, RD, CNSD, PharmD, BCNSP Clinical Associate Professor Pharmacy Practice and Science College of Pharmacy, The University of Arizona Tucson, Arizona Clinical Specialist, Nutrition Support Pharmacy University Medical Center Tucson, Arizona
john Rombeau, MD Professor of Surgery University of Pennsylvania Philadelphia, Pennsylvania
M. Bonnie Rosbolt, PharmD Clinical Assistant Professor College of Pharmacy University of Kentucky Lexington, Kentucky
Trish Fuhrman, MS, RD, FADA, CNSD Area Clinical Nutrition Marketing Manager Coram Healthcare St. Louis, Missouri
julie L. Roth, MD Anita Nucci, PhD, RD Manager, Clinical Nutrition/Nutrition Support & Intestinal Care Center Clinical Nutrition Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania
Assistant Professor of Medicine Feinberg School of Medicine Northwestern Memorial Hospital Wellness Institute Chicago, Illinois
Heather Rowe, RD, CNSD Mark Nunnally, MD Assistant Professor Department of Anesthesia and Critical Care University of Chicago Chicago, Illinois
Clinical Dietitian HomeMed University of Michigan Hospitals and Health Centers Ann Arbor, Michigan
Cesar Ruiz, MA, CCC/SLP julie E. Park, MD Resident, Department of Surgery Johns Hopkins Medical Institutions Baltimore, Maryland
Assistant Professor in Speech, Language, and Hearing Science Program laSalle University Philadelphia, Pennsylvania
Contributors
Mary Russell, MS, RD/LD, CNSD
Jeremy Z. Williams, MD
Director, Nutrition Services Duke University Hospital Durham, North Carolina
Resident, Division of Plastic Surgery Johns Hopkins Medical Institutions Baltimore, Maryland
Robert Schaffner, NP, DPh, MBA, CNSN, CD·N
Marion Winkler, MS, RD
Nurse Practitioner Nutrition Support Service University of Rochester Medical Center Rochester, New York
Surgical Nutrition Specialist Rhode Island Hospital Brown University School of Medicine Providence, Rhode Island
Phyllis Schiavone-Gatto, MSN, RN, C, CRNP
Steven E. Wolf, MD
Advanced Practice Nurse Department of Clinical Nutrition Support Services Hospital of the University of Pennsylvania Philadelphia, Pennsylvania
Associate Professor Department of Surgery University of Texas Medical Branch Director, Blocker Burn Unit Assistant Chief of Staff Shriners Hospital for Children Galveston, Texas
P.B. Soeters, MD, PhD Professor of Gastrointenstinal Surgery Department of Surgery University Hospital Maastricht Maastricht, The Netherlands
Ulrich Suchner, MD Clinic of Anesthesiology Grosshadern University Hospital Ludwig Maximilians University Munich, Germany
james S. Scolapio, MD Associate Professor of Medicine Director of Nutrition Division of Gastroenterology & Hepatology Mayo Clinic Jacksonville, Florida
Cynthia Thomson, PhD, RD Assistant Professor Department of Nutritional Sciences Arizona Cancer Center University of Arizona Tucson, Arizona
Clarivet Torres, MD Assistant Professor of Pediatrics Section of Pediatric Gastroenterology and Nutrition University of Nebraska Medical Center Omaha, Nebraska
jon A. Vanderhoof, MD Professor of Pediatrics and Internal Medicine Director, Joint Section of Pediatric Gastroenterology and Nutrition University of Nebraska Medical Center Omaha, Nebraska
Rosemary A. Kozar, MD, PhD Associate Professor of Surgery University of Texas Medical School Department of Surgery Houston, Texas
Kenneth J. Woodside, MD Resident in General Surgery Department of Surgery University of Texas Medical Branch Galveston, Texas
Donna Zimmaro Bliss, PhD, RN, FAAN Associate Professor Professor in Long Term Care of Elders University of Minnesota School of Nursing Minneapolis, Minnesota
Hans10achimG.jung, PhD Research Dairy Scientist US Dept of Agriculture Agricultural Research Service Adjunct Professor, Department of Agronomy University of Minnesota St. Paul, Minnesota
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Foreword
Extensive changes have occurred in the delivery of enteral nutritional care since publication of the last edition of this book in 1997. Perhaps the greatest of these changes is the need to continue to provide the highest quality care with fewer resources, and to render this care more efficiently and expeditiously. A continuing trend in enteral feeding is its increased provision at home rather than in the hospital. This shift in venue has created new challenges for both patient and health care practitioner. The relevance of these changes and their appropriate resolutions are well expressed within the contents of this edition. The indications for enteral feeding continue to be refined. In some conditions there is good "evidence-based" rationale to justifythe use of enteral feeding whereas in other instances there is woefully little data to support its clinical utility. Regardless of the availability or quality of evidence-based support, the clinician is still confronted with the dilemma of when and how to feed his or her patient. Moreover, the morally and ethically vexing alternative of permitting continued starvation frequently confounds these decisions. This edition remains true to the "raison d'etre" of the three previous editions, namely to communicate the highest quality of enteral nutritional science to enable the practitioner to feed patients safely and efficaciously. This information is well described in the sections entitled Physiology of the Gut and Nutrient Metabolism. Perhaps the fastest growing component of nutritional care delivery is its technology. The section Principles of Enteral Nutrition integrates the technologic advances within the context of feasibility, relevance, and cost effectiveness. This theme is underscored in the chapters on reimbursement and pharmacotherapeutics, which are integral to providing care within the context of today's fiscal realities. Perhaps the newest content of this edition is contained in the Disease Specific Section. Seventeen chapters are devoted to the intricacies and specifics of enteral feeding for diseases ranging from central nervous system trauma to immunodeficiencies. Cancer continues to be one of the most important indications for enteral feeding as exemplified in the five chapters devoted to this topic. The sacrosanct principle of improving quality of life and not prolonging suffering of cancer patients is underscored in this content. Finally, a major strength of this book is reflected in the extensive experience of its Editor and co-contributors. Dr. Rolando Rolandelli is a world renowned expert in enteral feeding and has contributed extensively to past editions of this book. He remains dedicated to providing both high quality science and the best available clinical information. Dr. Rolandelli has included a group of outstanding international contributors from a multitude of disciplines who share his commitment to academic excellence. In summary, enteral feeding continues to be an integral component of the care of many hospitalized and home patients. The science and application of this important therapy are well expressed in this book in a scholarly and clinically relevant manner. John L. Rambeau, MD Professor of Surgery University of Pennsylvania
xiii
Table of Contents
1
The multidisciplinary approach to enteral nutrition
3
2
Role of controlled gastrointestinal transit in nutrition and tube feeding 11
3
Mechanics and significance of gut barrier function and failure
23
4
Gene expression and nutrition
32
5
Nutritional requirements across animal species
43
6
Metabolism and life cycle : pregnancy and lactation
57
7
Nutrient metabolism in children
68
8
Metabolism in the life cycle : aging
75
9
Metabolism in acute and chronic illness
80
10
Fluid and electrolytes
95
11
Macronutrients
110
12
Vitamins
126
13
Minerals and trace elements
140
14
Non-nutritive dietary supplements : dietary fiber
155
15
Nutrition and wound healing
172
16
Nutrition focused history and physical examination
185
17
Access to the gastrointestinal tract
202
18
Enteral formulations : standard
216
19
Immunonutrition
224
20
Administration of enteral nutrition : initiation, progression, and transition
243
21
Dietary supplements
248
22
Pre-, pro-, and synbiotics in clinical enteral nutrition
265
23
Monitoring for efficacy, complications, and toxicity
276
24
Pharmacotherapeutic issues
291
25
Home enteral nutrition reimbursement
306
26
Enteral nutrition support in the critically ill pediatric patient
317
27
Enteral nutrition in the home
332
28
Enteral nutrition after severe burn
349
29
Trauma
364
30
Nutrition support in patients with sepsis
373
31
Brain and spinal cord injuries
381
32
Cardiac surgery
389
33
Severe obesity in critically ill patients
398
34
Enteral nutrition and the neurologic diseases
406
35
Disease specific enteral and tube feeding : acute pulmonary disease
414
36
Nutrition in stable chronic obstructive pulmonary disease
424
37
Acute pancreatitis
436
38
Chronic pancreatitis
445
39
Short bowel syndrome
451
40
Enteral nutrition in acute hepatic dysfunction
464
41
Enteral nutrition in renal disease
471
42
Enteral nutrition in human immunodeficiency virus infection
486
43
Diabetes mellitus
498
44
Cancer : head and neck
509
45
Esophageal/gastric/pancreatic cancer
516
46
Intestinal transplantation
523
47
Chronic liver disease and transplantation
530
48
Hematopoietic stem cell transplantation
544
• The Multidisciplinary Approach to Enteral Nutrition Peggi Guenter, PhD, RN, CNSN
CHAPTER OUTLINE Introduction Traditional Multidisciplinary Nutrition Support Teams Traditional Roles of Team Members Physician's Role Nurse's Role Dietitian's Role Pharmacist's Role Contemporary Definition
Evolution of the Nutrition Support Service Impact of Nutrition Support Teams on Patient Outcome Conclusion Editors' Note
INTRODUCTION Since the introduction of enteral nutrition therapy by John Hunter in 1790, a variety of health care professionals have been involved in this process. 1 Health care has been multidisciplinary as far back as Greek civilization and possibly earlier. The first medical text was a pharmaceutical compendium containing nutritional therapies from Mesopotamia circa 2100 Be. Three Greek gods personified the multidisciplinary concept: Asklepios, god of medicine; Hygieia, goddess of health maintenance (nursing); and Panacea, goddess of medication (pharmacy). Hippocrates was born during this time and contributed greatly to the fields of medicine and nursing." During the mid-1850s Florence Nightingale, founder of modern nursing, was very concerned about nutrition.' With the advent of nursing schools in the United States, student nurses were taught about "invalid cookery" and provided therapeutic diets to hospitalized patients. As providing nutrition became a more specialized role, the discipline of dietetics emerged in the early 1900s
with the founding of the American Dietetic Association in 1917.2 Formal nutrition support teams were not established until the development of parenteral nutrition in the early 19705, beginning with large medical centers. These teams had a multidisciplinary pattern and were generally made up of a physician, nurse, dietitian, and pharmacist. The number of these teams grew throughout the 1970s and 1980s.1n 1985, Dr.John Wesley wrote, "It is apparent that any well-organized multidisciplinary approach to nutrition support can be clinically and economically advantageous, whether or not it embodies a formal nutrition support team."? As the prospective payment system and capitated health care plans took hold and began to drive financing of hospitals, these teams began to disband, decentralize, or disperse. Despite a decrease in the use of formal nutrition support teams and insufficient administrative support in health care systems, the multidisciplinary group of health care professionals specializing in nutritional support and caring for the patient receiving enteral nutrition is vital. In the absence of the multidisciplinary group of specialists, despite well-intentioned policies and procedures, patient care can suffer. In this chapter the history, evolution, and impact of the multidisciplinary approach on the overall delivery of enteral nutrition will be presented.
TRADITIONAL MULTIDISCIPLINARY NUTRITION SUPPORT TEAMS With the development of nutrition support services (NSS) in the early 1970s,which were formed initially to care for patients receiving parenteral nutrition, came the reawakening of interest in the patient's nutritional status and the use of enteral nutrition. Advances in the composition of liquid diets resulted from the aerospace program, because of the need to nourish astronauts on the muchanticipated trip to and from the moon. Research into the development of more comfortable feeding tubes and enteral feeding pumps led to the expansion of NSS into care for tube-fed patients as well.'
3
4
1• The Multidisciplinary Approach to Enteral Nutrition
The American Society for Parenteral and Enteral Nutrition (AS.P.E.N.) was founded in 1976 to serve as a forum for nutrition support clinicians and researchers from all disciplines to exchange information about the care of patients with nutritional needs. The first purpose of A.S.P.E.N. is to promote professional communication among disciplines in the broad field of clinical nutrition including parenteral and enteral nutrition. The second purpose is to promote the application of clinical and research experience in the practice of nutritionally sound medicine (see www.nutritioncare.org/bylaws.html). The rapid growth in the numbers of nutrition support teams during the 1970s and early 1980s has been well documented.Yln a 1991 survey conducted by AS.P.E.N., 29% of hospitals with greater than 150 beds had a nutrition support team, suggesting that the growth of new teams had tapered off and many institutions did not perceive a need for a nutrition support team." However, The AS.P.E.N. Standards for Adult Hospitalized Patients have recently stated that if an institution does not have a defined nutrition support service or team, an interdisciplinary group of clinicians should provide specialized nutritional support," The purpose of the nutrition support team is to provide quality nutritional care. This is accomplished through identification of patients who are at risk nutritionally, performance of a comprehensive nutritional assessment that guides nutritional therapy, and provision of safe and effective nutritional support," To accomplish these goals, nutrition support teams have developed services that include inpatient consultations, staff educational programs, quality assurance protocols, research programs, and home nutrition support services. The overall goals of the nutrition support team include recognition and treatment of malnutrition and reduction of complications, morbidity, and mortality in a cost-effective manner." The quantitative impact of these teams on the delivery of enteral nutrition will be presented later in this chapter.
TRADITIONAL ROLES OF TEAM MEMBERS An organized nutrition support service or team should include a physician, nurse, dietitian, and pharmacist," Although the structure and function of NSS vary from one health care setting to the next based on needs and available personnel, some traditional roles are reviewed here.
Physician's Role The nutrition support physician needs to be familiar with all aspects of enteral nutrition care including patient screening and assessment, development and implementation of an enteral care plan, and termination of therapy. A distinctive role of the nutrition support physician is to select the appropriate feeding access, and, depending on his or her medical specialty, the actual placement of the feeding access. The physician must be capable of managing the policy, procedure, personnel, education,
finance, and quality improvement issues pertaining to nutritional support.'?
Nurse's Role The nurse's contribution comes from direct observation of enteral feeding delivery and patient response in all settings. The nurse on the nutrition service team communicates directly with the primary care nurses and other health care providers and serves as the liaison with other team members," The nurse's scope of practice includes direct patient care; consultation with other nurses and health care professionals; education of patients, caregivers, students, colleagues, and the public; and participation in research activities and administrative functions. J1
Dietitian's Role The dietitian provides nutrition screening and assessment, develops and implements a specialized nutrition support care plan, monitors the nutritional effectiveness of therapy, and develops the transitional feeding care plan." The dietitian's role also includes education and training of patients, caregivers, and health care professionals's; management of patients receiving home enteral and parenteral nutrition, and research.
Pharmacist's Role The role of the pharmacist in the care of the patient receiving enteral nutrition is derived from knowledge of pharmacokinetics, drug metabolism, and drug-drug and drug-nutrient interactions." The pharmacist's scope of practice in the nutrition support team includes direct patient care; administrative management of the specialized nutrition support program; quality improvement; education of health care professionals, patients, and caregivers; and research." A recent study of this role confirmed that pharmacists continue to intervene with patients receiving enteral nutrition in the clinical setting to ensure positive effects on patient care."
Contemporary Definition A more contemporary definition of the nutrition support team includes some of the discipline-specific role delineation described in the preceding paragraphs and elsewhere but also includes the recognition that clinicians, who are board-eertified in nutritional support are capable of addressing all of the nutrition support needs of patients in acute care, extended care, or home care settings. In addition, a board-eertified nutrition support team member, regardless of discipline, is responsible for a patients' nutritional assessment, plan of care, monitoring, discharge planning, and follow-up. Much of the nutritional care is based on shared knowledge, with team members
SECTION I • Introduction
accessing each other as consultants for questions or problems outside their knowledge base. This allows a team member to develop an in-depth relationship with the patient and thus the patient has to call only one nutrition support professional.
EVOLUTION OF THE NUTRITION SUPPORT SERVICE With the changes in health care financing in the 1990s came the need for hospitals to downsize, merge, and shift care to alternate sites. 16 Consequently, nutrition support team members were forced to justify their salaries and redistribute responsibilities when one or more team positions were eliminated. This health care movement led to an evolution from traditional nutrition support services and team roles. Thus, more quality improvement programs, cost analysis research projects, and innovative use of personnel came into the forefront. In this section some of those shifts and programs designed to better deliver enteral nutrition within cost constraints will be described. At the same time as many of these health care changes were occurring, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) in 1995 mandated compliance with specific nutrition care standards. Increased JCAHO requirements, at the same time that nutrition support teams were vanishing, necessitated greater vigilance in patient care, including quality improvement programs. 17 In one such program, practice changes were made to improve the percentage of enterally fed patients in the intensive care unit whose protein and energy goals were being met. A 70% reduction in the percentage of patients whose nutritional needs were not met was achieved." Another change in the health care arena was to shift much of the delivery of enteral nutrition from the hospital to the home. With this change, efforts were needed to establish a long-term enteral access site early in the patient's hospitalization, to develop more effective patient and caregiver education, to provide coordinated discharge planning, and to expand the roles of traditional inpatient personnel to home care companies. All nutrition support clinicians (dietitians, nurses, pharmacists, and physicians) may play a role in the management and monitoring of safe nutrition support therapy in patients receiving home enteral or parenteral nutrition. Coordination of care is essential between hospital-based and infusion provider nutrition support specialists. Another nutrition support-related position that has emerged is the reimbursement specialist. This team member may be available to educate others about thirdparty reimbursement, verifyinsurance coverage, and assist the team in providing cost-effective products and services. In a survey published in 1990,only a small number of dietitians were assuming responsibility for complete home enteral nutrition education." However, by the mid1990s, reports of dietitians being employed by home infusion organizations'" and carrying out most of the initial education of patients for home enteral therapy"
5
were being published. Pharmacists continue to be involved in outpatient care of patients requiring nutritional support. 15.22,23 Additionally, consultant pharmacists employed by home care or long-term care agencies are often involved with patients receiving enteral nutrition as wel1. 24 Other health care professionals who are not traditional nutrition support team members are now more involved in discharge planning and home enteral therapy. In the hospital, speech and language pathologists work with dysphagic patients who need enteral therapy to help smooth the transition to home or rehabilitative care." The hospital case manager and home visiting nurse agency are often involved early in the discharge planning and education process." The primary care physician, who may not have been directly involved in the patient's hospital care, must also be kept informed and involved in discharge decision making. Two surveys of nursing practice demonstrated that primary care nurses needed additional information on how to properly prepare and administer medication through feeding tubes.27,28 In the first study, when pharmacists gave assistance to the nurses, significantly fewer episodes of tube clogging due to medications were seen. As a result of the changes in the health care system, traditional nutrition support team members have had to expand their roles by increased sharing of their knowledge, skills, and contributions with other team members. This process has become a greater challenge as the care of patients requiring nutritional support has become more complex, and external expectations have expanded into new areas (e.g., dietary supplements and other alternative therapies). Increasingly, nutrition support team members are educating other health care professionals about enteral nutrition.
IMPACT OF NUTRITION SUPPORT TEAMS ON PATIENT OUTCOME To justify the resources needed to fund NSS, evidence must be available to demonstrate the team's impact on positive patient outcomes, including cost reduction, decreased incidence of complications, and decreased length of hospital stay and mortality. Although studies in the literature on this topic are fewer than those examining the effects of NSS on total parenteral nutrition (TPN) use, some research with enteral nutrition patients is available. An important function of most NSS is to recommend a route of feeding for the patient after a nutritional assessment. Using guidelines developed by A.S.P.E.N. and/or their institutions, three support services groups demonstrated cost savings by recommending enteral nutrition rather than parenteral nutrition when appropriate. In 1986, O'Brien and colleagues'" reviewed 14 cases of patients who did not receive the recommended enteral nutrition but instead received parenteral nutrition. For the 280 days of nutritional support that were considered outside the recommendations, the potential savings were estimated to be more than $70,000. In another study of children
6
1 • The Multidisciplinary Approach to Enteral Nutrition
with cancer who needed nutritional support, Bowman and colleagues" developed an algorithm for therapy. The use of this algorithm led to increased use of enteral nutrition from 9% of total patient-days in 1989 to 56% in 1996. In 2000, Ochoa and his team" reviewed their recommendations over a 9-year period and found a significant decrease in TPN use (616 patients receiving TPN in 1991 vs. 124patients receiving TPNin 1999) despite the fact that their assessment service grew to more than 1400 patients in 1999. The use of enteral nutrition use grew 387% in the intensive care unit, and these recommendations translated into a more than $2.5 million reduction in cost over this time period.P Another important function of the nutrition support team is to develop protocols and standards of care to promote positive patient outcome and reduce the incidence of associated complications. In 1997, Pattison and Young'" studied two groups of patients in whom percutaneous endoscopic gastrostomy (PEG) tubes were placed for enteral nutrition. They used 24 patients as a historical control group, and implemented a five-step standardized protocol for another group. The steps were multidisciplinary, preoperative evaluation; standardized PEG tube placement; administration of preoperative prophylactic antibiotics; surgical outpatient follow-up; and development of patient information booklets. The outcome was measured by the incidence of tube failure, stoma site infection, and gastrointestinal complications. Complications occurred in 92% of patients in the historical control group and in only 50% of the group who were treated using the standardized protocol (P < .05). The standards developed by their multidisciplinary team have since been incorporated into general practice. Another team developed an infusion protocol for intensive care unit patients receiving enteral nutrition. Spain and colleagues" found in a previous study that critically ill patients were receiving only 52% of their goal calories primarily owing to physician underordering, frequent cessation, and slow advancement of feedings. They developed an enteral tube feeding protocol that incorporated standardized physician ordering, nursing procedures, rapid advancement, and limited feeding interruption. With the use of this protocol, physician ordering improved to 82%versus a control value of 66% (P < .05) and delivery of calories improved to 56% of goal by 72 hours versus a control value of 14% (P < .05).33 Although some policies and procedures are intended to give health care providers who are not certified in nutritional support guidelines to manage patients requiring nutritional support, these may not succeed in the absence of specialists. To optimally test the value of having NSS, studies of use of teams versus no teams need to demonstrate the impact on patient outcome. Four such studies that specifically look at enteral nutrition delivery are available in the literature. In 1985, Weinsier and co-workers" retrospectively examined standard hospital nutritional care compared with nutritional support provided by an organized nutrition support service for 70 patients with burns. The group receiving enteral and parenteral nutrition support under the care of the nutrition support service experienced significantly less weight loss and shorter
hospital stays. This translated into significant cost savings. Powers and associates" conducted a study examining team versus no team management of patients receiving enteral nutrition at a Veterans Administration medical center. This prospective trial studied patient demographics; nutrition assessment; type, modifications, and amount of enteral formula delivered; and complications. The researchers found that significantly more team-managed patients attained 1.2 x basal energy expenditure in calories for a longer period of time; had a positive nitrogen balance; and had fewer metabolic, pulmonary, mechanical, or gastrointestinal abnormalities than did the nonteam-managed patients. The results of this study indicated that team-managed enteral nutritional support reduced abnormalities and was nutritionally more efficient compared with the non-team approach. This study was duplicated in a university teaching hospital and the findings were similar." In a more recent report published in 1994, Hassell and colleagues" studied team management of enteral nutrition in a community hospital. They found that the nutrition support team management of enterally fed patients was associated with reductions in mortality rate, length of stay in the hospital, and readmission rate. A cost-benefit analysis revealed that for every $1 invested in the nutrition support team management, a benefit of $4.20 was realized.
CONCLUSION The direct team versus non-team enteral feeding management studies, although limited in numbers, provide evidence for the effects of an organized multidisciplinary approach with protocols and recommendations based on published guidelines. Patients receiving enteral nutrition benefit from this approach, and despite changes in the health care arena, this approach should be used whether a formal team is in place or not. More studies are needed to justify the cost of teams now in the 21st century; however until these studies prove otherwise, this multidisciplinary management of enteral nutrition therapy is vital. REFERENCES 1. Randall HT: The history of enteral nutrition. In Rombeau JL, Caldwell MD (eds): Clinical Enteral and Tube Feeding, 2nd ed. Philadelphia, WB Saunders, 1990, p. 1. 2. Grant JA: Historical perspectives in nutritional support. In Grant JA, Kennedy-Caldwell C (eds): Nutritional Support Nursing. Philadelphia, Grune & Stratton, 1988, p. 1. 3. Nightingale F: Notes on Nursing: What It Is, What It Is Not. London, Harrison, 1859. 4. Wesley JR: Nutrition support teams: Past, present, and future. Nutr Clin Pract 1995;10:219-228. 5. McShane C, Fox HM: Nutrition support teams-A 1983 survey. JPENJ Parenter Enteral Nutr 1985;9:263-268. 6. Lipman T, Munyer TO, Hall C: Parenteral nutrition and nutritional support in the Veterans Administration Medical Centers. JPEN J Parenter Enteral Nutr 1983;7:835-836. 7. Regenstein M: Nutrition support teams-Alive, well and still growing. Nutr Clin Pract 1992;7:296-301. 8. ASPEN Board of Directors and Task Force on Standards for Specialized Nutrition Support for the Hospitalized Adult Patients:
SECTION I • Introduction Standards for specialized nutrition support: Adult hospitalized patients. Nutr Clin Pract 2002;17:384-391. 9. Hamaoui E: Assessing the nutrition support team. JPENJ Parenter Enteral Nutr 1987; 11:412-421. 10. ASPEN Board of Directors and Task Force on Standards for Nutrition Support Physicians: Standards of practice for nutrition support physicians. Nutr Clin Pract 2003;18:270-275. II. ASPEN Board of Directors: Standards of practice for nutrition support nurses. Nutr Clin Pract 2001;16:56-62. 12. Wade JE: Role of a clinical dietitian specialist on a nutrition support service. J Am Diet Assoc 1977;77:185-189. 13. ASPEN Board of Directors: Standards of practice for nutrition support dietitians. Nutr Clin Pract 2000;15:53-59. 14. ASPEN Board of Directors: Standards of practice for nutrition support pharmacists. Nutr Clin Pract 1999;14:275-281. 15. Cerrulli J, Malone M: Assessment of drug-related problems in clinical nutrition patients. JPEN J Parenter Enteral Nutr 1999;23: 218-221. 16. Nelson J: The impact of health care reform on nutrition supportThe practitioners' perspective. Nutr Clin Pract 1995;1O:295-35S. 17. Dougherty D, Bankhead R, Kushner R, et al: Nutrition care given new importance in JCAHO standards. Nutr Clin Pract 1995;10: 575-62S. 18. Schwartz DB: Enhanced enteral and parenteral nutrition practice and outcomes in an intensive care unit with a hospital-wide performance improvement process. J Am Diet Assoc 1996;96:484-489. 19. Skipper A, Rotman N: A survey of the role of the dietitian in preparing patients for home enteral feeding. J Am Diet Assoc 1990;90: 939-944. 20. Pantalos DC: Home health care: A new worksite for dietitians monitoring nutrition support. J Am Diet Assoc 1993;93:1146-1151. 21. McNamara EP, Flood R, Kennedy NP: Home tube feeding: An integrated multidisciplinary approach. J Hum Nutr Diet 2001; 14(1):13-19. 22. American Society of Health-System Pharmacists: ASHP guidelines on the pharmacist's role in home care. Am J Health-Syst Pharm 2000;57:1250-1255. 23. Brown RO, Dickerson RN, Abell TL, et al: One-year experience with a pharmacist-coordinated nutritional support clinic. Am J HealthSystPharm 1999;56:2324-2327. 24. Guenter P: Administering medications via feeding tubes: What consultant pharmacists need to know. Consultant Pharmacist 1999;14:41-48. 25. Martin-Harris B: The evolution of the evaluation and treatment of dysphagia across the health care continuum. Nutr Clin Pract 1999; 14(5S):13-20. 26. Goff K: Enteral and parenteral nutrition transitioning from hospital to home. Nurs Case Manag 1998;3(2):67-74. 27. Seifert CF,Frye JL, Belknap DC, et al: A nursing survey to determine the characteristics of medication administration through enteral feeding catheters. Clin Nurs Res 1995;4:290-305. 28. Mateo MA: Management of enteral tubes. Heart Lung 1996;25: 318-323. 29. O'Brien DD, Hodges RE, Day AT, et al: Recommendations of nutrition support team promote cost containment. JPEN J Parenter Enteral Nutr 1986; I 0:300-302. 30. Bowman LC, Williams R, Sanders M, et al: Algorithm for nutritional support: Experience of the metabolic and infusion support service of St. Jude Children's Research Hospital. Int J Cancer Suppl 1998; 11:76-80. 31. Ochoa JB, Magnuson B, Swintowsky M, et al: Long-term reduction in the cost of nutritional intervention achieved by a nutrition support service. Nutr Clin Pract 2000;15:174-180. 32. Pattison D, Young A: Effect of a multi-disciplinary care team on the management of gastrostomy feeding. J Hum Nutr Diet 1997;10: 103-109. 33. Spain DA, McClave SA,Sexton LK, et al: Infusion protocol improves delivery of enteral tube feeding in the critical care unit. JPEN J Parenter Enteral Nutr 1999;23:288-292. 34. Weinsier RL, Heimburger DC, Samples CM, et al: Cost containment: A contribution of aggressive nutritional support in burn patients. J Burn Care Rehabil 1985;6:436. 35. Powers DA, Brown RO, Cowan GS, et al: Nutritional support team vs. nonteam management of enteral nutritional support in a
7
Veterans Administration medical center teaching hospital. JPEN J Parenter Enteral Nutr 1986;10:635-638. 36. Brown RO, Carlson SD,Cowan GS, et al: Enteral nutritional support management in a university teaching hospital: Team vs nonteam. JPENJ Parenter Enteral Nutr 1987;11:52-56. 37. Hassell IT, Games AD, Shaffer B, et al: Nutrition support team management of enterally fed patients in a community hospital is cost-beneficial. J Am Diet Assoc 1994;94:993-998.
EDITORS' NOTE The practice of nutrition support has expanded both in knowledge base required and in the level of clinical expertise over the last several decades. During this time, clinicians on the front line discovered new dimensions in nutrition science through their direct care for patients. 1,2 As noted by Rhoads,' an unforeseen result of these advances has been the further development and subspecialization of the various disciplines involved in nutrition support-namely, medicine, nursing, dietetics, and pharmacy-which further improved patient care. The administration of nutritional support has become safe and effective through the multidisciplinary team of these health care providers.' Nutritional support has allowed the recovery of patients from catastrophic illnesses that previously were lethal. Two good examples are enterocutaneous fistula and short bowel syndrome. In addition, new forms of therapy that could not be undertaken without effective nutritional support have been developed. These include transplantation and multimodality oncotherapy. The success of the implementation of all of these forms of therapy for critically ill patients has depended on the multidisciplinary approach of medical providers. In an expeditious manner, medical providers from different disciplines contribute expertise and vantage points to help resolve clinical problems that had previously vexed individual medical practitioners. This team concept has long been recognized as desirable at the level of each discipline represented.r" The added bonus of discipline-specific knowledge has created an appreciation for the complexity of patient care that further fostered interdisciplinary nutrition support practice, as well as many other practices. The model of providing multidisciplinary care to patients requiring nutritional support continues, owing a lot to the pioneers in each discipline for bringing us to the point we are at today. Although each individual discipline was once the focus of an aspect of nutrition support practice, today's nutrition support specialist may come from any discipline. Clinicians have sustained collective efforts, incorporating unique attributes of their own disciplines to the shared common goals of patient care, education, and research in nutritional support. Nutrition support is a specialty now practiced in a variety of settings, regardless of discipline, by those with adequate training (education, experience, and interest) and as recognized by board certification. The day of defining discipline-specific roles based on the route of administration or on a set of monitoring parameters or on a function in obtaining a
8
1 • The Multidisciplinary Approach to Enteral Nutrition
product has thankfully passed. The role of the boardcertified nutrition support specialist is to manage the patient's care. The purpose of a team, whether as a formalized service or as a group of committed individuals, is to identify patients requiring nutritional support and assure that they receive safe and effective care. In so doing they educate themselves and other health care providers. Although cost containment has limited the existence of formal organized teams or services in all but a few institutions, the concept of multidisciplinary care continues to be important. A committed team of specialists is ideal; however, the model has changed to one in which perhaps only one specialist serves as a consultant to nonspecialist, patient care providers of all disciplines. For example, the nurse or pharmacist with little training in nutrition support who is called upon to care for such patients will benefit greatly from the help of a specialist, even one from another discipline. The integration into the nutrition support specialty of speech therapists, occupational and physical therapists, respiratory therapists, and others, who may not be otherwise considered by the primary team, may further improve the care of patients.
Each one of our four disciplines has contributed to the birth and growth of nutrition support. At this point, nutrition support can survive independent of each of us as a discipline, but still needs knowledgeable specialists to optimize patient care. REFERENCES 1. Rhoads JE: Memoir of a surgical nutritionist. JAMA 1994;272:
963-966. 2. Wilmore DW: Nutrition and metabolic support in the 21st century. JPEN J Parenter Enteral Nutr2000;24: 1-4. 3. Rombeau JL, Caldwell MD (eds): Introduction. In Clinical Nutrition: Parenteral Nutrition. Philadelphia, WB Saunders, 1986. 4. BlackburnGL, Bothe A, LaheyMA: Organization and administration of a nutrition support service. SurgClin North Am 1981;61:709-719. 5. SeltzerMH, Slocum BA, Cataldi-Betcher EL, et al: Nutrition support: Team approach. Am J IntravenTher 1981;8:13-46. 6. Smith EM: Total parenteral nutrition: A team concept. Nurs Times 1981;77:1464-1465. 7. Jensen TG, DudrickSJ: Implementation of a multidisciplinary nutritional assessment program. J Am DietAssoc 1981;79:258-266. 8. SkoutakisVA, DomingoRM, Miller WA, Dobbie RP: Team approach to total parenteral nutrition. AmJ Hosp Pharm 1975;32:693-697.
II Role of Controlled Gastrointestinal Transit in Nutrition and Tube Feeding Henry C. Lin, MD
Gregg W. Van Citters, PhD
CHAPTER OUTLINE Introduction Mouth and Esophagus Stomach Digestion Gastric Emptying Small Intestine Digestion The Ileal Brake The Jejunal Brake Importance of Nutrient-Regulated Intestinal Motility Colon The Ileocecal Junction The Colonic Brake Colonic Fermentation Bacterial Overgrowth Clinical Relevance of Transit Control to Enteral Feeding Conclusion
INTRODUCTION There are many excellent reviews':" and textbook chapters that describe the digestion and absorption of specific nutrients.v Because these topics have been well covered, we will not discuss in detail the enzymatic or transport processes ultimately responsible for nutrient uptake from the gastrointestinal eGI) tract. However, the role of GI motility in digestion and absorption is a neglected topic. In this chapter, we will focus on this area to provide information that is important to the clinician managing enteral feeding.
To understand and manage the problems encountered during enteral feeding, we must begin by reviewing the normal controls that operate to govern the transit of a meal through the GI tract. To begin, we will follow the course of a bolus of food from mouth to colon and present the physiology of the motility response of the GI tract to nutrients as it occurs in the context of tightly controlled transit of a meal. On occasion, we will make references to illustrative pathophysiologic states, highlighting the nutritional consequences when the control of transit is impaired or lost. In this chapter, we will not cover in detail the neural and hormonal pathways controlling motility, because information on these is readily available to the reader.r" Digestion and absorption are time-demanding events. If food traverses too rapidly through the GI tract, nutrients are lost in the toilet. The transit of a meal is therefore meticulously controlled by a nutrient-triggered feedback system that works to optimize nutrition by ensuring that there is adequate time for digestion and absorption. To achieve this goal, the GI tract consists of nutrient sensors distributed along the entire length of the small intestine that are recruited by their contact with nutrients to generate neuropeptidergic feedback signals that slow or speed transit. Because digestion requires both contact with the digestive enzyme and time for hydrolysis, rapid movement of a meal through the GI tract results in maldigestion. Absorption of nutrients similarly requires contact with the mucosal cell surface transport mechanisms; rapid transit of even a well-digested meal results in malabsorption." With the importance of adequate time for assimilation in mind, we begin with ingestion, mastication, and swallowing of a bolus.
MOUTH AND ESOPHAGUS Chewing stimulates salivation, including release of salivary enzymes. However, the degree of digestion in 11
12
2 • Role of Controlled Gastrointestinal Transit in Nutrition and Tube Feeding
the mouth attributable to these salivary enzymes is quite low because a bolus is rarely held in the mouth long enough for significant hydrolysis to occur before swallowing. Deglutition initiates GI transit of the bolus by triggering primary esophageal peristalsis that works to propel the movement of the meal from the pharynx to the stomach. No digestion or absorption occurs in the esophagus as the bolus moves aborally into the stomach over a span of time as short as 2 seconds.
STOMACH
Digestion Gastric digestion is critically important for two reasons. The first is to prepare chyme for efficient digestion and absorption in the small intestine and the second is to make available the end products of digestion required for the activation of the control of transit. Thus, in addition to providing improved substrates for enzymatic digestion in the small intestine, gastric digestion liberates sugars and oligosaccharides, oligopeptides and peptones, and fatty acids. Each of these components is important in nutrienttriggered inhibitory feedback that works to slow GI transit, allowing more time for digestion and absorption.
Physical Fragmentation, Gastric Sieving, and Peristalsis Digestion begins in the stomach. Gastric motility converts from the fasted to fed state in response to the same stimuli responsible for the cephalic and gastric phases of gastric secretion. When stimulated by cholinergic pathways and by peptides such as gastrin," the stomach contracts at its maximal frequency of three times per minute to generate a ring-like peristaltic wave that moves the content of the stomach in the antegrade direction toward the pyloric opening. Digestiblesolids break up into smaller fragments as food is caught between the strong, lumen-obliterating actions of the terminal antral contractions. I I This process pulverizes food into tiny particles that have the ideal large surface area-ta-mass ratio suitable for efficient hydrolysis by digestive enzymes in the small intestine. As the content of the stomach is squeezed by the moving ring-like peristaltic wave, gastric fluid and all the solids suspended in the fluid pick up aboral velocity to behave as a laminar flow. In that setting, only the smallest particles travel in the center of the flow and move at the highest velocity. Because the pylorus is positioned to receive the center of the flow, size selectivity takes place as the smallest particles are ejected through the pylorus whereas the larger chunks fall to the side for further fragmentation (trituration). This function, called gastric sieving, is a highly efficient property of the fed motility state that works to prevent solid particles larger than 0.1 mm from exiting the stomach's" and is responsible for the lag phase of the gastric emptying time course for digestible solids. Solids that are larger in size (e.g., a nasojejunal feeding tube) are only expelled from the stomach when motility reverts back to the fasted
state and cycles to the phase III of interdigestive motility (intestinal housekeeper wave). A feeding tube is then moved into the postpyloric small intestine during an intestinal housekeeper wave.
Chemical Hydrolysis Aside from physical fragmentation as a form of digestion, chemical hydrolysis also begins in the stomach. The gastric zymogens-pepsinogen I and II, progastricsin (pepsin C precursor), and prochymosin (in neonates)are secreted in response to initiation of feeding and activated by autocatalysis and structural rearrangement below pH 5.0,14 the typical range for gastric contents. The predominant peptic enzymes, pepsin 1, 3, and 5, operate mostly below pH less than 3.0.15 Gastric proteases are responsible for 10% to 20% of total protein digestion and are inactivated in the relatively high pH of the duodenum. This gastric protein digestion may be critically important for protein assimilation because intestinal absorption of protein in the setting of pancreatic insufficiency is significantly improved by incubation of the protein with stomach acid or pepsin." The contribution of gastric proteolysis is reduced by the use of antisecretory agents. Correspondingly, many patients treated with these agents are found to have a prolonged lag phase of solid emptying. An important outcome of this impairment of trituration is that patients may be mistakenly thought to have gastroparesis. Gastric proteolysis may also be important to fat digestion. In the setting of impaired biliary function, gastric proteolysis that liberates amphipathic peptides capable of stabilizing lipid emulsions functions to enhance gastric lipolysis." The digestion of carbohydrates that began in the mouth with saliva continues in the stomach. Salivary amylase survives pepsin hydrolysis and continues to work in the stomach as long as the gastric content is retained for at least 1 hour and the pH is greater than about 3.18,19 Salivary amylase activity can account for 55% to 60% of starch hydrolysis by the time the bolus enters the duodenum.Ps? Although only trace amounts of lingual lipase are secreted and contribute little if anything to lipid hydrolysis during a meal in the adult," the stomach is very important to fat digestion. Gastric lipase and acid are cosecreted in the fundus by vagal cholinergic stimulation in response to feeding. Gastric lipase is responsible for 10% to 30% of total triglyceride hydrolysis22,23 and is aided in this process by emulsification of lipids secondary to duodenogastric reflux of bile. 24 The retrograde entry of bile salts into the stomach is then not only normal but also quite important to optimal fat digestion. Gastric lipase is most active at pH values between 2 and 725 and contributes to further hydrolysis in the duodenume-" and jejunurn.P' Gastric lipase is equally efficient at hydrolysis of liquid and solid fat, whereas pancreatic lipase is more efficient at hydrolysis of fat in the liquid than solid state." Gastric lipolysis enhances emulsification of the meal," which is important for providing readily hydrolyzable substrate for pancreatic lipase. 29-31 Most importantly, the process of fat digestion begins in the stomach so that gastric emptying can be tightly
SECTION II • Physiology of the Alimentary Tract
controlled. Because the inhibitory feedback that slows gastric emptying is triggered by the end products of fat digestion such as fatty acids, the availability of some end products of lipid digestion early in the course of gastric emptying allows for the control of gastric emptying to be activated in time to govern the movement of most of the meal.
Gastric Emptying Gastric emptying of solids can be separated into two phases: lag, during which large food particles are triturated into smaller particles suitable for digestion, and linear, during which the gastric content exits via the pylorus into the lumen of the proximal small intestine. Gastric emptying of liquids begins rapidly and slows to approximate an exponential decay." For liquids, the rate of gastric emptying depends on the volume of the gastric content (firstorder kinetics). For solids, the rate of gastric emptying is rate-limited by the process of trituration so that the amount emptied per unit time remains fixed and independent of the volume of the gastric content (zero-order kinetics). Because the assimilation of solids takes more time, by limiting the amount that is delivered into the small intestine, the GI tract is able to optimize digestion and absorption by ensuring that the capacity of the proximal small intestine to assimilate food is not overwhelmed.
Nutrient-Regulated Gastric Emptying Gastric emptying is controlled by nutrients hydrolyzed from the mea133-35 by titratable acidity and pH35,36 and by osmolarity." Incomplete digestion and absorption of a meal increases the osmolarity within the lumen." Gastric emptying is slowed by increased osmolarity because of increased outflow resistance owing to stimulated duodenal nonpropagated motility." This is an example of an inhibitory feedback on gastric emptying that does not involve a change in the motility of the stomach itself. In the setting of maldigestion, undigested and unabsorbed nutrient substrates escape complete assimilation within the length of the small intestine to present to the bacterial flora of the large intestine. An important consequence of such abnormal presentation is the conversion of the maldigested food to osmotically active substances via bacterial fermentation, further increasing the osmotic load and promoting secretory diarrhea. Osmotic inhibition of gastric emptying thus reduces the osmotic load presented to the small intestine and extend the available time for digestion and absorption of a meal. Inhibition of gastric emptying is also nutrient-specific. Whereas it takes 1000 mM glucose to generate maximal inhibition of gastric emptying." it takes only 27 mM oleate to do the same." The greater potency of fat can be explained on the basis of the slower rate of assimilation of fat compared with that of glucose and the lengthdependent mechanism for determining the slowing of gastric emptying. For the same amount of nutrient, fat would linger in the intestinal lumen longer than glucose to access a longer length of the small intestine. As a result,
13
more nutrient sensors would be stimulated and recruited to generate greater inhibitory feedback after fat than glucose. Despite the importance of nutrient-specific potency and the great variability of fat content in the formulas that are used in clinical practice, the nutrient-specific inhibition of gastric emptying of one formula versus another is rarely taken into account in enteral feeding.
Load-Dependent Inhibition Gastric emptying decreases proportionally to increasing load of nutrients. 39,4o The nutrient load of a meal is linked to other digestive responses of the GI tract. For example, pancreatic secretion is proportional to the nutrient load because it depends on the saturation of the proximal mucosal absorptive surface, the spillover of nutrients to more distal parts of the intestinal mucosa, and the exposure of the mucosa of the distal small intestine to the still unabsorbed nutrient load. 41,42 Load-dependent inhibition of gastric emptying extends the available time for digestion and absorption. Load-dependent inhibition of gastric emptying is possible through a length-dependent inhibitory feedback mechanism. After 500 mL of glucose solution was delivered into the stomach (0 M saline control; glucose concentrations of 0.25 M, 0.5 M, or 1.0 M), the meal with the largest glucose load emptied from the stomach at the slowest rate and the meal with the smallest load emptied at the fastest rate." This load-dependent slowing of gastric emptying is generated as follows: early in the meal, there is no intestinogastric inhibitory feedback from the small intestine because the small bowel is devoid of nutrients. During that brief period without feedback, the rate of gastric emptying of a liquid meal follows firstorder kinetics whereby the rate is greater with a larger volume of liquid in the stomach. After a large meal, more nutrients squirt out of the stomach with the initial gastric output, whereas after a smaller meal, fewer nutrients are released per unit time. This load-dependent initial surge is critical in setting the feedback response because the intensity of the inhibitory feedback depends on the length of the small intestine exposed to nutrients.V" Lengthdependent inhibitory feedback is generated by the recruitment of stimulated nutrient sensors along the length of the small intestine so that after a large meal, nutrients spread along a longer length of the small intestine to trigger a great number of nutrient sensors. The extent of the spread of a nutrient-eontaining meal down the length of the small intestine depends on how quickly the exposed intestine can absorb the nutrients as well as how quickly the meal moves down the intestine. As absorptive capacity is exceeded the meal will travel further down the intestine to recruit more absorptive surface and hence trigger additional inhibitory feedback. When the ileum is exposed to glucose, inhibition of gastric emptying of a solid meal is threefold greater than when the jejunum is exposed to glucose." Thus, larger and more nutrient-dense liquid meals are likely to initially travel further down the intestine and recruit more nutrient sensors. This will result in more potent inhibitory feedback as the nutrient density of the
14
2 • Role of Controlled Gastrointestinal Transit in Nutrition and Tube Feeding
meal increases. Gastric emptying is therefore slower after a can of enteral formula containing a 1.5 kcallmL nutrient load than a formula containing a 1.0 kcallmL nutrient load. Feeding large volumes of a high-calorie formula could lead to physiologic accumulation of the formula in the stomach so that the delivery of nutrients to the small intestine does not overwhelm the assimilation capacity of the gut.
Delayed Gastric Emptying This gastric residual volume (GRV) is the amount of an enteral feeding product that remains in the stomach after some length of time. When this volume reaches an arbitrarily determined threshold," the patient is often but erroneously considered to have impaired gastric emptying. Feeding is typically halted in this situation because excessive GRV has been reportedly associated with increased risk of pulmonary aspiration of formula in some sltuations." GRV is a balance between input to the stomach from endogenous secretions and ingestion and output from the stomach as controlled by nutrient-triggered inhibitory feedback based on the nutrient load of the stomach output. On the input side of the equation, saliva plus gastric secretions accounts for approximately 188 mUhr in a normally fed adult human," and enteral formula is delivered at rates ranging from 25 to 125mt/hr." On the output side of the equation, gastric emptying rates commonly range from less than 20% to more than 50% of the stomach contents per hour when a patient is fed with a typical iso-osmolar formula 34,36 and depend on the total load and nutrient composition (fat, carbohydrate, and protein) of the stomach contents. When input into the stomach equals output from the stomach, equilibrium is reached and GRV plateaus. However, if input exceeds output, then GRV will theoretically increase unbounded. Although an unlimited increase in GRV should be considered pathologic impairment of gastric emptying (assuming the enteral delivery rate is reasonable), reaching an equilibrium state should be considered normal and should not require intervention unless the total GRV is poorly tolerated and generates symptoms (pain from distension, nausea, and vomiting). When we subjected this equilibrium model to mathematical analysis," we found that even with a fairly high rate of formula delivery of 100 mUmin, the GRV exceed 2000 mL only when the rate of gastric emptying dropped below 10%/hr. The capacity of a normal adult stomach is 4000 to 6000 mL,48 so most rates of formula delivery and gastric emptying should not result in GRV greater than that of the normal postprandial stomach, which may exceed 3000 mL.6 The most important reason for a reduced rate of gastric emptying is nutrient-triggered inhibitory feedback. The magnitude of this physiologic slowing of gastric emptying depends on the nutrient load of the delivered formula. Although increased delivery of formula may accelerate intestinal transit via a volumedependent mechanism,49-52 the greater formula delivery concurrently increases load-dependent nutrient-triggered inhibitory feedback. The net effect on transit then depends
on the balance between these two forces. Because the nutrient load in even the most calorically dense formulas does not slow gastric emptying below 20%/hr, GRV should remain within the normal postprandial range. Therefore, an absolute value of GRV is not a sign of a pathologic impairment or an indication for stopping enteral feeding. Rather, it is more important to determine the temporal trend in GRV (increasing vs. plateau) after at least 6 hours to decide whether to discontinue feeding. Withholding enteral feedings for an arbitrarily determined low threshold of GRV is not a physiologically sound practice and may unnecessarily place the patient at increased risk of malnutrition.
Accelerated Gastric Emptying Patients complaining of early satiety and postprandial pain, distention, nausea, and vomiting are often given the clinical label "gastroparesis" with an expectation that these symptoms are always the result of abnormally slow gastric emptying. In the enterally fed patient the assumption is that these symptoms are related to high GRV. However, these symptoms may also be triggered from the small intestine as demonstrated by the onset of nausea when triglycerides are infused into the duodenum of test subjects.P A common setting in which similar symptoms are generated from the small intestine is after ulcer surgery. After gastrectomy patients, postmeal bloating, pain, and nausea are often grouped under the term dumping syndrome. In this case, the problem is related to accelerated rather than delayed gastric ernptying.f This accelerated emptying increases delivery of nutrients to the small intestine, triggering exaggerated nutrient-triggered inhibitory feedback that generates the Gl symptoms of dumping syndrome. The same scenario occurs in the context of a rapidly emptying liquid meal. Although gastric emptying of a solid meal is normally held back by the requirement of trituration.P" liquid fats (oils) need not be triturated and therefore empty more rapidly from the stomach." Fat intolerance is a common complaint of many patients. These patients may complain of bloating, pain, and nausea after a meal containing liquid fat (e.g., creamy soup) but have no symptoms after a meal containing solid fat (e.g., well-marbled steak). Even though the symptoms suggest gastroparesis, fat intolerance is associated with abnormally accelerated gastric emptying.56 Thus, when an enteral formula is administered into the stomach, symptoms may be generated from either the stomach or the small intestine as a result of either abnormally delayed or abnormally accelerated gastric emptying, respectively. The importance of the small bowel as the source of symptoms of gastroparesis symptoms is reinforced by the bloating, pain, and nausea that may be encountered during nasojejunal feeding. Regardless of the underlying physiologic dysfunction, patients receiving enteral feeding who complain of symptoms normally associated with gastroparesis should be suspected of having exaggerated feedback. Lowering the fat content and reducing the formula delivery rate may improve tolerance in these patients.
SECTION II • Physiology of the Alimentary Tract
SMALL INTESTINE
Digestion The end products of digestion that are liberated from a meal control the remainder of the processes of digestion and absorption in part by regulating transit of the meal through the small bowel. As the partially digested gastric content empties into the duodenum, bile and pancreatic exocrine secretions are released to mix with the chyme. Gut peptides including cholecystokinin (CCK) and secretin are secreted in response to the end products of gastric fat digestion, stimulating both biliary and pancreatic secretion as well as gall bladder contractions." CCK release is attenuated in the absence of gastric digestion'" because the end products of digestion are not available but are needed to stimulate release of the peptide. Acid in the duodenal lumen also triggers bicarbonate release because the threshold for stimulation of pancreatic exocrine secretion is less than pH 4.5.59
Protein Protein is digested in the intestine by a set of pancreatic endopeptidases (trypsin, chymotrypsin, and elastase) and exopeptidases (carboxypeptidase [ and II). Enterokinase activates the digestion of trypsinogen to trypsin; trypsin in turn activates the other protease zymogens to produce the active proteases." Even in the absence of pancreatic protease secretion, up to 37% of ingested protein still can be digested by intestinal acid proteases.F'" The end products of luminal protein digestion are primarily oligopeptides of two to eight amino acids, which are further hydrolyzed and assimilated in the brush border." Similar to load-dependent slowing of gastric emptying, intestinal transit time depends on the total protein load contained in the meal. Asmeal protein content increased, intestinal transit time decreased and protein uptake increased without significantly altered efficiency of uptake.F The magnitude of the inhibitory feedback depends on the contact of the protein with the small intestine. Because a predigested formula is rapidly assimilated, less content would be available in the intestinal lumen to activate inhibitory feedback. Compared with a prehydrolyzed formula, a formula containing intact protein more potently triggered greater inhibitory feedback response.f Partially digested protein in the form of oligopeptides may be more completely assimilated by stimulating pancreatic enzyme and bicarbonate secretion to further enhance protein digestion."
Starch Salivary amylase activity resumes in the relatively neutral environment of the proximal small intestine.'? In addition, a-amylase secreted by the pancreas begins digestion of alA starch bonds'" to produce oligosaccharides and a-limit dextrins. The degree of starch hydrolysis depends on the source of starch64-66 and [eaves an average of 10% of ingested starch undigested through the
15
small intestine." Undigested carbohydrate in the ileum not only slows gastric emptying but can also stimulate further release of pancreatic enzymes, particularly arnylase.f
Fatty Acids Fatty acids, the end product of triglyceride digestion, are critically important in the control of postprandial motility. Maximal lipolysis requires emulsification of the lipid components of the meal. Although meal lipids are substantially emulsified by the mechanical and enzymatic actions in the stomach,28,68 the formation of mixed micelles requires the phospholipids and bile salts in bile. Mixed micelles are required for optimal lipid absorption." These mixed micelles containing acylglycerols, cholesterols, phospholipids, and their hydrolytic products as well as bile salts facilitate further digestion of dietary fat by promoting hydrolytic interaction with pancreatic Iipase/colipase, bile salt-activated lipase, and phospholipase A2.31 In the absence of colipase, the high concentrations of bile salts normally found in the duodenum are sufficient to disrupt lipolysis." Although colipase anchors lipase to the lipid interface, minute quantities are sufficient for this function."
Bile Acids and Bile Salts Completion of fat absorption within the small bowel is important because fatty acids stimulate secretory diarrhea." Depending on the load, fat absorption normally occurs throughout the small Intestine." The amount of bile secreted in response to intestinal fat is mediated by bile salt-induced inhibitory feedback on gallbladder emptying." Thus, the presence of unemulsified bile salts in the intestinal lumen slows the release of bile. Because bile salts (similar to fatty acids) also stimulate a secretory diarrhea.F" the existence of bile salt-induced inhibitory feedback on gallbladder emptying ameliorates bile saltinduced diarrhea. Bile salts are actively reabsorbed by the terminal ileum. Recovery of bile salts is necessary because the amount of bile salts moving through the small intestine each day is four times the maximal synthetic capability of the liver." Although resection of less than 100 ern of ileum may lead to loss of bile salts into the colon, causing watery diarrhea that can be corrected by bile acid sequestration" resection of more than 100 em of the distal small intestine leads to loss of bile acids in excess of the hepatic synthetic rate," causing steatorrhea. With severe depletion of the bile acid pool, the micellar phase of fat digestion and absorption is impaired, reducing fat digestion in the proximal gut and resulting in steatorrhea. 72,78,79 In substitution, peptic protein digests are able to somewhat replace the role of bile salts in lipid emulsification." Bile acids precipitate in an acidic environment" and become unavailable for emulsification and stimulation of lipolysis. Enteral feeding is difficult under these circumstances because the feeding tube may occlude from protein and bile salt precipitates. One strategy that may prevent feeding tube occlusion in an acidic environment is to include 20 mM taurocholate in the formula."
16
2 • Role of Controlled Gastrointestinal Transit in Nutrition and Tube Feeding
The Ileal Brake As lipolysis progresses, the end products of fat digestion become available to serve as triggers to slow intestinal transit by activating proximal and distal motility/transit control mechanisms. The distal control mechanism responsible for regulating intestinal transit was first described as the "ileal brake." The concept of the ileal brake arose from human studies by Spiller and associates 82 and Read and colleagues'" in 1984. These investigators separately but concurrently described the slowing of intestinal transit by fat emulsions perfused into the distal small intestine. Read and colleagues'" showed that the orocecal transit time of an indigestible carbohydrate was slowed when Intralipid triglyceride emulsion was administered into the distal small intestine 205 em from the teeth compared with a saline perfusion. Both gastric emptying and intestinal transit of a solid meal were still more delayed compared with the jejunal carbohydrate bolus. Spiller and associates's demonstrated similar slowing of intestinal transit when partially hydrolyzed Intralipid containing ",,60 mM free fatty acids was perfused into the ileum 170 em from the teeth. Jejunal motility was slowed regardless of the nature of the jejunal content (saline vs. nutrient). A putative duodenal brake was described in the early 1970s. 84,85 This neurohormonally mediated, nutrienttriggered inhibitory feedback in response to duodenal perfusion with acid, glucose, or fat slowed gastric emptying. However, the duodenum was taken out of continuity with the stomach but remained in continuity with the jejunum, suggesting that the observed effects may have been caused by activation of more distal braking mechanisms.
The Jejunal Brake Clinical observations in the 1970s also suggested that the ileal brake was not the only control mechanism for intestinal transit. Woolf and co-workers'" reported in patients with short bowel syndrome who had resection of the ileum that the total calories excreted in the stool remained constant even after the fat intake was increased threefold. In these patients lacking an ileal brake, such adjustment for the higher fat load would only be possible if a control mechanism located outside of the distal small intestine were available to slow transit so that there was more time to process the greater workload. Indeed, there is indeed another transit control mechanism located in the proximal small intestine that is known as the jejunal brake." This proximally located control mechanism responds to the presence of end products of fat digestion (i.e., fatty acids) in the jejunum. The existence of transit control mechanisms in both the proximal and distal small intestine allows for graded inhibitory feedback on intestinal transit. As with the control of gastric emptying, after a larger meal, nutrients spill farther down the small intestine to activate both proximal and distal braking mechanisms. This extensive spread of nutrients allows for the activation of the jejunal
brake and ileal brake in the setting of a large nutrient load to provide more time for digestion and absorption of the meal and therefore to minimize potential nutrient loss. When the dose responses of the jejunal brake and the ileal brake to fatty acid were compared, the ileal brake was observed to be more potent than the jejunal brake.f This difference in potency is useful for a proper response to the work required for assimilation. If nutrients were to escape processing by the proximal small intestine to enter the distal small bowel, intestinal transit should be more potently slowed to avoid the loss of nutrients into the large intestine. Although the jejunal brake is less potent, it may be more important than the ileal brake because this proximal gut control is able to respond rapidly to the meal as it empties from the stomach. The jejunal brake may be the only available control mechanism for regulated intestinal transit in the setting of extensive ileal resection.
Importance of Nutrient-Regulated Intestinal Motility Many standard antidiarrheal agents act by slowing intestinal transit, which may be accomplished by changing the pattern of intestinal motility from propagative to nonpropagative. As a result of an increase in the contact time between the luminal contents and the absorptive rnucosa/" the incidence of diarrhea is reduced." However, nutrients may be more effective than these traditional antidiarrheal agents. By exploiting regionspecific differences in the slowing of intestinal transit, our knowledge of nutrient-regulated intestinal motility presents a unique opportunity to manipulate the interaction of food and the gut to optimize digestion and absorption. The roles of these controls can be discussed in terms of the following four examples.
Example J: Distal versus Proximal Gut Resection The first example is taken from surgical literature. In dogs with the distal 50% of the small intestine taken out of continuity as a Thiry-Vella fistula, intestinal transit was accelerated and fecal fat recovery increased 80% to 90% of the fat intake compared with values of 8% to 10% in dogs without a fistula." In contrast, removing 50% or even 70% of the proximal small intestine was far less harmful, with only 15% to 24% of the fat intake being recovered in the stool." Similarly, Reynell and Spray'" observed more rapid intestinal transit in rats with distal compared with proximal gut resection. Because fat absorption is known to be less efficient in the distal small intestine and transit was faster and steatorrhea was far worse after the removal of the distal segment, these findings could not be explained by a difference in the kinetics of fat absorption. Instead, these observations can all be explained by the greater potency of the ileal brake. With a loss of the ileal brake, transit becomes so uncontrolled that 90% of the ingested fat ends up in the stool.
SECTION II • Physiology of the Alimentary Tract
Example Z: Soy Protein The second example of region-specific control of transit and absorption is taken from a comparison of the effects of delivery of an intact soy protein formula into the small intestine versus delivery of a hydrolyzed form of the same protein.P We found that when the load of protein was increased from 24 to 48 g, intestinal transit was slowed in a load-dependent fashion by both intact and hydrolyzed soy protein, soy protein inhibited intestinal transit more potently in the intact than the hydrolyzed form, the efficiency of protein absorption was maintained at a high and nearly constant level of 82.6% to 87.4% for intact soy protein compared with 89.0% to 92.3% for hydrolyzed soy protein, and absorption of nutrients increased when intestinal transit was slowed. Specifically, when the protein load was doubled, intestinal transit slowed significantly for intact but not hydrolyzed protein. Because the mean amount of protein recovered from the midintestinal fistulous output increased from 2.3 to 4.7 g for intact soy protein but only from 1.2 to 1.8 g for hydrolyzed soy protein, the fourfold greater protein load delivered into the distal half of the small intestine was responsible for triggering the greater slowing of intestinal transit in response to intact protein. As intact protein spilled into the distal small intestine, the ileal brake was triggered. Intestinal transit was slowed, and digestion and absorption were more complete because more time was available for assimilation.
Example 3: Fiber The third example of region-specific control of transit and absorption is taken from the effect of fiber-supplemented formulas in displacing nutrients to the distal small intestine. Diarrhea is a common complication of enteral feeding that affects up to 68% of patients receiving this form of nutritional support.P-" Based on the idea that increased flow through the intestinal lumen accelerates transit of a meal, a frequently recommended treatment of tube feeding-related diarrhea is to reduce the rate of formula delivery." Although this does indeed ameliorate the accelerating effect of a high flow rate, it also reduces the amount of nutrients delivered. Because intestinal transit is slowed by nutrient-triggered inhibitory feedback, decreasing the delivery rate may also reduce the slowing effect of nutrients. Alternatively, high-fiber formulas are now widely used to prevent the occurrence of tube feeding-related diarrhea because the incidence of this complication is reduced and bowel function is improved in patients given a high-fiber formula compared with those given a low-fiber formula. 96,97 Because fiber thickens the unstirred water layer at the surface of the absorptive mucosa and decreases the rate of nutrient absorption/" the addition of fiber to a formula should displace unabsorbed nutrients more distally along the gut. Indeed, soluble fiber prolongs colonic transit, suggesting a role for nutrient-triggered inhibitory feedback.'" We hypothesized that a high-fiber formula achieves its beneficial effect on tube feeding-related diarrhea by shifting the balance between the opposing effects of nutrient
17
flow and load in favor of nutrient-triggered inhibition from the distal small intestine. To test this hypothesis, we compared intestinal transit while two different formulas (low vs. high fiber) were perfused into the small intestine at 50 or 100 mUhr. In addition, we also compared intestinal transit when the formulas were excluded from the distal half of the small intestine to test the idea that the inhibitory effect of high-fiber formula depended on the spread of nutrients into the distal intestine. We found that the effect of increasing the rate of formula delivery on intestinal transit was different between the formulas. Although intestinal transit of the low-fiber formula was accelerated by a higher flow rate, this flowdependent accelerating effect was absent with the highfiber formula. Addition of fiber to an enteral formula delays the absorption of nutrients from the small intestinal lumen by increasing the thickness of the unstirred water layer. This effect may then increase the inhibitory feedback triggered by nutrients because the length of the small intestine that ultimately comes into contact with nutrients is increased. Fiber may also achieve its slowing effect by increasing the amount (load) of nutrients that spreads into the distal small intestine. The idea that the potent inhibitory effect of fiber depended on this spread of nutrients to the distal gut was strongly supported by the intestinal transit results when the formulas were diverted completely and excluded from the distal half of the small intestine. We found that there was no longer a difference in intestinal transit between the formulas. This change was primarily the result of a 400% difference in the speed of transit for the undiverted high-fiber formula compared with mid-gut diversion of the same formula. Diverting the low-fiber formula had no significant effect on intestinal transit. Therefore, decreasing the rate of delivery of a low-fiber enteral formula may slow intestinal transit but is unlikely to affect the transit of a high-fiber formula.
Example 4: Oleic Acid The fourth example of region-specific control of transit and absorption is taken from our clinical observations using a premeal containing a fatty acid (oleic acid) to slow intestinal transit before a meal.'?" We administered an emulsion consisting of a liquid enteral formula with 0, 1.6, and 3.2 mL of oleic acid to 45 patients with chronic diarrhea and compared their intestinal transit times to those of 7 healthy control subjects. The oleic acid premeal was swallowed 30 minutes before the test meal to trigger inhibitory feedback on GI transit. The clinical condition of patients tested with this novel, nutrient-based treatment included acquired immunodeficiency syndrome (AIDS), diabetes, idiopathic diarrhea, postgastrectomy dumping syndrome, and short bowel syndrome. The mean basal transit time (0 mL of oleic acid) for healthy subjects was 102 minutes compared with 29 minutes for the patient group. We observed dose-dependent slowing of intestinal transit by oleic acid: transit time increased to 57 minutes at 1.6 mL of oleic acid and 83 minutes at 3.2 mL of oleic acid. In most patients transit time was more than doubled with at least one of the doses.
18
2 • Role of Controlled Gastrointestinal Transit in Nutrition and Tube Feeding
Both frequency and volume of stool also decreased with continued oleic acid treatment.
COLON The Ileocecal Junction The ileocecal junction may play a significant role in orocecal transit time as evidenced by accelerated transit after resection 101,102 and delayed transit after ileocecal valve reconstruction.F' Reduced transit time after ileocecal resection may depend on altered nutrient-triggered inhibitory feedback'?'; i.e., the ileocecal junction is a traffic controller that does not rely on nutrient sensing per se. Specifically, the accelerating effect of ileocecal resection is even greater when a significant length of the ileum is lost along with the ileocecal junction. Because the density of nutrient sensors is greatest in the terminal ileum, ileocecal resection may result in substantial loss of cells capable of responding to nutrient triggers of inhibitory feedback.
The Colonic Brake Nutrient-triggered inhibitory feedback has recently been described in the colon l04.105 as the colonic brake. The presence of undigested or unabsorbed nutrients in the colonic lumen is associated with delayed gastric emptying and slowed intestinal transit. 104. 106 The intestinally derived hormones pyylO5-107 and to a lesser extent GLP-I I05 participate in this feedback control. The colonic brake is inactive when the colon is not in continuity with the small intestine (e.g., i1eostrom patients). In that setting, nutrient triggers are not elicited and consequently no nutrient-triggered inhibitory feedback to the stomach or small intestine is possible. This may explain the difficulty in maintaining nutritional homeostasis in patients lacking both ileum and colon.
Colonic Fermentation The presence of undigested nutrients in the colonic lumen also results in bacterial fermentation of these substrates. Up to 20% of daily starch intake may remain undigested by the time it enters the colon. 108 Enteric bacteria avidly ferment undigested starches and dietary fibers, producing hydrogen, carbon dioxide, methane and other gases as well as short-ehain fatty acids (SCFAs), mainly propionate and butyrate. 109-1 I I On average, 80% to 90% of soluble fiber is utilized by the colonic bacteria, with some being virtually 100% degraded to produce gases and SCFAs.llO.lll In patients consuming low-fiber diets, energy salvage from SCFAs constitutes 2% to 7% of the daily caloric intake.'!' This figure may be considerably higher for patients with maldigestion and malabsorption in whom a larger volume of fermentable substrates is presented to the colonic microflora. Unabsorbed carbohydrate in the colonic lumen triggers inhibitory feedback on upper digestive tract secretion,
including gastric, pancreatic, and biliary secretlons.l'
Bacterial Overgrowth Loss of the ileocecal junction or gross disruption of transit in the setting of active disease or intestinal resection may permit colonic bacteria to populate the small intestine, which is normally nearly devoid of bacteria.'?' This small intestinal bacterial overgrowth (S180) has a number of detrimental effects on GI motility and nutrient digestion and absorption. Phase III of the migrating motor complex (MMC) is the strong propulsive interdigestive "housekeeping" wave that empties the stomach and propels the intestinal content aborally, normally lasting about 5 minutes," Although inhibition of the MMC is associated with subsequent S180,119 it is not clear whether motility abnormalities are permissive for S180 or whether S180 results in altered motility. The frequency and duration of the intestinal housekeeper wave are reducedl20.l21 or absent'P in patients with 5180. In these patients, antral motility is severely reduced whereas duodenojejunal motility is increased.F' Complete eradication of the bacterial overgrowth restores normal responsiveness to nutrient triggers of inhibitory feedback. S180 is associated with weight loss and diminished nutritional status.P' probably caused by monosaccharide, ll9 protein.F' and fat l26 malabsorption and vitamin deficiencies'i" possibly coupled with anorexia or nausea.!" Bile acid metabolism is disturbed in 5180, resulting in increased amounts of total and unconjugated bile acids'!" and probably exacerbating fat malabsorption. SCFAs and byproducts of bacterial substrate
SECTION II • Physiology of the Alimentary Tract
degradation may be poorly absorbed and accumulate in the ileurn.F" Acidic byproducts reduce the pH in the lumen'P' and increase the osmotic load. Gases produced during the fermentation process further contribute to distension of the gut wall, which accelerates intestinal transit to propel the intestinal content distally.P The net effect of these nutrient-bacteria interactions is to speed transit, creating diarrhea leading to maldigestion and malabsorption.
CLINICAL RELEVANCE OF TRANSIT CONTROL TO ENTERAL FEEDING The clinical goal of enteral feeding is to meet the caloric and nutrient requirements of the patient without precipitating symptoms. Feeding decisions include route of formula delivery (gastric vs. jejunal), type of formula (nutrient/caloric load), and rate and pattern of formula delivery (bolus vs. continuous). The gastric route of delivery is typically chosen because of the convenience of tube placement and maintenance. Jejunal tube placement is often time-consuming and requires radiologically guided placement and verification. Certain conditions may be associated with a greater risk of intolerance with the use of gastric feeding, e.g., severely impaired gastric emptying or markedly out-of-control blood glucose concentrations in diabetes. In these settings, the jejunal route is most appropriate because it bypasses poor or erratic gastric emptying as a barrier. The decision to move from gastric to jejunal feeding is then most often predicated on the confirmation that abnormal gastric emptying is a barrier to adequate feeding. Additionally, many clinicians hope to lower the risk of aspiration of the gastric content by placing the feeding tube beyond the pylorus. This is an imperfect and controversial solution because some retrograde movement of the duodenal content back into the stomach is normal, and aspiration may occur just as easily with oropharyngeal or gastric secretions. Because daily gastric secretion may reach 2 L, the delivery of formula directly into the jejunum would not prevent the occurrence of aspiration pneumonia in patients whose airway is not protected. The nutritional status and metabolic requirements of the patient typically dictate the formula chosen for enteral feeding. The daily caloric infusion is a product of nutrient load and delivery rate over 24 hours. Initially, the rate of formula delivery is arbitrarily selected. The current method is to begin with a slow delivery rate (:==25 mUhr) and titrate the rate upward over a period of several days until the daily caloric goal is met. However, there is no physiologic basis for this common practice. There is no evidence to support the assumption that gastric emptying can be "warmed up" over such a time period so that the final formula delivery rate would be better tolerated. Because the question faced by the clinician is whether it is possible to feed the patient to the target caloric goal without inducing symptoms, a protocol of slowly titrating up the rate may only result in several days being wasted before feeding failure is observed. Because a slow titrating protocol may not result in a different
19
outcome from that obtained by immediately trying the final target rate, the slow titration method should be abandoned. By delivering feeding right away at the target rate, the clinician and the patient benefit from knowing more rapidly that a barrier exists to feeding and that the approach must be changed. For an individual patient, delayed gastric emptying may be a combination of pathologic impairment (that may be nonexistent in many patients) and physiologic, nutrient load-dependent inhibitory feedback (that exists in every patient). The rate of gastric emptying in response to a given nutrient load as well as the presence of physiologic impairment is not known a priori. We propose that the target delivery rate should be used initially, with normal checking of gastric residual volume to detect impaired gastric emptying. With this approach, the clinician will learn sooner whether a change in approach is needed. Bolus feeding should not be used when the route of delivery is directly into the jejunum. When the protective mechanism of controlled gastric emptying is bypassed, the risk of this practice is that the digestive and absorptive capacity of the small intestine to spread abnormally undigested nutrients down the length of the intestine may be overwhelmed and exaggerated inhibitory feedback and symptoms may result. The intolerance symptoms associated with bolus jejunal feeding are similar to those of the dumping syndromepain, distention, nausea, and vomiting. Diarrhea may also be a complicating symptom. Continuous feeding should be used whenever a feeding tube is placed beyond the pylorus. The upper limit for a jejunal feeding rate can be calculated on the basis of the amount of fat that is normally allowed to enter the small intestine under controlled gastric emptying. In humans, the delivery of liquid oil into the small intestine is 6.6 g/hr. 129 Because the entry of fat in excess of this threshold produces symptoms, the maximal jejunal feeding rate that mimics the control entry of fat can be estimated from the fat content of a given formula. For example, a formula that contains 100 g of fat/L (0.1 g/mL) cannot be delivered at 100 mUhr because the amount of fat entering the small intestine (10 g/hr) exceeds the physiologic ceiling. Instead, the maximal rate would be 66 mUhr with this formula. Because the small intestine has a large capacity, the rate-limiting factor is usually the nutrient load rather than the volume. Jejunal feeding rates above such a physiologic ceiling pose a risk of intolerance due to exaggerated intestinal feedback. Whenever possible, the feeding tube should be kept in the stomach so that physiologic control of gastric emptying is available to protect the patient against abnormal feedback. By relying on the stomach to govern the entry of food, it does not matter whether the formula is delivered all at once or over the space of several hours because the inhibitory feedback system ensures that the formula is delivered to the intestine at a rate that is physiologic. Thus, when a feeding tube is in the stomach that empties normally, the feeding rate is largely based on the need to meet the caloric goals and the decision to use bolus versus continuous feeding is an issue of practicality.
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2 • Role of Controlled Gastrointestinal Transit in Nutrition and Tube Feeding
Even with the large volume capacity of the jejunum, a high rate of jejunal perfusion with enteral formula may initiate diarrhea. Strategies available to avoid this problem include using a high-fiber formula, lowering the volume/ delivery rate, or increasing the formula concentration (to increase the slowing effect of nutrient load). As discussed in detail in preceding sections, fiber spreads nutrient triggers distally to activate the potent ileal brake response; volume reduction allows avoidance of distention-triggered diarrhea and increasing the nutrient load triggers greater inhibitory feedback. True gastroparesis typically leads to the use of a prokinetic agent. The commercially available prokinetic agent most commonly used today is erythromycin. When this motilin-mimlcking drug is given at the dose of 50 mg, phase III of MMe, the intestinal housekeeper wave, is stimulated to push out the stomach content. Erythromycin does not, however, normalize gastric emptying but rather expels the gastric content at the expense of physiologic gastric sieving. Thus, similar to the situation in a patient with an antrectomy, food nearing the original swallowed size (vs. particles <0.1 mm in diameter) enters the small intestine. Such large chunks of food cannot be properly digested and absorbed within the length of the small intestine. As a result, the expelled food is presented to a longer length of the small intestine to generate exaggerated feedback. Thus, the use of erythromycin in gastroparesis may paradoxically result in worsening of symptoms. Because the symptoms of distention, nausea, vomiting, and pain are similar regardless of whether gastric emptying is too fast (overwhelming feedback) or too slow (true gastroparesis), a gastric emptying study should be performed when the cause of the symptoms is in doubt. Empirical use of prokinetic agents should be done cautiously because the inadvertent addition of a prokinetic agent to a patient with rapid gastric emptying may only worsen symptoms.
CONCLUSION The speed of transit of a meal through the GI tract determines the amount of time available for digestion and absorption. The nutrient content of the meal in turn regulates GI transit. In pathologic settings such as gastrectomy or intestinal resection, this carefully controlled meal movement is disrupted and results in bloating, pain, nausea, diarrhea, steatorrhea, and ultimately malnutrition. The clinician may see similar symptoms in patients receiving tube feeding. To meet the patient's nutritional goals and avoid symptoms, clinicians must apply their understanding of the physiology of nutrient-triggered intestinal feedback in the selection and administration of tube feeding. REFERENCES 1. Thomson AB. Keelan M, Thiesen A, et al: Small bowel review: Normal physiology part 1. Dig Dis Sci 2001;46:2567-2587. 2. Phan CT, Tso P: Intestinal lipid absorption and transport. Front Biosci 2001;6:0299-0319.
3. Wright EM, Loo DO: Coupling between Na', sugar, and water transport across the intestine. Ann NY Acad Sci 2000;915: 54-66. 4. Reuss L: One-hundred years of inquiry: The mechanism of glucose absorption in the intestine. Ann Rev Physiol 2000;62: 939-946. 5. Guyton AC, Hall JE: Textbook of Medical Physiology, 10th ed. Philadelphia, WB Saunders, 2000. 6. Ganong WF: Review of Medical Physiology, 20th ed. Stamford, CT: Appleton & Lange, 2001. 7. Bueno L, Fioramonti 1: Neurohormonal control of intestinal transit. Reproduction, nutrition, development. Reprod Nutr Dev 1994;34: 513-525. 8. Samsom M, Smout AJ: Abnormal gastric and small intestinal motor function in diabetes mellitus. Dig Dis 1997;15:263-274. 9. Olsson C, Holmgren S: The control of gut motility. Comp Biochem Physiol A Mol Integr Physiol 128:481-503. 10. Holgate AM, Read NW: Can a rapid small bowel transit limit absorption? Gut 1982;23:A912. II. Meyer JH: The physiology of gastric motility and gastric emptying. In Yamada T (ed): Textbook of Gastroenterology. Philadelphia, Lippincott, 1991, pp 137-158. 12. Meyer JH, Thomson JB, Cohen MB, et al: Sieving of solid food by the canine stomach and sieving after gastric surgery. Gastroenterology 1979;76:804-813. 13. Mayer EA, Thomson JB, Jehn D, et al: Gastric emptying and sieving of solid food and pancreatic and biliary secretions after solid meals in patients with nonresective ulcer surgery. Gastroenterology 1984; 87:1264-1271. 14. Richter C, Tanaka T, Yada RY: Mechanism of activation of the gastric aspartic proteinases: Pepsinogen, progastricsin and prochymosin. Biochem J 1998;335:481-490. 15. Walker V, Taylor WH: Ovalbumin digestion by human pepsins 1, 3 and 5. Biochem J 1978;176:429-432. 16. Curtis KJ, Gaines HD, Kim YS: Protein digestion and absorption in rats with pancreatic duct occlusion. Gastroenterology 1978;74: 1271-1276. 17. Meyer JH, Stevenson EA, Watts HD:The potential role of protein in the absorption of fat. Gastroenterology 1976;70:232-239. 18. Hodge C, Lebenthal E, Lee PC, Topper W: Amylase in the saliva and in the gastric aspirates of premature infants: Its potential role in glucose polymer hydrolysis. Pediatr Res 1983;17:998-1001. 19. Murray RD, Kerzner B, Sloan HR, et al: The contribution of salivary amylase to glucose polymer hydrolysis in premature infants. Pediatr Res 1986;20:186-191. 20. James AH: The nature of the gastric contents in man. In James AH (ed): The Physiology of Gastric Digestion. London, Edward Arnold, 1957, pp 1-24. 21. DeNigris SJ, Hamosh M, Kasbekar OK, et al: Lingual and gastric lipases: Species differences in the origin of prepancreatic digestive lipases and in the localization of gastric lipase. Biochim Biophys Acta 1988;959:38-45. 22. Carriere F, Barrowman JA, Verger R, Laugier R: Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology 1993;105: 876-888. 23. Pafumi Y, Lairon D, de la Porte PL, et al: Mechanisms of inhibition of triacylglycerol hydrolysis by human gastric lipase. J Bioi Chem 2002;277(31):28070-28079. 24. Sonnenberg A, Muller-Lissner SA, Weiser HF, et al: Effect of liquid meals on duodenogastric reflux in humans. Am J Physiol 1982; 243:G42-G47. 25. Ville E, Carriere F, Renou C, Laugier R: Physiological study of pH stability and sensitivity to pepsin of human gastric lipase. Digestion 2002;65:73-81. 26. Carriere F, Laugier R, Barrowman JA, et al: Gastric and pancreatic lipase levels during a test meal in dogs. Scand J Gastroenterol 1993;28:443-454. 27. Carriere F, Renou C, Lopez V, et al: The specific activities of human digestive lipases measured from the in vivo and in vitro lipolysis of test meals. Gastroenterology 2000;119:949-960. 28. Armand M, Borel P, Dubois C, et al: Characterization of emulsions and lipolysis of dietary lipids in the human stomach. Am J Physiol 1994;266:G372-G381.
SECTION II • Physiology of the Alimentary Tract 29. Gargouri Y, Pieroni G, Riviere C, et al: Importance of human gastric lipase for intestinal lipolysis: An in vitro study. Biochim Biophys Acta 1986;879:419-423. 30. Bernback S, Blackberg L, Hernell 0: Fatty acids generated by gastric lipase promote human milk triacylglycerol digestion by pancreatic colipase-dependent lipase. Biochim Biophys Acta 1989; 1001:286-293. 31. Bernback S, Blackberg L, Hernell 0: The complete digestion of human milk triacylglycerol in vitro requires gastric lipase, pancreatic colipase-dependent lipase, and bile salt-stimulated lipase. J Clin Invest 1990;85:1221-1226. 32. Dubois A, Natelson BH, van Eerdewegh P, Gardner JD: Gastric emptying and secretion in the rhesus monkey. Am J Physiol 1977;232:EI86-EI92. 33. Lin HC, Doty JE, Reedy TJ, Meyer JH: Inhibition of gastric emptying by acids depends on pH, titratable acidity, and length of intestine exposed to acid. Am J Physiol 1990;259:GI025-G1030. 34. Lin HC, Doty JE, Reedy TJ, Meyer JH: Inhibition of gastric emptying by glucose depends on length of intestine exposed to nutrient. Am J Physiol 1989;256:G404-G411. 35. Hunt IN, Knox MT: In Code CF (ed): Handbook of Physiology. Baltimore, Waverly Press, 1966,pp 1917-1935. 36. Lin HC, Doty JE, Reedy TJ, Meyer JH: Inhibition of gastric emptying by sodium oleate depends on length of intestine exposed to nutrient. Am J Physiol 1990;259:GI031-G1036. 37. Lin HC, Elashoff JD, Kwok GM, et al: Stimulation of duodenal motility by hyperosmolar mannitol depends on local osmoreceptor control. Am J Physiol 1994;266:G94O-G943. 38. Binder HJ: Pathophysiology of acute diarrhea. Am J Med 1990; 88:25-4S. 39. McHugh PR,Moran TH: Calories and gastric emptying: A regulatory capacity with implications for feeding. Am J Physiol 1979;236: R254-R260. 40. Williams NS, Elashoff J, Meyer JH: Gastric emptying of liquids in normal subjects and patients with healed duodenal ulcer disease. Dig Dis Sci 1986;31:943-952. 41. Meyer JH, Kelly GA: Canine pancreatic responses to intestinally perfused proteins and protein digests. Am J Physiol 1976;231: 682-691. 42. Meyer JH, Kelly GA, Jones RS: Canine pancreatic response to intestinally perfused oligopeptides. Am J Physiol 1976;231 :678-681. 43. Lin HC, Kim BH, Elashoff JD, et al: Gastric emptying of solid food is most potently inhibited by carbohydrate in the canine distal ileum. Gastroenterology 1992; 102:793-801. 44. McClave SA, Snider HL, Lowen Cc. et al: Use of residual volume as a marker for enteral feeding intolerance: Prospective blinded comparison with physical examination and radiographic findings. JPEN J Parenter Enteral Nutr 1992;16:99-105. 45. Mullan H, Roubenoff RA, Roubenoff R: Risk of pulmonary aspiration among patients receiving enteral nutrition support. JPEN J Parenter Enteral Nutr 1992;16:160-164. 46. Kohn CL, Keithley JK: Enteral nutrition. Potential complications and patient monitoring. Nurs Clin North Am 1989;24:339-353. 47. Lin HC, Van Citters GW: Stopping enteral feeding for arbitrary gastric residual volume may not be physiologically sound: Results of a computer simulation model. JPEN J Parenter Enteral Nutr 1997;21 :286-289. 48. Spiro HM: Clinical Gastroenterology, 3rd ed. New York, Macmillan, 1983. 49. Lin HC, Perdomo OL, Zhao XT: Intestinal transit in dogs is accelerated by volume distension during fat-induced jeju nal brake. Dig Dis Sci 2001;46:19-23. 50. Huge A, Weber E, Ehrlein HJ: Effects of enteral feedback inhibition on motility, luminal flow, and absorption of nutrients in proximal gut of minipigs. Dig Dis Sci 1995:40:1024-1034. 51. Read NW: Diarrhee motrice. Clin Gastroenterol 1986;15:657-686. 52. Lin HC, Zhao XT, Chu AW, et al: Fiber-supplemented enteral formula slows intestinal transit by intensifying inhibitory feedback from the distal gut. Am J Clin Nutr 1997;65:1840-1844. 53. Hebbard GS, Samson M, Andrews JM, et al: Hyperglycemia affects gastric electrical rhythm and nausea during intraduodenal triglyceride infusion. Dig Dis Sci 1997;42:568-575. 54. Machella TE: Mechanism of the post-gastrectomy dumping syndrome. Gastroenterology 1968;54(suppl 2):721-722.
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55. Houghton LA, Mangnall YF, Read NW: Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 1990;31: 1226-1229. 56. Alin HC, Van Citters GW, Zhao XT, Waxman. Fat intolerance depends on rapid gastric emptying. Dig Dis Sci 1999;44:330-335. 57. Hildebrand P, Beglinger C, Gyr K, et al: Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic and biliary responses in man. J Clin Invest 1990;85:640-646. 58. Czako L, Hajna1 F, Nemeth J, et al: Effect of a liquid meal given as a bolus into the jejunum on human pancreatic secretion. Pancreas 1999;18:197-202. 59. Singer MV: Pancreatic secretory response to intestinal stimulants: A review. Scand J Gastroenterol Suppl 1987;139:1-13. 60. Caspary WF: Physiology and pathophysiology of intestinal absorption. Am J Clin Nutr 1992;55(1suppl):2995-30SS. 61. Ono A, Minami H, Kondoh M, Hagihira H: Changes in the intraluminal protein digestion of pancreatic duct-ligated rats. J Nutr Sci VitaminoI1985;31(1):53-68. 62. Zhao XT, Miller RH, McCamish MA, et al: Protein absorption depends on load-dependent inhibition of intestinal transit in dogs. Am J Clin Nutr 1996;64:319-323. 63. Zhao XT, McCamish MA, Miller RH, et al: Intestinal transit and absorption of soy protein in dogs depend on load and degree of protein hydrolysis. J Nutr 1997;127:2350-2356. 64. O'Dea K, Wong S: The rate of starch hydrolysis in vitro does not predict the metabolic responses to legumes in vivo. Am J Clin Nutr 1983;38:382-387. 65. O'Dea K, Snow P, Neste1 P: Rate of starch hydrolysis in vitro as a predictor of metabolic responses to complex carbohydrate in vivo. Am J Clin Nutr 1981;34:1991-1993. 66. Cummings JH, Englyst HN: Measurement of starch fermentation in the human large intestine. Can J Physiol Pharmacal 1991;69: 121-129. 67. Jain NK, Boivin M, Zinsmeister AR, DiMagno EP: The ileum and carbohydrate-mediated feedback regulation of postprandial pancreaticobiliary secretion in normal humans. Pancreas 1991 ;6:495-505. 68. Armand M, Borel P, Pasquier B, et al: Physicochemical characteristics of emulsions during fat digestion in human stomach and duodenum. Am J Physiol 1996;271:G172-G183. 69. Hofmann AF, Borgstrom B: The intraluminal phase of fat digestion in man: The lipid content of the micellar and oil phases of intestinal content obtained during fat digestion and absorption. J Clin Invest 1964;43:247-257. 70. Morgan RG, Hoffman NE: The interaction of lipase, lipase cofactor and bile salts in triglyceride hydrolysis. Biochim Biophys Acta 1971;248:143-148. 71. Gaskin KJ, Durie PR, Lee L, et al: Colipase and lipase secretion in childhood-onset pancreatic insufficiency. Delineation of patients with steatorrhea secondary to relative colipase deficiency. Gastroenterology 1984;86:1-7. 72. Hofmann AF, Poley JR: Cholestyramine treatment of diarrhea associated with ileal resection. N Engl J Med 1969;281:397-402. 73. Lin HC, Zhao XT, Wang L: Fat absorption is not complete by midgut but is dependent on load of fat. Am J Physiol 1996;271:G62-G67. 74. Lin HC, Zhao XT, Kwok GM, et al: Bile salt-dependent inhibition of gallbladder emptying. Am J Physiol 1995;269:G988-G993. 75. Mekhjian HS, Phillips SF: Perfusion of the canine colon with unconjugated bile acids. Effect on water and electrolyte transport, morphology, and bile acid absorption. Gastroenterology 1970;59: 120-129. 76. Wingate DL, Krag E, Mekhjian HS, Phillips SF: Relationships between ion and water movement in the human jejunum, ileum and colon during perfusion with bile acids. Clin Sci Mol Med 1973;45:593-606. 77. Hofmann AF: The enterohepatic circulation of bile acids in man. Adv Intern Med 1976;21:501-534. 78. Hofmann AF, Poley JR: Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection. I. Response to cholestyramine or replacement of dietary long chain triglyceride by medium chain triglyceride. Gastroenterology 1972;62:918-934. 79. Borgstrom B, Lundh G, Hofmann AF: The site of absorption of conjugated bile salts in man. Gastroenterology 1963:45:229-238.
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2 • Role of Controlled Gastrointestinal Transit in Nutrition and Tube Feeding
80. Roy CC, Weber AM, Lepage G, et al: Digestive and absorptive phase anomalies associated with the exocrine pancreatic insufficiency of cystic fibrosis. J Pediatr Gastroenterology Nutr 1988;7(suppl 1):SI-S7. 81. Yeoh 0, Zhao XT, Sanders SL, et al: Bilesalt inhibits acid-promoting feeding tube occlusion. Nutr Clin Pract 1996;11:105-107. 82. Spiller RC, Trotman IF, Higgins BE, et al: The ileal brakeInhibition of jejunal motility after ileal fat perfusion in man. Gut 1984;25:365-374. 83. Read NW, McFarlane A, Kinsman RI, et al: Effect of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels of neurotensin and enteroglucagon, Gastroenterology 1984;86:274-280. 84. Shahidullah M, Kennedy TL,Parks TG: Proceedings: The duodenal brake-Hormonal or vagal? Br J Surg 1973;60:912-913. 85. Shahidullah M, Kennedy TL, Parks TG: The vagus, the duodenal brake, and gastric emptying. Gut 1975;16:331-336. 86. Woolf GM, Miller C, Kurian R, Jeejeebhoy KN: Diet for patients with a short bowel: High fat or high carbohydrate? Gastroenterology 1983;84:823-828. 87. Lin HC, Zhao XT, Wang L: Jejunal brake: Inhibition of intestinal transit by fat in the proximal small intestine. Dig Dis Sci 1996; 41:326-329. 88. Lin HC, Zhao XT, Wang L: Intestinal transit is more potently inhibited by fat in the distal (ileal brake) than in the proximal (jejunal brake) gut. Dig Dis Sci 1997;42:19-25. 89. Barrett KE, Dharmsathaphom K: Pharmacological aspects of therapy in inflammatory bowel diseases: Antidiarrheal agents. J Clin Gastroenterol 1988;10:57-63. 90. Chang EB, Sitrin MD, Black DO: Gastrointestinal, Hepatobiliary, and Nutritional Physiology. Philadelphia, Lippincott-Raven Publishers, 1996. 91. Kremen AJ, Linner JH, Nelson CH: An experimental evaluation of the nutritional importance of proximal and distal small intestine. Ann Surg 1954;140:439-448. 92. Reynell P, Spray G: Small intestinal function in the rat after massive resections. Gastroenterology 1956;31 :361-368. 93. Eisenberg P: An overview of diarrhea in the patient receiving enteral nutrition. Gastroenterol Nurs 2002;25:95-104. 94. Mobarhan S, DeMeo M:Diarrhea induced by enteral feeding. Nutr Rev 1995;53:67-70. 95. DeWitt RC, Kudsk KA: Enteral nutrition. Gastroenterol Clin North Am 1998;27:371-386. 96. Homann HH, Kemen M,Fuessenich C, et al: Reduction in diarrhea incidence by soluble fiber in patients receiving total or supplemental enteral nutrition. JPENJ Parenter Enteral Nutr 1994;18:486-490. 97. Shankardass K, Chuchmach S, Chelswick K, et al: Bowel function of long-term tube-fed patients consuming formulae with and without dietary fiber. JPEN J Parenter Enteral Nutr 1990;14: 508-512. 98. Fuse K, Bamba T, Hosoda S: Effects of pectin on fatty acid and glucose absorption and on thickness of unstirred water layer in rat and human intestine. Dig Dis Sci 1989;34:1109-1116. 99. Meier R, Beglinger C, Schneider H, et al: Effect of a liquid diet with and without soluble fiber supplementation on intestinal transit and cholecystokinin release in volunteers. JPENJ Parenter Enteral Nutr 1993;17:231-235. 100. Lin HC, Van Citters GW, Heimer F, Bonorris G: Slowing of gastrointestinal transit by oleic acid: A preliminary report of a novel, nutrient-based treatment in humans. Dig Dis Sci 2001;46:223-229. 101. Thompson JS, Quigley EM, Adrian TE, Path FR: Role of the ileocecal junction in the motor response to intestinal resection. J Gastrointest Surg 1998;2:174-185. 102. Fallingborg J, Pedersen P, Jacobsen BA: Small intestinal transit time and intraluminal pH in ileocecal resected patients with Crohn's disease. Dig Dis Sci 1998;43:702-705. 103. Ricotta J, Zuidema GO, Gadacz TR, Sadri 0: Construction of an ileocecal valve and its role in massive resection of the small intestine. Surg Gynecol Obstet 1981;152:310-314. 104. Nightingale JM, Kamm MA, van der Sijp JR, et al: Disturbed gastric emptying in the short bowel syndrome. Evidence for a 'colonic brake.' Gut 1993;34:1171-1176.
105. Wen J, Phillips SF,Sarr MG, Kost LJ, et al: PYY and GLP-1 contribute to feedback inhibition from the canine ileum and colon. Am J PhysioI1995;269(6 Pt 1):G945-G952. 106. Nightingale JM, Kamm MA, van der Sijp JR, et al: Gastrointestinal hormones in short bowel syndrome. Peptide YY may be the 'colonic brake' to gastric emptying. Gut 1996;39:267-272. 107. Wen J, Luque-de LE, Kost LJ, et al: Duodenal motility in fasting dogs: Humoral and neural pathways mediating the colonic brake. Am J Physiol 1998;274(1 Pt 1):Gl92-G195. 108. Stephen AM, Haddad AC, Phillips SF: Passage of carbohydrate into the colon. Direct measurements in humans. Gastroenterology 1983;85:589-595. 109. Jenkins OJ,JenkinsAL, WoleverTM, et al: Fiber and starchy foods: Gut function and implications in disease. Am J Gastroenterol 1986;81:920-930. 110. Topping DL: Soluble fiber polysaccharides: Effects on plasma cholesterol and colonic fermentation. Nutr Rev 1991;49:195-203. Ill. Koruda MJ: Dietary fiber and gastrointestinal disease. Surg Gynecol Obstet 1993;177:209-214. 112. Jian R, Besterman HS, Sarson DL, et al: Colonic inhibition of gastric secretion in man. Dig Dis Sci 1981;26:195-201. 113. Owyang C, Green L, Rader 0: Colonic inhibition of pancreatic and biliary secretion. Gastroenterology 1983;84:470-475. 114. Layer P, Peschel S, Schlesinger T, Goebell H: Human pancreatic secretion and intestinal motility: Effects of ileal nutrient perfusion. Am J Physiol 1990;258(2 Pt 1):Gl96-G201. 115. Ropert A, Cherbut C, Roze C, et al: Colonic fermentation and proximal gastric tone in humans. Gastroenterology 1996;111:289-296. 116. Jain NK, Boivin M, Zinsmeister AR, et al: Effect of ileal perfusion of carbohydrates and amylase inhibitor on gastrointestinal hormones and emptying. Gastroenterology 1989;96(2 Pt 1):377-387. 117. Piche T, Zerbib F, Varannes SB, et al: Modulation by colonic fermentation of LES function in humans. Am J Physiol 2000;278: G578-G584. 118. Roberfroid M: Dietary fiber, insulin, and oligofructose: A review comparing their physiological effects. Crit Rev Food Sci Nutr 1993;33:103-148. 119. Lifshitz F, Wapnir RA, Wehman HJ, et al: The effects of small intestinal colonization by fecal and colonic bacteria on intestinal function in rats. J Nutr 1978;108:1913-1923. 120. Pimentel M, Soffer EE, Chow EJ, et al: Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth. Dig Dis Sci 2002;47:2639-2643. 121. Pimentel M, Chow EJ, Lin HC: Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95:3503-3506. 122. Stotzer PO, Bjomsson ES, Abrahamsson H: Interdigestive and postprandial motility in small-intestinal bacterial overgrowth. Scand J Gastroenterol 1996;31:875-880. 123. Riordan SM, Mclver CJ, Walker BM, et al: Bacteriological method for detecting small intestinal hypomotility. Am J Gastroenterol 1996;91:2399-2405. 124. livonen MK, Ahola TO, Matikainen MJ: Bacterial overgrowth, intestinal transit, and nutrition after total gastrectomy. Comparison of a jejunal pouch with Roux-en-Yreconstruction in a prospective random study. Scand J Gastroenterol 1998;33:63-70. 125. Cater RE: The clinical importance of hypochlorhydria (a consequence of chronic Helicobacter infection): Its possible etiological role in mineral and amino acid malabsorption, depression, and other syndromes. Med Hypotheses 1992;39:375-383. 126. Saltzman JR, Russell RM: Nutritional consequences of intestinal bacterial overgrowth. Compr Ther 1994;20:523-530. 127. Riordan SM, Mciver CJ, Wakefield 0, et al: Small intestinal bacterial overgrowth in the symptomatic elderly. Am J Gastroenterol 1997;92:47-51. 128. Thompson JS, Quigley EM, Adrian TE: Factors affecting outcome following proximal and distal intestinal resection in the dog: An examination of the relative roles of mucosal adaptation, motility, luminal factors, and enteric peptides. Dig Dis Sci 1999;44:63-74. 129. Meyer JH, Elashoff JD, Lake R: Gastric emptying of indigestible versus digestible oils and solid fats in normal humans. Dig Dis Sci 1999;44:1076-1082.
II Mechanisms and Significance of Gut Barrier Function and Failure Louis J. Magnotti, MD Edwin A. Deitch, MD
CHAPTER OUTLINE Introduction The Gut Barrier and Physiology of Gut Barrier Function Bacterial Translocation Relationship of Nutrition to Gut Barrier Function limitations of Human Studies The Gut as an Inflammatory Organ and the Role of the Mesenteric Lymphatic Vessels Conclusion
INTRODUCTION Our understanding of the biology of intestinal barrier function, its potential clinical importance, and the pathophysiology and consequences of gut barrier failure has evolved considerably over the past 30 to 40 years. It is now clear that the intestinal mucosa has a physiologic role as a local defense barrier that prevents bacteria and endotoxin, normally present within the intestinal lumen, from escaping and reaching extraintestinal tissues and organs and that loss of intestinal barrier function appears to playa role in the development of systemic infection or multiple organ failure in selected patients.' Although its mechanics are not fully understood, the phenomenon of bacteria crossing the mucosal barrier and invading extraintestinal tissues has been termed bacterial translocation? More recently, it has become clear that the ischemic and/or stressed gut can become a proinflarnmatory organ" and that gut-derived factors liberated from the gut can lead to distant organ and cellular dysfunction and activate neutrophils and other proinflamrnatory cells.'
Although intestinally derived factors were proposed as being important contributors to shock in critically ill and injured patients in the 1960s,5 this notion was not generally accepted by the medical community and was largely ignored until the 1980s.6 This resurgence of interest in gut barrier failure and bacterial translocation in the 1980s was based on clinical observations that trauma patients, bum patients, and critically ill patients, especially those developing multiple organ failure, often had lifethreatening bacteremias with enteric organisms in the absence of an identifiable focus of infection.' These clinical observations lead to a large body of work investigating the relationships between gut barrier function, intestinal bacterial flora, systemic host defenses, and injury in an attempt to delineate the mechanisms by which bacteria contained within the gastrointestinal (GI) tract can translocate to cause systemic infections." From these and subsequent studies, the current roles of the gut and gut barrier function in the prevention and potentiation of systemic infections and multiple organ failure have evolved. In the context of this work, nutrition and maintenance of gut barrier function have been found to be of major importance. To put this work into perspective, we will firstdescribe the physiology of intestinal barrier function, then outline the mechanisms associated with gut barrier failure after which studies investigating the relationship between nutrition and gut barrier function will be reviewed as will clinical studies investigating gut barrier function and bacterial translocation. Lastly, we will present our current hypothesis on the role of the gut and gut barrier function in multiple organ failure.
THE GUT BARRIER AND PHYSIOLOGY OF GUT BARRIER FUNCTION The gut is a complex organ, the primary function of which is the digestion and absorption of nutrients. However, in addition to nutrient absorption, the gut must function as
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3 • Mechanisms and Significance of Gut Barrier Function and Failure
a barrier to prevent the spread of intraluminal bacteria and endotoxin to systemic organs and tissues. Intestinal barrier function can be seen to be of major importance when one considers that the distal small bowel and colon contain enormous concentrations of bacteria (1010 anaerobes and 105 to 108 each of Gram-positiveand Gram-negative aerobic and facultative microorganisms per gram of tissue) and enough endotoxin to kill the host thousands of times over. Nevertheless, in a normal, healthy individual, bacterial translocation and/or gut origin sepsis does not occur. This is because the host has developed multiple defense mechanisms to prevent the bacteria from colonizing the gut and their products from crossing the mucosal barrier and translocating to systemic tissues. Conceptually, bacterial translocation occurs through a series of steps. The initial step involves the adherence of luminal bacteria to the epithelial cell surface or to ulcerated areas of intestinal mucosa. Once adherence to the epithelium has occurred, the bacteria must then cross the mucosal barrier and reach the lamina propria in a viable state, at which point bacterial translocation has technically occurred. However, unless these bacteria can successfully spread from the lamina propria to systemic organs, the process is of no clinical significance. In response, the host has developed a complex series of defense mechanisms that function together to prevent potentially pathogenic bacteria from adhering to the intestinal mucosa. These defense mechanisms of the gut barrier provide four generalized levels of protection: the stabilizing influence of the normal intestinal bacterial flora, mechanical, and immunologic defenses and the gut-liveraxis (Table 3-1). Indigenous intestinal microflora comprise the first major component of the gut barrier. The protective role of the normal intestinal microflora in preventing intestinal infections and bacterial translocation was originally described more than 30 years ago by van Der Waaij and associates." They showed that the resistance of the gut to infection by potential pathogens could be altered by the administration of various nonabsorbable oral antibiotic preparations and that overgrowth of pathogens is related to disruption of the normal gut microflora. The term colonization resistance was used to describe the
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Components of the Gut Barrier
Microbial Contact inhibition Colonization resistance Mechanical Mucous layer Peristalsis Epithelial barrier Junctional complexes Desq uamation Irnmunologic Gut-associated lymphoid tissue (GALT) Secretory immunoglobulins Gut-liver axis Bile salts Reticuloendothelial function
protective role of the normal intestinal microflora in preventing overgrowth by potential pathogens. It appears that the obligate anaerobic bacteria are largely responsible for the phenomenon of colonization resistance, because of their high intestinal population levels and the fact that they associate closely with the intestinal epithelium to form, in effect, a physical barrier that limits direct attachment or intimate association of potential pathogens to the mucosa. As will be described later, loss of this obligate anaerobic bacterial barrier facilitates the direct attachment of potential pathogens to the intestinal epithelium and thereby promotes bacterial translocation. In addition to colonization resistance, the normal intestinal microflora also maintains communal stability within itself by a series of complicated interactions termed bacterial antagonism. This includes such diverse processes as contact inhibition, the production of various antimicrobial factors, and competition for nutrients and attachment sites. Although the means by which the normal intestinal microflora maintains stability and limits colonization by potential pathogenic bacteria are not well understood, it is clear that disruption of the normal ecology of the gut microflora may promote the overgrowth of potential pathogens and lead to bacterial translocation. A second component of the gut barrier involves the mechanical defenses of the gut. These include the mucus layer, intestinal peristalsis, and the epithelial cell barrier. The intestinal epithelium is coated by a mucus gel layer 30 to 50 urn thick that functions to prevent the adherence of bacteria to epithelial cell receptors and also provides a favorable environment for anaerobic bacteria, with which it is densely colonized. The presence of a normal, continuous mucus layer, colonized with anaerobic bacteria, has been shown to prevent tissue colonization by potential pathogens, and elimination of this mucus layer results in both bacterial overgrowth with Gram-negative enteric bacteria and increased numbers of these bacteria adhering directly to the intestinal epithelium," Normal peristalsis in the small intestine also protects against bacterial translocation, by preventing prolonged stasis of bacteria in close proximity to the intestinal mucosa, thereby reducing the possibility that bacteria will have adequate time to penetrate the mucus gel layer and attach to the epithelial surface. In fact, peristaltic waves continuously wash bacteria through the intestinal tract. If the peristaltic clearance of bacteria is impaired, either by mechanical small bowel obstruction or ileus, bacterial stasis will occur. Under these circumstances, bacterial overgrowth occurs rapidly and penetration of the mucus gel layer and bacterial adherence to the epithelial cells will occur, in turn promoting bacterial translocation. The intestinal epithelium consists of a variety of cell types, including (1) columnar epithelial cells (enterocytes) that function to absorb nutrients, (2) goblet cells that secrete mucus, (3) intraepithelial leukocytes that play an active role in the immune function of the gut, and (4) amine precursor uptake decarboxylase cells that secrete gastrointestinal hormones and other regulatory peptides. These cells are bound by junctional complexes consisting of a tight junction (surrounds each cell and
SECTION II • Physiology of the Alimentary Tract
joins the plasma membranes of the entire epithelium together), an intermediate junction and belt desmosomes, which allow diffusion of small molecules and ions but, under normal circumstances, prevent the paracellular migration of macromolecules and bacteria. Because the epithelial cells at the tips of the villi are constantly desquamated and replaced by new cells migrating up from the crypts, this is a potential site for loss of barrier function. However, the few bacteria that have adhered to the epithelial cells are expelled into the intestinal lumen along with the desquamated epithelial cells to which they are attached. Epithelial cell migration and desquamation are extremely rapid processes that result in complete renewal of the epithelial surface every 2 to 3 days in rodents and every 4 to 5 days in man. Although desquamation of epithelial cells creates a potential portal for the translocation of bacteria or endotoxin, the defect rapidly decreases in size, aided by an adenosine triphosphate-dependent, neurally mediated subepithelial shortening of the villi to reduce the surface area in need of resurfacing. In addition, the tight junctional elements undergo rapid rearrangement and expansion at the basolateral surfaces of the cell. As the extruding cell extends into the lumen, existing junctional elements expand along the periphery while maintaining contact with neighboring cells. The neighboring cells also extend their basal processes to close the space vacated by the extruded cell and establish new junctional complexes. In this way, access by bacteria and luminal factors to the basement membrane is effectively limited during the process of normal epithelial cell turnover. The intestinal immune system, also known as the gutassociated lymphoid tissue (GALT), regulates the local immune response to soluble and particulate antigens within the gut. The exact role of the GALT in preventing bacterial adherence and translocation is unclear. Nevertheless, it is commonly accepted that secretory (immunoglobulin A) IgA produced by antigen-primed B cells that line the mucosal surfaces plays a major role in the defense against mucosal invasion by bacteria." Secretory IgA is unique among the various classes of immunoglobulins, in that it binds to bacteria but does not activate the effector arms of the immune system. In this way, it prevents bacterial adherence to the intestinal mucosa without creating a local inflammatory reaction, which, in turn, could impair the normal absorptive processes of the gut. Although much less is known about the anti-endotoxin defenses of the gut, it appears that bile salts playa major role in preventing the release of endotoxin from the gut. Bile salts are thought to prevent endotoxemia by binding to intraluminal endotoxin and forming poorly absorbed detergent-like complexes." Although small amounts of endotoxin may enter the portal circulation even under normal circumstances, the reticuloendothelial cells of the liver are efficient in clearing endotoxin from the portal blood and systemic endotoxemia does not occur unless the reticuloendothelial cell function of the liver has been severely impaired." Bile salts also appear to be important in preventing bacterial translocation. Experimental studies indicate that bile duct ligation as well as bile
25
diversion from the gut is associated with intestinal bacterial overgrowth and bacterial translocation.P Each of these defense mechanisms may be impaired in critically ill patients at risk of developing multiple organ failure. These patients are frequently immune suppressed, and many receive broad-spectrum antibiotics that disrupt the normal ecology of the gut microflora, resulting in impaired colonization resistance and subsequent bacterial overgrowth by potential pathogens. Alkalinization of the stomach for prophylaxis against stress ulcer bleeding may result in abnormal colonization of the stomach with bacteria and permit survival of orally ingested bacteria. The presence of ileus may result in small bowel stasis and bacterial overgrowth. The use of vasoactive drugs may cause a decrease in splanchnic blood flow, resulting in ischemic injury to the gut epithelium and loss of the epithelial barrier. Hyperosmolar enteral feedings or parenteral feedings may disrupt the ecology of the indigenous gut microflora as well as impair the mechanical defenses of the gut. Intestinal edema due to hypoalbuminemia and capillary leak syndrome may impair peristalsis, resulting in bacterial stasis, bacterial overgrowth, and altered gut permeability to intestinal luminal contents. In addition, hepatic failure or obstructive jaundice may allow endotoxin to reach the systemic circulation, where it may induce a septic-like state. Thus, these and other conditions commonly seen in critically ill patients may promote failure of the gut mucosal barrier to bacteria and endotoxin.
BACTERIAL TRANSLOCATION The underlying mechanisms of how and under what circumstances bacteria contained within the gut translocate across the mucosal barrier have been extensively studied. The results of these experimental studies indicate that certain conditions that are commonly found in critically ill patients will promote bacterial translocation. In addition, bacterial translocation is associated with failure of at least one of the host's gut barrier defenses described above. Although bacterial translocation can be induced in a variety of animal models, it appears that at least one of three basic pathophysiologic factors must be present for it to occur (reviewed in reference 7). These basic conditions include the following: 1. Disruption of the normal gut flora, resulting in bacterial overgrowth with Gram-negative enteric bacteria, 2. Physical disruption or impairment of the gut mucosal barrier, and/or 3. Impaired host immune defenses. A second important concept that has evolved from these studies is that bacterial translocation is not an allor-nothing phenomenon. Disruption or impairment of a single major intestinal defense system will consistently promote bacterial translocation to the mesenteric lymph nodes and occasionally to the liver or spleen. However, the bacteria do not usually multiply in the mesenteric lymph nodes or spread systemically. Instead, they are locally contained and eventually eradicated as the host recovers. In conditions that more closely mimic the
26
3 • Mechanisms and Significance of Gut Barrier Function and Failure
clinical situation, in which animals receive several simultaneous or sequential insults, translocating bacteria not only reach the mesenteric lymph nodes but also invade systemic organs and the bloodstream? (Fig. 3-1). In some of these combined injury models, the animals survive, although bacteria can be transiently recovered from their livers and spleen. In other models, such as mice with thermal injury" or protein-malnourished mice" receiving nonlethal doses of endotoxin, death often occurs from the translocating bacteria. Although both an intact epithelial barrier and a normal functioning immune system are important for adequate gut barrier function, it appears that an intact mucosa will prevent bacterial translocation in rats with selectively impaired cell-mediated immunity." Thus, the physical barrier function of the mucosa may be of primary importance in preventing or limiting bacterial translocation, especially in a host with a normal gut flora, whereas the immune system may serve a secondary or supportive role to the intestinal mucosal barrier. This would not be surprising, because a similar role is played by other mechanical barriers, such as the skin. The importance of loss of mucosal barrier function in the pathogenesis of bacterial translocation after thermal injury, limited periods of hemorrhagic shock, or endotoxin challenge is underscored by the results of our studies documenting that bacterial translocation can be largely prevented by limiting mucosal injury." In fact, one of the factors that most of the stress and injury models of bacterial translocation share is reduced splanchnic blood flow coupled with histologic evidence of mucosal edema and/or injury. Mucosal injury in these models appears to be caused by a gut ischemia-reperfusion injury mediated in part by xanthine oxidase-generated oxidants, because inhibition of xanthine oxidase with allopurinol or inactivation of xanthine oxidase activity by a molybdenum-free tungsten diet largely prevents mucosal injury and limits the extent of bacterial translocation." More recently, activation of the inducible form of nitric oxide synthasec, leading to the increased production of nitric oxide, has been implicated in the pathogenesis of gut injury, intestinal barrier dysfunction, and bacterial translocation." Large amounts of nitric oxide may lead to intestinal mucosal injury in a variety of ways. For example, prolonged exposure of cells to large amounts of nitric oxide may cause cellular damage in a paracrine or autocrine fashion, inhibit cellular respiration, cause maldistribution of regional blood flow, increase gut
permeability, and result in the increased production of the oxidant peroxynitrite." The generation of peroxynitrite from nitric oxide requires the presence of increased levels of the oxygen-free radical superoxide, which is produced by intestinal xanthine oxidase in conditions associated with ischemia-reperfusion of the gut. Thus, altered mesenteric blood flow, resulting in an ischemiareperfusion injury, mediated by xanthine oxidasegenerated oxidants and the increased production of nitric oxide, appears to be a common pathway of mucosal injury, gut inflammation, and bacterial translocation (Fig. 3-2). Consequently, a major concept has evolved from these studies: Because the splanchnic circulation is sensitive to alterations in intravascular volume, injury- or stress-induced splanchnic vasoconstriction may ultimately lead to an ischemia-reperfusion injury of the intestinal mucosa and thereby result in impaired intestinal barrier function and intestinal inflammation. These preclinical experimental studies provided important information, because impairment of many of the gut barrier defense mechanisms that are associated with bacterial translocation and gut injury/inflammation in experimental models also occur in critically ill and injured patients.
RELATIONSHIP OF NUTRITION TO GUT BARRIER FUNCTION Because of the potentially important relationship between nutrition, infection, and gut barrier function, continuously increasing clinical and experimental attention has been focused on this relationship over the past two decades. As stated earlier, gut barrier failure may result from one or more of the following three basic pathophysiologic conditions: (1) disruption of the normal ecologic balance of the indigenous gut microflora, with resultant overgrowth of Gram-negative enteric bacilli; (2) impaired host immune defenses; and (3) physical disruption of the gut mucosal barrier. Each of these variables may be affected by various dietary factors and/or the host's nutritional status. For example, starvation and protein malnutrition have been documented to impair host immune and antibacterial defenses, disrupt the normal ecology of the gut microflora, and lead to mucosal atrophy.'? Thus, there is good indirect evidence to suggest that nutritional variables may have a profound impact on gut barrier function. In fact, because nutritional problems are relatively common in severely traumatized or
SECTION II • Physiology of the Alimentary Tract
PARS Activation
27
Neutrophil activation
AMP
Xanthine dehydrogenase
Xanthine oxidase Hypoxanthine
~~=====~~--_---"::~~::::-'-_-------IUrate + 02 - +
H202
I Reperfusion I FIGURE 3-2. The proposed pathway by which reactive oxidants and nitrogen intermediates generated by the ischemia-reperfusion phenomenon result in microvascular and tissue injury. AMP, adenosine monophosphate; ATP, adenosine triphosphate; iNOS, inducible nitric oxide synthase; PARS, polyadenosine diphosphate-ribose synthetase.
critically ill patients, the resultant alterations in intestinal barrier function are likely to be extremely important in clinical practice. The role of selective intestinal malnutrition in the evolution of gut failure began largely with the work of Kudsk and associates'" in the early 1980swho found that animals fed enterally survive better after a septic challenge than animals fed an identical diet parenterally. This experimental observation that parenteral feeding is associated with more infectious complications than enteral feeding has been verified in several prospective randomized clinical studies involving burn" and trauma patients." The ability of high-protein enteral feedings to improve clinical outcome was first demonstrated conclusively by Alexander and colleagues" in a prospective study of burned children randomly assigned to receive either enteral or parenteral nutritional support. The enterally fed children had less impairment of their systemic immune defenses and fewer infectious complications and survival longer. These studies and the results of other human and animal studies indicate that the route by which patients are fed may influence the immunoinflarnrnatory and metabolic response to injury, affect the incidence of infectious complications, and modulate clinical outcome. A meta-analysis of eight prospective randomized trials of early enteral versus total parenteral (TPN) feeding further supports the concept that early enteral feeding reduces septic complications in high-risk surgical patients.P Although nitrogen balance was better in the TPN-fed patients, the overall incidence of infectious
complications in the patients fed enterally was less than half that in the TPN-fed patients. There is also evidence from randomized clinical trials that TPN may be harmful." In a study of 395 malnourished preoperative patients randomly assigned to receive TPN for 7 to 15 days or no TPN,24 the overall infection rates were 14.1% and 6.4%, respectively. Thus, not only are there clinical studies indicating that enteral feeding is beneficial, but also there are studies indicating that TPN may be injurious in certain subgroups of patients. One finding from the experimental studies on nutrition and the gut is that enteral feeding preserves intestinal barrier function better than parenteral feeding. Additionally, animal studies have demonstrated that immediate enteral feeding after thermal injury reduces the hypermetabolic response by maintaining gut mucosal mass and preventing the excessive release of catabolic hormones." Moreover, Fong and co-workers," using human volunteers, showed an exaggerated splanchnic and systemic response of glucagon, epinephrine, and cytokine production to endotoxin challenge after 7 days of bowel rest and TPN compared with enteral feedings. This was associated with an enhanced acute-phase protein response, peripheral amino acid mobilization, and increased peripheral lactate production. Thus, TPN may exacerbate the metabolic derangements seen in sepsis through an enhancement of cytokine production as well as an exaggerated response by counter-regulatory hormones. However, simply providing nutrients via the enteral route does not necessarily guarantee fully normal
28
3 • Mechanisms and Significance of Gut Barrier Function and Failure
gut barrier or immune function, because animal studies have shown that elemental and standard commercial enteral liquid diets will promote bacterial translocation and are associated with impaired immune function; all of which may be reversed by refeeding rats a normal chow diet. 27,28 Wilmore and associates" suggested that current methods of parenteral feeding are not capable of adequately supporting the structural and functional integrity of the gut as well as the immune system largely because of the lack of glutamine in these solutions. This conclusion is based on the following data. First, glutamine appears to be the primary respiratory fuel of the gut, because its uptake by the gut far exceeds that of any other nutrient. In fact, the highest concentration of glutaminase, the enzyme responsible for glutamine metabolism, is found in the enterocytes of the jejunum. Not only does the metabolism of glutamine provide energy for the enterocytes, but it also results in the release of alanine to be utilized in gluconeogenesis by the liver. Second, in certain stress states, glutamine uptake and utilization by the gut as well as immune cells are markedly increased, indicating that glutamine may be a conditionally essential nutrient of the gut and immune system during stress. Although glutamine clearly promotes small intestinal growth and limits mucosal atrophy, its beneficial effects on gut barrier function are less clear, because experimental studies have not consistently shown that glutamine administration preserves gut barrier function. 30,31 Clinical studies to date on the use of glutamine have been largely encouraging, but more data are needed. 32,33 Work by Zaloga and colleagues" suggested that the source of protein in the enteral formula is important in maintaining gut mucosal mass. They fed unstressed rats enteral diets consisting of either amino acids, peptides, or complex proteins. The diet containing complex proteins stimulated gut mucosal growth more effectivelythan did diets containing peptides or amino acids as their protein source. Other substrates, in addition to protein, may be important in maintaining gut structure and function.
Short-ehain fatty acids, especially butyrate, are produced by the fermentation of fiber by the enteric bacteria and are the preferred fuel of the colonocytes. Delivery of short-ehain fatty acids to the gut has been shown to result in increased colonic mucosal height and DNA content and may exert trophic effects on the small bowel as well." Subsequent studies indicated that the provision of nonfermentable or bulk-type fiber would prevent both TPN-induced and elemental diet-induced bacterial translocation and preserve gut barrier function." However, fiber was only partially effective in restoring TPN-induced immune depression. Therefore, the composition of the diet seems to be just as important as the route by which it is administered. Clearly, these and similar experimental studies have demonstrated that liquid elemental and certain defined formula diets (including TPN) are associated with gut barrier failure, bacterial translocation, and immune suppression (Fig. 3-3). These findings, in tum, have led to the clinical development of new immune-enhancing and gut-protective liquid enteral diets. The new diets contain factors (glutamine, bulk fiber, ro-3 fattyacids, nucleosides, and high levels of arginine) that support enterocyte growth and function as well as the immune response. In fact, a meta-analysis of 15 randomized, controlled trials comparing patients receiving standard enteral nutrition with those receiving commercially available immuneenhancing diets showed that the patients fed the immuneenhancing formulas had significant reductions in rate of infection, number of days needing ventilator support, and overall length of hospital stay, although there was no statistically beneficial effect on mortality." In addition, a prospective randomized multicenter clinical trial showed that administration of an immune-enhancing enteral diet resulted in a significant reduction in mortality as well as in the incidence of infectious complications in septic patients in an intensive care unit (ICU).38 Thus, optimal nutrition of the gut and the rest of the body may be one of the best ways of protecting immunecompromised, stressed, or injured patients.
Normal small intestine
I TPN I
I Morphologic I
IBiomechanicall
I Villous atrophy I
LMucosal protein DNA or RNA
I Immunologic I I Intestinal flora I -1.slgA production -1.Cellular immunity
iLevel of gram(-) enteric bacilli
I Barrier function I Ttntestinal permeability bacterial translocation
FIGURE 3-3. Schematic diagram illustrating the adverse consequences of TPN on the normal small intestine as a predisposing factor to gut barrier failure. slgA, secretory immunoglobulin A.
SECTION /I • Physiology of the Alimentary Tract
LIMITATIONS OF HUMAN STUDIES One of the major problems with many of the published studies examining the relationship between nutritional modulation and gut barrier function is that many of these studies have not measured gut barrier function per se but instead have measured changes in certain parameters chosen to be reflective of gut barrier function. In fact, human studies measuring bacterial translocation to the mesenteric lymph nodes are limited. However, results do suggest that many of the conditions associated with bacterial translocation in experimental models do occur in patients. For example, translocating bacteria have been recovered from a relatively high percentage of patients with small bowel obstruction" or inflammatory bowel disease." In these same studies, only 5%of patients without bowel disease who had elective surgery had viable bacteria recovered from their mesenteric lymph nodes, suggesting that bowel obstruction or inflammation is associated with bacterial translocation. In a recent study of 279 surgical patients, cultures of organisms from nasogastric aspirates were compared with those obtained from mesenteric lymph nodes taken at laparotomy and with organisms recovered from subsequent infectious complications." Bacterial translocation occurred in 21% of these patients and was significantly more common in patients with multiple organisms in their nasogastric aspirates. Furthermore, in 45% of the postoperative septic complications, the same organism was identified in the mesenteric lymph node as the postoperative septic focus. Thus, proximal gut bacterial colonization appears to be associated with both increased bacterial translocation and septic morbidity. However, in trauma patients, the results of studies measuring bacterial translocation to the mesenteric lymph nodes are somewhat confusing. In these studies, bacterial translocation to the mesenteric lymph nodes was consistently demonstrated when nonculture methodology, such as electron microscopy, was used." However, in three clinical studies in which culture techniques were used, the rates of bacterial translocation to the mesenteric lymph nodes were 33%,43 25%,44 and 0%.45 In addition, in these studies, in which bacterial culturing methodology was used, it was not possible to show an association between bacterial translocation and outcome, suggesting that bacterial translocation was not of clinical relevance in trauma patients. A second clinical approach to assessing gut barrier failure and its relationship to sepsis and multiple organ dysfunction syndrome (MODS) has been by measuring intestinal permeability. In some studies in burn patients, a correlation between the extent of the burn injury and the degree of increased gut permeability has been found," whereas in others an association between the magnitude of the increase in gut permeability and the susceptibility to infection has been seen." A prospective study by Doig and associates" found that increased intestinal permeability predicted the development of MODS and that ICU patients who developed MODS had persistently abnormal levels of intestinal permeability compared with patients who did not develop MODS. When endotoxemia was examined as a marker of loss of gut barrier function or
29
bacterial translocation, the results are similar to those observed in the gut permeability studies. Studies in trauma, septic, or ICU patients generally find some evidence of endotoxemia; however, in only a few studies was there an association between endotoxemia and MODS.49 Thus, the human studies in which gut barrier function was evaluated, whether as bacterial translocation, gut permeability, or endotoxemia, do not provide a clear answer about the association between gut barrier failure and the subsequent development of MODS. In fact, the study by Moore and co-workers," who failed to find bacteria or endotoxin in the portal blood of severely-injured trauma patients cast doubt on the clinical relevance of bacterial translocation. Nevertheless, based on both animal and to a lesser extent clinical studies, it appears that gut-origin sepsis and MODS do occur. This paradox prompted us and others to reevaluate the phenomenon and pathophysiology of gut-origin sepsis and bacterial translocation.
THE GUT AS AN INFLAMMATORY ORGAN AND THE ROLE OF THE MESENTERIC LYMPHATIC VESSELS Over the past 20 years, the gut-origin hypothesis of MODS has undergone a series of conceptual changes. Originally, it was thought that gut barrier failure and intestinally derived bacteria and/or endotoxin transloeating to the bloodstream and systemic tissues triggered a septic state, promoting the development of MODS, I and that the persistent systemic inflammatory state induced by the translocating bacteria and endotoxin could lead to further gut injury. This, in turn, would lead to further bacterial and endotoxin translocation resulting in further increases in gut injury through the induction of an uncontrolled inflammatory response. Nevertheless, bacterial translocation was just one of several potential components involved in gut barrier failure and the pathogenesis of gut-induced MODS. As conflicting data from human studies accumulated, it became clear that translocating bacteria and endotoxin were not primarily responsible for the development of MODS. Nevertheless, there remained compelling data from clinical trials of early enteral feeding, studies using gastric tonometry, and splanchnic-directed therapies that gut dysfunction was playing a major role in systemic sepsis and distant organ failure." Over the last several years, the role of the gut in the development of systemic sepsis and MODS has been redefined. In fact, it has been shown that shock-, trauma-, or sepsis-induced gut injury and inflammation can result in the gut becoming a cytokine-generating organ." That is, many of the same insults that lead to gut barrier failure and promote bacterial translocation also induce the gut and GALT to produce cytokines and other inflammatory mediators that may contribute to the development of systemic inflammation and distant organ failure. Moreover, experimental evidence'>' indicating that nonbacterial gut-derived inflammatory factors are being released from the ischemic gut via the intestinal lymphatic vessels rather than the portal circulation helps
30
3 • Mechanisms and Significance of Gut Barrier Function and Failure
!Insult
I
I Gut ischemia-reperfusion injury I ~
I Gut inflammatory response I
I Loss of gut barrier function I I Bacterial translocation
I
Escape of bacterial products
Neutrophil activation
Inflammatory mediators
Gut-derived inflammatory factors carried in mesenteric lymph
I MODS I FIGURE 3-4. Schematic illustration of gut-origin sepsis and MODS: An insult, such as shock or trauma, leads to gut ischemia, which in turn causes loss of gut barrier function and gut inflammation. The gut then becomes a proinflammatory organ and contributes to the development of MODS via the liberation of gut-derived proinflammatory and tissue-injurious factors into the mesenteric lymphatic vessels.
explain the failure to detect endotoxin and/or bacteria in the portal blood of severely injured trauma patients, including those developing MODS.44 The concept that gut-derived toxic and inflammatory factors are reaching the systemic circulation via the intestinal lymphatics is consistent with the extensive clinical and experimental evidence documenting a connection between gut ischemia/injury and the subsequent development of distant organ injury. Studies indicating that gut-induced distant organ injury is related to gut barrier failure and the subsequent production of gut-derived factors, which are carried in the mesenteric lymph rather than the portal blood, provide new insights into the role of the gut in the development of MODS. In fact, gut ischemia appears to be the dominant link by which splanchnic hypoperfusion is transduced from a hemodynamic event into an immunoinflammatory event via the release of biologically active factors into the mesenteric lymphatics. These studies, coupled with the facts that gut injury leads to the gut being a cytokine and proinflammatory factor-generating organ and that the intestinal vasculature can serve as a priming bed for circulating neutrophils, have led to a more complete understanding of the role of the gut in the pathogenesis of MODS (Fig. 3-4).
CONCLUSION The gut barrier, when intact, functions to prevent the spread of intraluminal bacteria and endotoxin to systemic organs and tissues. Loss of gut barrier function has been implicated in the development of systemic sepsis and multiple organ failure. Maintenance of normal gut barrier function requires the complex interaction of numerous defense mechanisms, including the normal ecologic balance of the indigenous gut microflora, peristalsis, an intact mucous layer, an intact epithelial cell barrier, normal epithelial cell turnover, normal immune function, and the gut-liver axis. Numerous factors that complicate the care of the critically ill or injured patient may result in impairment of gut barrier function. Therapeutic measures that aid in the support of gut barrier function include maintenance of an effective circulating blood volume, early definitive surgery, prompt recognition and control of infectious processes, the judicious and appropriate use of antibiotics, and optimal nutritional support. Acknowledgment This work supported in part by National Institutes of Health Grant GM 59841 (to E.A.D.).
SECTION II • Physiology of the Alimentary Tract
REFERENCES 1. Deitch EA: Multiple organ failure: Pathophysiology and potential future therapies. Ann Surg 1992;216:117-134. 2. Berg RD: Promotion of the translocation of enteric bacteria from the gastrointestinal tracts of mice by oral treatment with penicillin, clindamycin or metronidazole. Infect lmmun 1981;33:854-861. 3. Deitch EA,Xu DZ, Franko L, et al: Evidence favoring the role of the gut as a cytokine generating organ in rats subjected to hemorrhagic shock. Shock 1994;1:141-146. 4. Deitch EA: Role of the gut lymphatic system in multiple organ failure. Current Opin Crit Care 2001;7:92-98. 5. Woodruff PW, O'Carroll DE, Koizumi S, et al: Role of the intestinal flora in major trauma. J Infect Dis 1973;128(suppl):S290-S294. 6. Deitch EA, Berg RD: Bacterial translocation from the gut: A mechanism of infection. J Burn Care Rehabil 1987;8:475-482. 7. Deitch EA: Bacterial translocation of the gut flora. J Trauma 1990; 30(suppl) :SI84-S 189. 8. van Der Waaij D, Berghuis-de Vries JM, Lekkerkerk-van der Wees JEC:Colonization resistance of the digestive tract and the spread of bacteria to the lymphatic organs in mice. J Hyg Camb 1972;70: 335-342. 9. Rozee KR, Cooper D, Lam K, et al: Microbial flora of the mouse ileum mucus layer and epithelial surface. Appl Environ Microbiol 1982;43:1451-1463. 10. Diebel L,Liberat D, Dulchavsky S, et al: Synergistic effect of hyperoxia and immunoglobulin A on mucosal barrier defenses. J Trauma 1999;46:374-379. 11. Bertok L: Physio-ehemical defense of vertebrate organisms: The role of bile acids in defense against bacterial endotoxins. Perspect Bioi Med 1977;21:70-76. 12. McCuskey RS, McCuskey PA, Urbascheck R, et al: Kupffer cell function in host defense. Rev Infect Dis 1987;9:61!Mi19. 13. Slocum MM, Sittig KM, Spec ian RD, et al: Absence of intestinal bile promotes bacterial translocation. Am Surg 1992;58:305-310. 14. Deitch EA, Berg RD: Endotoxin but not malnutrition promotes bacterial translocation from the gut. J Trauma 1987;27:161-166. 15. Deitch EA, Winterton J, Ma L, et al: The gut as a portal of entry for bacteremia: Role of protein malnutrition. Ann Surg 1987;205: 681-692. 16. Maddaus MA, Wells CL,Platt JL, et al: Effect of T cell modulation on the translocation of bacteria from the gut and mesenteric lymph node. Ann Surg 1988;207:387-398. 17. Mishima S, Xu DZ, Lu Q, et al: Bacterial translocation is inhibited in inducible nitric oxide synthase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth. Arch Surg 1997;132:1190-1195. 18. Salzman AL: Nitric oxide in the gut. New Horiz 1995;3:33-45. 19. Deitch EA: Nutrition and the gut mucosal barrier. Curr Opin Gen Surg 1993;85-91. 20. Kudsk KA, Stone JM, Carpenter G, et al: Enteral and parenteral feeding influences mortality after hemoglobin E coli peritonitis. J Trauma 1983;23:605-609. 21. Alexander JW, MacMillan BG,Stinnett JD, et al: Beneficial effects of aggressive protein feeding in severely burned children. Ann Surg 1980;192:505-517. 22. Kudsk KA, Croce MA, Fabian TC, et al: Enteral versus parenteral feeding: Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503-513. 23. Moore FA, Feliciano DV, Andrassy RJ, et al: Early enteral feeding compared with parenteral, reduces postoperative septic complications: The results of a meta-analysis. Ann Surg 1992;216: 172-183. 24. VACooperative Study Group: Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991;325:525-532. 25. Saito H, Trocki 0, Alexander JW, et al: The effect of route of nutrient administration on the nutritional state, catabolic hormone secretion and gut mucosal integrity after burn injury. JPEN J Parenter Enteral Nutr 1987;11:1-7. 26. Fong Y, Marano MA, Barber A, et al: Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans. Ann Surg 1989;210:449-457.
31
27. Alverdy J, Chi HS, Sheldon GF:The effect of parenteral nutrition on gastrointestinal immunity: The importance of enteral stimulation. Ann Surg 1985;202:681-684. 28. Mainous MR,Xu D, Lu Q, et al: Oral TPN-induced bacterial translocation and impaired immune defenses are reversed by refeeding. Surgery 1991;110:277-284. 29. Wilmore DW, Smith RJ, O'Dwyer ST, et al: The gut: A central organ after surgical stress. Surgery 1989;104:917-923. 30. Xu D, Lu Q, Thirstrup C, et al: Elemental diet-induced bacterial translocation and immunosuppression is not reversed by glutamine. J Trauma 1993;35:821-824. 31. Wells CL, Jechorek RP, Erlandsen SL, et al: The effect of dietary glutamine and dietary RNA on ileal flora, ileal histology and bacterial translocation in mice. Nutrition 1990;6:70-75. 32. Kelly D, Wischmeyer PE: Role of t-glutamine in critical illness: New insights. Curr Opin Clin Nutr Metab Care 2003;6:217-222. 33. Buchman AL: Glutamine: Commercially essential or conditionally essential? A critical appraisal of the human data. Am J Clin Nutr 2001;74:25-32. 34. Zaloga GP, Ward KA, Prielipp RC: Effect of enteral diets on whole body and gut growth in unstressed rats. JPEN J Parenter Enteral Nutr 1991;15:42-47. 35. Friedel D, Levine GM: Effect of short chain fatty acids on colonic function and structure. JPEN J Parenter Enteral Nutr 1992;16:1-4. 36. Mosenthal AC, Xu DZ, Deitch EA: Elemental and intravenous total parenteral nutrition diet-induced gut barrier failure is intestinal site specific and can be prevented by feeding non fermentable fiber. Crit Care Med 2001;30:396-402. 37. Beale RJ, Bryg DJ, Bihari DJ: 1mmunonutrition in the critically ill: A systemic review of clinical outcome. Crit Care Med 1999;27: 2799-2805. 38. Galban C, Montejo JC, Mesejo A, et al: An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med 2000;28:643-648. 39. Deitch EA: Simple intestinal obstruction causes bacterial translocation in man. Arch Surg 1989;124:699-701. 40. Ambrose NS,Johnson M, Burdon DW,et al: Incidence of pathogenic bacteria from mesenteric lymph nodes and ileal serosa during Crohn's disease surgery. Br J Surg 1984;71:624-625. 41. MacFie J, O'Boyle C, Mitchell CJ,et al: Gut origin sepsis: A prospective study investigating associations between bacterial translocation, gastric microflora and septic morbidity. Gut 1999;45:223-228. 42. Reed LL, Martin M, Manglano R, et al: Bacterial translocation following abdominal trauma in humans. Circ Shock 1994;42:1-6. 43. Kale IT, Kuzu MA, Berkem H, et al: The presence of hemorrhagic shock increases the rate of bacterial translocation in blunt abdominal trauma. J Trauma 1998;44:171-174. 44. Moore FA, Moore EE, Poggetti R, et al: Gut bacterial translocation via the portal vein: A clinical perspective with major torso trauma. J Trauma 1991;31:629-638. 45. Peitzman AB, Udekwu AO, Ochoa J, et al: Bacterial translocation in trauma patients. J Trauma 1991;31:1083-1087. 46. Ryan CM, Yarmush ML, Burke JF, et al: Increased gut permeability early after bums correlates with the extent of burn injury. Crit Care Med 1992;20:1508-1512. 47. LeVoyer T, Cioffi WG, Pratt L, et al: Alterations in intestinal permeability after severe thermal injury. Arch Surg 1992;127:26-29. 48. Doig CJ, Sutherland LR, Sandham 10, et al: Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients. Am J Respir Crit Care Med 1998;158:444-451. 49. Kollef MH, Eisenberg PR: A rapid qualitative assay to detect circulating endotoxin can predict the development of multiple organ dysfunction. Chest 1997;112:173-180. 50. Deitch EA, Sambol JT: The gut-origin hypothesis of multiple organ dysfunction syndrome. In Deitch EA, Windson A, Vincent JL (eds): Sepsis and Multiple Organ Dysfunction. Philadelphia, WBSaunders, 2002, pp. 105-116. 51. Magnotti U, Upperman JS, Xu DZ, et al: Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock. Ann Surg 1998;228:518-527.
II Gene Expression and Nutrition Carolyn D. Berdanier, PhD
CHAPTER OUTLINE Introduction Protein Synthesis and Gene Expression Mutation versus Polymorphisms DNA Characteristics Transcription Translation Nutrient-Gene Interactions in Health and Disease
INTRODUCTION The characteristics of every living creature are as much a result of the environment as they are a result of that creature's genetic material, deoxyribonucleic acid (DNA). DNA is a double-stranded helix composed of four bases: two pyrimidines (cytosine and thymine) and two purines (adenine and guanine) that are joined together by ribose and phosphate groups (Fig. 4-1). This DNA determines whether the creature is a mushroom, a bacterium, a rose, a chicken, a cow, or a human. Within each species there is variability in form and function that again is due to the specific base sequence of that particular DNA.l Nuclear DNA is organized into units called chromosomes of which there are 46 in the human. The chromosomes are found in pairs and contain the individual units called genes that encode every protein component of the living cell. Although all cells contain the same DNA, not all genes are expressed in every cell; some are specific to specific cell types. The genetic information contained in the cell is found in the nucleus and the mitochondria. Whereas the nuclear DNA comes from both the mother and the father, that found in the mitochondria comes only from the mother. At conception the sperm mitochondria and DNA are lost and very little is contributed to the resultant embryo. Nuclear DNA in contrast is a mixture of that contributed by both parents. Two copies of each gene are found in this DNA; one copy comes from the mother and the other from the father.
32
The Human Genome project has detailed the specific base sequence of nuclear DNA in the human cell. The mitochondrial genome has been completely sequenced and mapped.' Mapping means the identification, within the DNA, of each segment and the protein it encodes. The nuclear DNA has not been completely mapped. The sequence is known, but the location of all its many genes is not. In addition, we do not know all of the details of the regulation of the expression of the many genes contained within this DNA. Elements of the environment (including nutrition) can determine whether and when the genes contained in the DNA are expressed and in what fashion. Nutrients play a variety of roles in gene expression and it is the purpose of this chapter to discuss how nutrition and specific nutrients affect the expression of a variety of genes.
PROTEIN SYNTHESIS AND GENE EXPRESSION By definition, gene expression includes all those steps in the production and activation of a specific gene product. This product is a protein or peptide that has a specific function in the cell and whole body.' Extracellular and intracellular signals can stimulate or suppress gene expression. These signals can be environmentally induced, e.g., by a dietary change, a sudden exposure to danger or injury, a change in environmental temperature, or a change in lighting patterns. All of these environmental variables have been shown to result in changes in cell constituents and in the metabolism of the whole body through changes in gene expression. In some instances, the metabolic change is an increase (or decrease) in specific enzymes or metabolic pathways. In others, the change in gene product might be a change in a hormone level or the release of a metabolic signal that in tum could involve a change in behavior or a change in energy balance. As can be seen, there are many different genes that can be expressed in many different ways with many different end results. The process whereby proteins are synthesized provides the basis for understanding genetic differences. It is also the basis for understanding how the unique properties of each cell type are maintained because the properties
SECTION II • Physiology of the Alimentary Tract
33
FIGURE 4-1. The bases that comprise the DNA polynucleotide chain arejoined together by phosphodiesterase bonds using ribose as the common link between the bases. A, adenine; C, cytosine; G, guanine; T, thymine; R, ribose. Labile sites for DNA damage are indicated by arrows.
that make cells unique are usually determined by the proteins within them. Some of these proteins are the structural elements of the cell. Others are enzymes that catalyze specific reactions and processes that characterize the cell in question. Still other proteins allow the cell to perform a particular biochemical function. The amino acid sequence of a particular protein is dictated by the base (adenine, guanine, thymine, and cytosine) sequence of DNA. Each amino acid is dictated by a particular triplet of bases called a codon. Some amino acids have more than one codon. The bases are condensed to form the DNA chain in a process analogous to the condensation of amino acids that make up the primary structure of a protein. In mammals the adenine-thymine content varies from 45% to 53%. The guanine-cytosine content varies from 50% to 55%. Small amounts of the base, 5-methyicytosine, as well as methylated derivatives of the other bases can also be found. The chain of nucleotides that is DNA, is formed by joining the bases through phosphodiester bonds using ribose as the common linkage. The phosphodiester linkage is between the 5'-phosphate group of one nucleotide and the 3'-OHgroup of the adjacent nucleotide. This provides a direction (5' to 3') to the chain. A typical segment of the chain is illustrated in Figure 4-1. The hydrophobic properties of the bases plus the strong charges of the polar groups within each of the component units are responsible for the helical conformation of the nuclear DNA chain. The bases themselves interact such that in the nucleus, the two chains are intertwined and form a double helix. Hydrogen bonding between the bases stabilize this conformation. Other factors also stabilize the structure of the DNA. Unwinding of a small portion of
the DNA, a necessary step in the initiation of transcription, occurs when these stabilizing factors are perturbed, and signals are sent to the nucleus that transcription should begin. Unwinding exposes a small ('"17 kb) segment of the DNA (the gene) allowing its base sequence to be available for complementary base pairing, which happens when messenger ribonucleic acid (mRNA) is synthesized (transcription). The segment that is exposed contains not only the 600- to 1800-nucleotide structural gene but also a sequence called the promoter region. The promoter region precedes the start site of the structural gene and is said to be upstream of the structural gene. Those bases after the start site are downstream. The nucleotides that code for a specific protein may not be adjacent to each other on the DNA strand but may be located nearby in a coil of the DNA helix and have intervening noncoding sequences interspersed between the coding sequences. These noncoding regions are called
introns. In the mitochondria the DNA is circular with connections between the light and heavy strands (Fig. 4-2). In contrast to the nuclear genes with their nearby promoter sequences, the 13 structural genes found in the mitochondrial genome are all served by a single promoter region found in the displacement loop (D-loop). Although the nuclear DNA has many noncoding bases, the mitochondrial genome has few. Transcription of the mitochondrial genome is controlled by nuclear encoded mitochondrial proteins that bind to specific base sequences of the D-loop promoter. These transcription factors are in some instances unique to the organelle.' That is, they may be similar to factors active in the nucleus but not identical to them. Just as nuclear transcription is
34
4 • Gene Expression and Nutrition
FIGURE 4-2. Mitochondrial DNA map showing the locations of the structural genes as well as the D-Ioop promotor region, the location of the tRNAs and the ribosomal RNAs.
influenced by nutritional state and specific nutrients, so too is mitochondrial transcription. The DNA base sequence is unique for each protein synthesized in the body. Although only a few bases are used for the DNA, the sequences of the bases used in each gene is unique to each gene product. Thus, the function of DNA is to determine the properties of the cell through the provision of a multitude of genes that are each coded for a particular protein found in that cell. Another of its functions is to transmit genetic information from one generation to the next in a given species, and, in this way, DNA ensures the identity of both specific cell types and specific species. The DNA in the nucleus is very stable with respect to the base sequence and content. It can be damaged by certain chemicals, free radicals, x-rays, and other agents. In Figure 4-1 arrows point to vulnerable spots in the DNA where such damage can occur. If an attack by free radicals occurs, for example, the DNA strand is broken and a base is set free. Replacement of that base can occur, and the strand is repaired.v' However, in some instances, the base used for the repair might not be identical to the
one lost and a base substitution will be made. Although the nucleus has a very efficient repair process, the mitochondrial DNA does not. If a change in the base sequence does occur and is not repaired or is incorrectly repaired, a mutation is said to have occurred. Both base substitution and base deletion can occur as mutations. This mutation will then become part of the genetic information transmitted to the next generation. Some base substitutions have no effect on the gene product because more than one combination of bases (codon) can stipulate a particular amino acid in the gene product.
MUTATION VERSUS POLYMORPHISMS If a mutation in the sequence of bases that comprise the genetic code for a given protein occurs, the amino acid sequence generated in that protein will be incorrect. Whether this substitution of one amino acid for another in the protein being generated affects the functionality of the protein being generated depends entirely on the
SECTION II • Physiology of the Alimentary Tract
amino acid in question. Some amino acids can be replaced without affecting the secondary, tertiary, or quaternary structures of the protein (and, hence, its chemical and physical properties) whereas others cannot. In addition, genetic errors in amino acid sequence may pose no threat to the individual if the protein in question is of little importance in the maintenance of health and well-being, or these errors can have significant effects on health if the protein is a critical one. For example, in the synthesis of the important protein, hemoglobin, the genetic code calls for the use of valine instead of the usual glutamic acid in the synthesis of the ~ chain in the hemoglobin molecule." This amino acid substitution affects the solubility of the hemoglobin in the red blood cell cytosol by causing an increase in the intermolecular adhesion. Thus, an aggregation of deoxyhemoglobin occurs. This, in turn, affects the shape of the red blood cell, changing it from a "dumbbell"-shaped donut to a shape resembling a "sickle" and hence the name for this condition-sickle cell anemia. The increased aggregation of the hemoglobin subunits as well as the decreased solubility of the hemoglobin can be understood if one remembers the relative polarity of the glutamic acid and valine molecules. The glutamic acid side chain is more ionic and thus contributes more to the solubility of the protein than the nonpolar carbon chain of valine. This change in pH decreases its solubility in water, and, of course, a change in solubility leads to increased viscosity of the blood as the red cells rupture, spilling their contents into the bloodstream. The net result of this condition is a decrease in the survival time of the sickled cells, leading to anemia and also to an aggregation of the distorted cells in capillaries. Such aggregations cause blockage and downstream ischemia and infarction of the organs supplied by these capillaries. The amino acid sequence within a given species for a given protein is usually similar. However, some individual variation does occur. An example of an "acceptable" amino acid substitution would be one that accounts for the species differences in the hormone insulin." As a hormone, insulin has a variety of important functions in the regulation of carbohydrate, lipid, and protein metabolism. Yet, even though there are species differences in the amino acid sequence of this protein, insulin from one species can be given to another species and be functionally active. Obviously, the species differences in the amino acid sequence of this protein are not at locations in the insulin molecule that determine its biologic function in promoting glucose use. The deletion or substitution of a base could occur in a noncoding region of the DNA or in an area that encodes a nonactive portion of the gene product. Other base substitutions that have little effect on the functional or conformational characteristics of the resultant protein also occur. For example, a mutation that would result in an amino acid substitution of one neutral amino acid for another could occur. This substitution might be seen in a region outside of the active site(s) of the protein and have little effect on that protein's size and shape. Actually, such mutations and resultant amino acid substitutions are not mutations per se but polymorphisms. The resultant
35
gene product retains its premutation function yet has a slightly different amino acid sequence. Such polymorphisms are useful tools because they allow population geneticists to track mutation and evolutionary events through related family members. Particularly useful in this respect are the polymorph isms in mitochondrial DNA. Anthropologists use this information to track population shifts that have occurred over time."
DNA CHARACTERISTICS In the nucleus, DNA is found in the chromosomal chromatin. Chromatin contains very long double strands of DNAand a nearly equal mass of histone and nonhistone proteins. Histones are highly basic proteins varying in molecular mass from approximately 11,000 to approximately 21,000 daltons. As a result of their high content of basic amino acids, histones interact with the polyanionic phosphate backbone of the DNA to produce uncharged nucleoproteins. The histones also keep the DNA in a very compact form and, as well, protect this DNA from free radical attack. In mammals, the mitochondrial DNA does not have this protective histone coat. It is "naked" and much more vulnerable to damage. In addition, approximately 90% of oxygen free radicals are generated in the mitochondria, providing the means for such damage should the enzyme superoxide dismutase not suppress these radicals. The damage can be quite severe, yet because each mitochondrion contains 8 to 10 copies of its genome and there are so many mitochondria in each cell (up to 2,000), the effects of this damage might not be apparent. Having the codes in the nucleus for the synthesis of protein in the cytoplasm implies a communication between the cytoplasm and the nucleus and between the nucleus and the cytoplasm. Signals are sent to the nucleus that "inform" this organelle of the need to synthesize certain proteins. We do not know what all these signals are. Some are substrates for the needed proteins, some are nutrients, some are hormones, and some are signal compounds that have yet to be identified. In the other direction, the communication between the nucleus and the cytoplasm is carried out by messenger RNA (mRNA).
TRANSCRIPTION mRNAsynthesis using DNAas the template in the nucleus is called transcription. 1 The mRNA carries genetic information from the DNAof the chromosomes to the surface of the ribosomes (Fig. 4-3). It is synthesized as a single strand. Chemically, RNA is similar to DNA. It is an unbranched linear polymer in which the monomeric subunits are the ribonucleoside 5'-monophosphates. The bases are the purines, adenine and guanine, and the pyrimidines, uracil and cytosine. Thymine is not used in mRNA. Instead, uracil is used. This base is not present in DNA. RNA is single stranded rather than double stranded. It is held together by molecular base pairing. RNA, particularly the mRNA, is a much smaller molecule
36
4 • Gene Expression and Nutrition Transcription Trans factors (+/-)
I)
A
pro~oter1 region
~~~:-{
Structural gene
Cis factors ( +/-
~ NA
)
I
11
:
Cap
.~ i mRNA
Pol A Itail
:
+-- Nuclear Nucleotides (Introns)
membrane
U
~A.~~~O acids
DNA
~ Degraed~~~~
Translation
ADP
J l~
FIGURE 4-3. Schematic representation of the gene expression pathway. The pathway starts with the synthesis of mRNA and finishes with the production of new protein. ADP, adenosine diphosphate; pll, polymerase II.
New
Post translation
.:
acids tRNA Amino acids
Functional protein (gene product)
than DNA and is far less stable. It has a very short half-life (from minutes to hours) compared with that of nuclear DNA (years). Because it has a short half-life, the bases that comprise it must be continually resynthesized. Purine and pyrimidine synthesis requires a number of micronutrients as well as energy," This explains some of the symptoms of malnutrition. Among these symptoms are skin lesions. These occur because the epithelial cells are among the shortest lived cells and must be constantly renewed. This renewal depends on a supply of both adequate energy and amino acids and on the micronutrients (niacin, riboflavin, pyridoxine, folacin, cobalamin, copper, iron, sulfur, zinc, magnesium, and phosphorus) that are involved in mRNA synthesis as well as cell renewal. Another symptom is anemia. Again this is due to the short half-life of the red blood cell (=60 days). Micronutrients are involved in red cell production." Among these are iron, copper, magnesium, folacin, vitamin B12, and pyridoxine, and, of course, energy and protein sufficient to support this synthesis. The synthesis of mRNA from DNA occurs in several stages: initiation, elongation, editing (processing), and termination. Initiation follows the unwinding of the
DNA helix that exposes the gene to be transcribed. A wide variety of control mechanisms that regulate transcription exist. Central to this regulation are protein-DNA interactions and protein-protein interactions. At initiation, basal transcription factors recognize and bind the start point for transcription on DNA. They form a complex with RNA polymerase II. RNA polymerase is the enzyme that catalyzes the formation of mRNA. Transcription factors bind to regions or particular base sequences of the DNA. These sequences are called elements. Upstream of the transcription start site on the DNA is a region called the promoter region (see Fig. 4-3). Within the promoter region there are a number of elements to which specific promoter proteins bind. For example, approximately 25 bp upstream of the start site is a consensus sequence called the TATA box, which contain A-T base pairs. One of the basal transcription factors, the TATA binding protein, recognizes this sequence of DNA and binds here. Other transcription factors can do likewise. In this example, the process of transcription initiation begins as the transacting TATA binding protein binds to the TATA box and together with other transcription factors a large complex of transcription factors and RNA polymerase II is formed.
SECTION II • Physiology of the Alimentary Tract
The regulation of transcription occurs at the initiation step, and it is here that many nutrients have their effects on gene expression. The promoter region contains many cis-acting elements or base sequences, with each named for the factor that controls it. Examples include the retinoic acid response elements (RARE and RXRE) , vitamin D response element (YDRE) , heat shock element (HSE), and cyclic adenosine monophosphate response element (CRE). The trans-acting factors that bind these elements are proteins with at least two domains: a DNA binding domain and a transcription activation domain. Recently it has been shown that co-activating proteins are needed to bind transcription factors and increase transcription by both interacting with basal transcription factors and altering chromatin structure. I Corepressors act to decrease transcription at the level of both basal transcription factors and chromatin structure. I The regulation of transcription also occurs through the regulation of transcription factors. I I These factors can be regulated by rates of synthesis or degradation, phosphorylation or dephosphorylation, ligand binding, cleavage of a protranscription factor, or release of an inhibitor. One class of transcription factors important for nutrition is the nuclear hormone receptor superfamily that is regulated by ligand binding." Ligands for these transcription factors include retinoic acid (vitamin A), fatty acids, vitamin D, thyroid hormone, and steroid hormones. All members of this superfamily of receptors contain two zinc fingers in their DNA binding domains." Zinc is bound to histidine- and cysteine-rich regions of the protein that envelops the DNA in a shape that looks like a finger. The zinc finger is shown in Figure 4-4. The zinc ion plays an enormous role in gene expression because of its central use in the zinc finger. There are numerous proteins aside from those of the steroid receptor superfamily that bind to specific base sequences in the promoter region. Some of these bind minerals, some bind other hormones, and some are, by themselves, transcription factors that have control properties. On top of these specific transcription agents we have proteins that control gene expression in specific
Zinc FingerDetail
FIGURE 4-4. Details of the zinc finger showinq the linkage between the amino acids, histidine and cysteine and zinc.
37
cell types. These proteins determine whether the cell is a muscle cell, a brain cell, an insulin-producing cell, or another cell type. These proteins are selectively present and are probably acquired very early in embryogenesis. For example, specific enzymes are needed for the conversion of a fibroblast to a myocyte (muscle cell). During embryogenesis, some cells acquire a transcription regulatory protein (Myo Dl) that stimulates the transcription of the genes for these enzymes." When these genes are stimulated, the enzymes are produced, and the cell becomes a myocyte. The mammalian skeletal muscle cell is very large and multinucleated. It is formed by the fusion of myoblasts (myocyte precursor cells) and contains characteristic structural proteins as well as a number of other proteins that function in muscle-nerve signaling. When muscle is being synthesized, all of these proteins must be synthesized at the same time. In proliferating myoblasts very few of these proteins are present; yet, as these myoblasts fuse, the mRNAs for these proteins increase as does the synthesis of these proteins. These findings indicate that the transcription of all of these genes is under the influence of a single transcription factor. Research has shown that this factor is Myo D1. In addition to the receptor proteins that bind to certain base sequences in the promoter region, we also have smaller molecules that similarly stimulate or suppress transcription. One of these is the glucose molecule. It stimulates the transcription of the enzyme glucokinase. IS The gene for glucokinase has a glucose-sensitive promoter region. Only the ~ cell and the hepatocyte DNA have this region exposed and only these cell types express the glucokinase gene. Other cells have the gene but do not express it probably because their glucose promoter site is unexposed. Instead, these other cell types express a similar (but different) gene for the enzyme hexokinase. Both enzymes catalyze the phosphorylation of glucose. However, the hexokinase also catalyzes the phosphorylation of other monosaccharides. There are a number of instances in the nutrition science literature in which specific nutrients influenced the transcription of genes that encode enzymes or receptors or carriers that are important to the use of that nutrient. These are summarized in Table 4-1. Many nutrients have more than one function in gene expression. Some influence both transcription and translation whereas others enhance the transcription of one gene while suppressing the transcription of another. Note that a nutrient's merely having an effect on the transcription or translation of a gene does not automatically result in more of the active gene product. There are many instances for which a dramatic increase in a specific mRNA can be observed but with no increase in gene product activity. This finding verifies the complicated nature of metabolic control. Simply synthesizing more message units or more enzyme protein does not automatically mean an increase in enzyme activity, an increase in a metabolic pathway, or an increase in a metabolic product. After initiation, the mRNA is elongated. Elongation is the actual process of RNA formation through the use of a DNA template in the 5' to 3' direction. After elongation, the 5' end of mRNA is capped by 7-methylguanosine
38
4 • Gene Expression and Nutrition
E~ ~::a Some Examples of Nutrient Effects on Gene Expression Nutrient
Gene/Gene Product
Effect
Potassium Vitamin B" Vitamin D
Aldosterone synthetase Steroid hormone receptor Many genes
Glucose
Glucokinase, S14 gene, lipogenic enzymes
Copper Fatly acids Selenium Sodium Zinc
Metallothionine Fatly acid synthetase, SI4 gene, fatly acid binding protein Glutathione peroxidase, 5'-delodlnase Endothelin 1 Zinc transporters
Calcium Iron
c-fos, c-jun, c-myc Ferritin
Increases transcription in adrenal cortex!" Suppresses transcrtptton" Increases transcription of genes for calcium binding proteins but only in those cells possessing a vitamin D binding protem" Increases transcription; some of this action may be cell specific 15,19-21 Increases transcrtptlon" Suppresses transcription in liver 23,24 Increases transcrtptlon" Increases transcrtptton" Increases transcrlptlon'" Increases transcription, also essential as part of the zinc fingers of DNA binding proteins" Increases transcrlptton" When bound to ferritin, mRNA allows translation to
Ascorbic acid Vitamin E Vitamin K
Procollagen, lysyl oxidase All genes Prothrombin, bone GLA protein, osteocalcin Many genes
Increases transcription and translation" Protects DNAfrom free radical attack" Cosubstrate in the post-translational carboxylation of glutamic acid reslduesv Increases transcrtptlon-P'
proceed"
Vitamin A (retinoic acid)
triphosphate. This cap stabilizes the mRNA and is necessary for processing and translation. The third step is the termination of the chain. When the bases are joined together in the nucleus to form mRNA, it must then be edited and processed. Processing includes the capping of the mRNA, and the nucleolytic and ligation reactions that shorten the mRNA, followed by terminal additions of nucleosides (see Fig. 4-3). Some nucleoside modifications also occur. Through this processing, less than 10% of the original mRNA moves from the nucleus to the small ribosome where it attaches before translation. The editing and processing are needed because immature RNA contains all those bases corresponding to the DNA introns. The removal of these segments is a cut and splice process whereby the intron is cut at its 5' end, pulled out of the way, and cut again at its 3' end. After this group of bases is excised, the bases corresponding to the two DNA exons are joined. This cut and splice routine is continued until all the introns are removed and the exons are joined. Some editing of the RNA also occurs with base substitutions made as appropriate. Finally, a 3' terminal poly(A) tail is added. The editing and processing step is now complete. The mature mRNA now leaves the nucleus and moves to the cytoplasm for translation. The nucleotides that have been removed during editing and processing are either reused or degraded. The process of editing is also a mechanism for the degradation of the whole message unit that controls the amount of mRNA. The endonucleases and exonucleases used in the cut and splice processing also come into play in the regulation of mRNA stability. Some mRNAs have very short half-lives (seconds to minutes) whereas other have longer half-lives (hours). This difference in half-life is important because some gene products are needed for only a short time. Gene products such as
hormones and cell signals must be short lived, and the body needs to control/counterbalance their synthesis and action. One of the ways this is done is by regulation of the amount of mRNA (number of copies of mRNA for each gene product) that leaves the nucleus. Thus, this regulation is a key step in metabolic control.
TRANSLATION After transcription is translation. Translation is the synthesis of the protein using the order of the assemblage of constituent amino acids as dictated by the mRNA. This process is influenced by nutritional status as well as by specific nutrients. Protein synthesis depends upon the simultaneous presence of all the amino acids necessary for the protein being synthesized and upon the provision of energy. If there is an insufficient supply of either, protein biosynthesis will not proceed at its normal pace. This is an example of one consequence of malnutrition on gene expression. Malnourished individuals will not be able to support the full range of de novo synthesis of body proteins because their diets are energy poor and/or contain proteins of poor quality. Another example of an effect of malnutrition on gene expression is iron deficiency anemia. The anemia is characterized by low levels of hemoglobin and low numbers of red blood cells. The oxygen-earrying capacity of the blood is thus compromised. Iron is essential for hemoglobin synthesis as well as for the synthesis of the iron-containing cytochromes and for a number of enzymes of intermediary metabolism. Iron storage in cells occurs through chelation to a protein called ferritin. This occurs at the outer aspect of the mitochondrial membrane. This ferritin is found in hepatocytes, reticuloendothelial cells, bone marrow cells, and cells found in the
SECTION II • Physiology of the Alimentary Tract
gastrointestinal system. Its synthesis is highly regulated by iron. In iron deficiency, the mRNAstart site for ferritin translation is covered up by an iron-responsive proteln." This protein binds the 3' untranslated region and inhibits the movement of the 40S ribosome from the cap to the translation start site. When the diet contains sufficient iron and iron status is improved, the start site is uncovered and translation then proceeds. The actual site of translation is on the ribosomes; some ribosomes are located on the membrane of the endoplasmic reticulum (microsomes) and some are free in the cell matrix. Ribosomes consist almost entirely of ribosomal RNA and ribosomal protein. Ribosomal RNA makes up a large fraction of total cellular RNA. Ribosomal RNA is synthesized via RNA polymerase I in the cell nucleus as a large molecule; there this RNA molecule is cleaved and leaves the nucleus as two subunits, a large one and a small one. The ribosome is reformed in the cytoplasm by the reassociation of the two subunits; the subunits, however, are not necessarily derived from the same precursor. The large ribosome serves as the "docking" point for the activated amino acids bound to the transfer RNA (tRNA) whereas the small ribosome holds the mRNAthat dictates the amino acid polymerization sequence. The two ribosomes associate in the cytosol for the translation step. tRNA is used to bring an amino acid to the large ribosome, the site of protein synthesis. Each amino acid has a specific tRNA. Each tRNA molecule is thought to have a cloverleaf arrangement of nucleotides. With this arrangement of nucleotides, the opportunity exists for the maximum number of hydrogen bonds to form between base pairs. A molecule that has many hydrogen bonds is very stable. tRNA also contains a triplet of bases known, in this instance, as the anticodon. The amino acid carried by tRNA is identified by the codon of mRNA through its anticodon; the amino acid itself is not involved in this identification. A few general statements can be made about the distribution of ribosomes in cells that have different capacities for the synthesis of proteins. (1) Cells that synthesize large numbers of proteins have numerous ribosomes; conversely, cells that synthesize small numbers of proteins contain few. (2) Of the proteins synthesized by a cell to be secreted from that cell for use elsewhere, most of the ribosomes are attached to the endoplasmic reticulum. (3) Cells that synthesize protein primarily for intracellular use have relatively few ribosomes attached to the endoplasmic reticulum membrane. Small groups of ribosomes called polysomes are involved in protein synthesis; under physiologic conditions, polysomes are bound to the endoplasmic reticulum. The ribosome is bound to the membrane through its large subunit; the small subunit is involved in the binding of mRNA to the ribosome. The ribosomes have two binding sites used in protein synthesis: the amino acyl site and the peptidyl site. These two sites have specific functions in protein synthesis. Translation takes place in four stages as illustrated in Figure 4-3. Each stage requires specific cofactors and enzymes. The first stage involves the esterification of the
39
amino acids via specific amino acid esterases to specific tRNAs. Each of these esterification reactions requires a molecule of ATP. Here again is an explanation of why provision of sufficient energy is crucial to protein synthesis. If a protein contains several hundred amino acids, this step in translation will require several hundred molecules of adenosine triphosphate (ATP). Energy-deficient diets thus will not be able to provide this much ATP and so protein synthesis is compromised. During the second stage, the initiation of the synthesis of the polypeptide chain occurs. Initiation requires that mRNA binds to the small ribosome. An initiation complex is formed by the binding of mRNA cap and the first activated amino acidtRNA complex to the small ribosomal subunit. The ribosome finds the correct reading frame on the mRNA by "scanning" for an AUG codon. The large ribosomal unit then attaches, thus forming a functional ribosome. A number of specific protein initiation factors are involved in this step. In the third stage of protein synthesis, the peptide chain is elongated by the sequential addition of amino acids from the tRNA complexes. The amino acid is recognized by base pairing of the codon of mRNA to the bases found in the anticodon of tRNA, and a peptide bond is formed between the peptide chain and the newly arrived amino acid. The ribosome then moves along the mRNA; this brings the next codon in the proper position for attachment of the next activated amino acyl-tRNA complex. The mRNA and nascent polypeptide appear to "track" through a groove between the two ribosomal subunits. This protects the protein being synthesized from attack by enzymes in the surrounding environment. The final stage of translation in protein synthesis is the termination of the amino acid chain. The termination is signaled by one of three special codons (stop codons) in the mRNA.After the carboxyl-terminal amino acid is attached to the peptide chain, it is still covalently attached to tRNA, which is, in turn, bonded to the ribosome. A protein release factor promotes the hydrolysis of the ester link between the tRNA and the amino acid. Once the polypeptide chain is generated and free of the ribosome, it assumes its characteristic three-dimensional structure. If, during the course of synthesis, there is any interference in the continuity of the supply of all of the needed amino acids, synthesis is stopped. Here lies the basis for the time factor of protein synthesis, a feature that nutritionists have recognized for several decades." On the basis of animal feeding experiments, it was established that protein synthesis would not occur if all the needed amino acids were not provided at the same time. This is an important consideration in the planning of vegetarian diets. Plant sources of proteins must be blended so that the proteins in these plant sources have a complementary array of amino acids. Reliance on a single plant source for protein will not provide all the needed amino acids to support protein biosynthesis. In addition, because protein biosynthesis is very costly in terms of its energy requirement, synthesis is severely inhibited by starvation or energy restriction." In experimental animals, it has been shown that starvation
40
4 • Gene Expression and Nutrition
inhibits the polymerization of mRNA units, thus significantly reducing the activity of the transcription process. As mentioned earlier, a shortfall of ATP could also compromise protein synthesis. Other studies have shown that animals starved and then refed "overcompensate" for this period of reduced mRNA synthesis by a marked increase in mRNA synthesis above normal during the period of realimentation after the starvation period. This starved-refed-induced increase in mRNA is manifested as an increase in the synthesis of enzymes necessary for the metabolism of the various ingredients in the diet used for realirnentation." The signal(s) for the release of the starvation-induced inhibition of mRNA and enzyme synthesis include the macronutrients in the diet as well as the hormones glucocorticoid, thyroxine, insulin, and others. 384o After translation is complete, the primary structure is complete. Atthis point some post-translation modification can occur and again specific nutrients can influence the process. For example, after the translation of osteocalcin and prothrombin, two proteins that have glutamic acidrich regions, these glutamate residues are carboxylated. This post-translational carboxylation requires vitamin K.33 If vitamin K is in short supply, this carboxylation will not occur (or will occur in only a limited way), and these proteins will not be able to bind calcium. Both must bind calcium to function. Hence, vitamin Kdeficiency is characterized by prolonged blood clotting times and poorly mineralized bone.
NUTRIENT·GENE INTERACTIONS IN HEALTH AND DISEASE The genetic heritage of a living creature dictates its physical characteristics, its lifespan, and the diseases that it contracts. This is as true of humans as well as other living creatures. Humans differ in susceptibility to chronic and acute diseases and in part this difference in susceptibility is due to an interaction of genes and nutrition. The leading causes of death in the United States are heart disease, cancer, stroke, and diabetes. Contributing to these chronic diseases is obesity or excess body fat stores. In each of these diseases genetic linkages have been identified. For example, more than 150 mutations that associate with the development of diabetes have been identified.41,42 Numerous mutations, especially in the genes for the lipid-carrying proteins, have been identified as being associated with heart disease." Other mutations that associate with one or more of the diseases generically referred to as cancer have been reported. Although many of these genetic signatures have been associated with specific diseases, not all people who have these genetic characteristics actually develop the associated disease. This finding suggests that one must not only have the genetic characteristic, but also the environment for the disease to flourish must be present. An excellent example of this was reported many decades ag0 44--46 by Cohen, in Israel, who studied newly arrived and long-term, established residents of Israel. Few of the newly arrived immigrants had diabetes, whereas in the
established Yemenite population in Israel as much diabetes as Jewish populations from other parts of the world. Cohen and associates then studied the diets and lifestyles of these population groups as well as those of a matched group of Arabs living in the same locations in Israel. The diets of the Jews and the indigenous Arabs were not particularly different, yet the disease was far more prevalent in the Jews than in the Arabs. Analyses of the diets consumed in Yemen versus that in Israel revealed that the diets were basically the same with one exception: In Yemen very little refined carbohydrate was consumed. Sugar was not readily available and what was available was very expensive. When the Yemenites aculturated to the Israeli diet, their sugar consumption rapidly increased. Cohen suggested that the change in disease prevalence in the Yemenite group was due to an interaction between their genetic heritage and their increased consumption of refined carbohydrate. This report was the first to suggest such an interaction, yet, today, diabetologists have acknowledged that there are far more people with the diabetes genotype than with the diabetes phenotype. Many individuals with the diabetes phenotypes take years to develop diabetes. which suggests that with appropriate lifestyle choices diabetes may never develop or it might develop very rapidly with other choices. In support of this argument, one has only to look at the numbers of new cases of diabetes in times of abundant food supplies and times of food restriction. During World War II when food was rationed (as was gasoline for automobiles), people ate less and were more active." During this period the number of new cases of type 2 diabetes fell." The number of new cases of type 1 diabetes (autoimmune diabetes or insulin-dependent diabetes) remained fairly constant.f During this same time fewer people were obese, and this factor probably contributed to the lack of diabetes development. Obesity or excess body fat could also be the result of a genetic mutation-lifestyle choice interaction. A number of genetic mutations that affect food intake regulation and thus energy balance have been found." If the brain does not receive an appropriate appetitesuppressing signal then excess energy is consumed, resulting in excess body fat stores. Excess fat stores, particularly in the adipocyte, interfere with the action of insulin in facilitating the entry of glucose into the fat cell. When this occurs, abnormal glucose metabolism develops and type 2 diabetes follows. Even though we know that these chronic diseases have a genetic linkage we cannot, at present, identify by genetic testing individuals in whom the disease is likely to develop before it occurs. Knowing that these conditions are influenced by lifestyle choices, if we could identify susceptible individuals, it should be possible to develop effective strategies to forestall disease development. It might not be possible to eliminate the problem but perhaps we could delay its appearance appreciably. In another setting, we know that genetic heritage influences metabolism; thus, it can be suggested that nutrient requirements are also genetically dictated. It should be possible to classify people genetically such that appropriate nutrient intake recommendations can
SECTION II • Physiology of the Alimentary Tract
be made. These intake recommendations would optimize health and minimize the genetic potential for disease. In a study of rats having a diabetes-associated mutation in the mitochondrial genome, it was learned that the onset of the diabetic trait could be forestalled if the animals were fed a diet containing three times the recommended intake of vitamin A for rats.51,52 This level of intake was not needed by rats with a normal mitochondrial genome. If these results can be extrapolated to humans, it would appear that people with genetic tendencies for mitochondrial diabetes could require more than normal amounts of vitamin A in their diets. Population studies of vitamin Astatus have revealed that people with diabetes are more likely to have low levels of this vitamin in their blood; however, this was not found in all humans with the disease. 53,54 Far more research will be needed before individual nutrient intake recommendations can be made. REFERENCES I. Garrett RH, Grisham CM: Biochemistry, 2nd ed. Part IV Information Transfer, Philadelphia, Sanders College Publishing, 1999, pp 949-1126. 2. Anderson S,Bankier AT, Barrell BG,et al: Sequence and organization of the human mitochondrial genome. Nature 1981;290:457-465. 3. EvertsHB, Berdanier CD: Regulation of mitochondrial gene expression by retinoids. IUBMB-Life 2002;54:1-5. 4. Nelson JW, LeDoux SP, Wilson GL: Repair of 06-methylguanine in rat pancreatic ~ cells after exposure to N-methyl-N-nitrosourea. Diabetes 1993;42:1187-1194. 5. LeDoux SP, Patton NJ, Avery U, Wilson GL: Repair of N-methyl purines in the mitochondrial DNA of xeroderma pigmentosum complementation group 0 cells. Carcinogenesis 1993;14:913-917. 6. Strachan T, Read RP: Human Molecular Genetics. New York, BIOS Scientific Publications, 1996, p 424. 7. Norman AW, Litwack G: Hormones, 2nd ed. New York, Academic Press, 1997, pp 193-228. 8. Stoneking M: Mitochondrial DNA and human evolution. J Bioenerg Biomembr 1994;26:251-259. 9. Berdanier CD: Advanced Nutrition: Micronutrients. Boca Raton, FL, CRC Press, 1998,pp 15-18. 10. Hendricks LK, Kutlar A: Anemias. In Berdanier C (ed): Handbook of Nutrition and Food. Boca Raton, FL, CRC Press, 2001, pp 941-959. II. Semenza GL: Transcriptional regulation of gene expression: Mechanisms and pathophysiology. Hum Mutat 1994;3:180-199. 12. Reichel RR,Jacob ST:Control of gene expression by lipophilic hormones. FASEB J 1993;7:427-436. 13. Bray P, Lichter P, Thiesen HJ, et al: Characterization and mapping of human genes encoding zinc finger proteins. Biochemistry 1991; 88:9563-9567. 14. Chien KR, Zhu H, Knowlton KU, et al: Transcriptional regulation during cardiac growth and development. Annu Rev Physiol 1993; 55:77-95. 15. Magnuson MA: Glucokinase gene structure. Functional implications of molecular genetic studies. Diabetes 1990;39:523-527. 16. Holland OB,Carr B: Modulation of aldosterone synthetase messenger ribonucleic acid levels by dietary sodium and potassium and by adrenocorticotropin. Endocrinology 1993; 132:2666-2673. 17. Allgood VE, Powell-Oliver FE, Cidlowski JA: Vitamin B6 influences glucocorticoid receptor-dependent gene expression. J Bioi Chern 1990;265: 12424-12433. 18. Whitfield GK, Hsieh JC,Jurutka PW, et al: Genomic actions of 1,25 dihydroxyvitamin 0 3 J Nutr 1995; 125:16905-1694S. 19. Hillgartner FB, Charron T: Glucose stimulates transcription of fatty acid synthetase and malic enzyme in avian hepatocytes. Am J Physiol 1998;274:E493-E501. 20. Magnuson M, Jetton TL: Tissue specific regulation of glucokinase. In Berdanier C and Hargrove JL (eds): Nutrition and Gene Expression. Boca Raton, FL, CRCPress, 1993, pp 143-168.
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21. Perez-Castillo A, Hernandez A, Pipaon C, et al: Multiple regulation of SI4 gene expression during brown fat differentiation. Endocrinology 1993;133:545-552. 22. Chen Y, Saari JT, Kang YJ: Copper deficiency increases metallothionine-I mRNA content selectively in rat liver. J Nutr Biochem 1995;6:572-576. 23. Clarke SO, Jump 0: Regulation of gene transcription by polyunsaturated fatty acids. Prog Lipid Res 1993;32:139-149. 24. Blake WL, Clarke SO: Suppression of rat fatty acid synthetase and SI4 gene transcription by dietary polyunsaturated fat. J Nutr 1990;120:1727-1729. 25. Veerkamp JH, Maatman RGHJ: Cytoplasmic fatty acid binding proteins: Their structure and genes. Prog Lipid Res 1995;34: 17-52. 26. Bermano G, Nicol F, Dyer JA, et al: Selena-protein gene expression during selenium-repletion of selenium depleted rats. Bioi Trace Elem Res 1996;51:211-223. 27. Feron 0, Salomone S, Godfraind T: Influence of salt loading on the cardiac and renal preproendothelin-l mRNA expression in stroke prone spontaneously hypertensive rats. Biochem Biophys Res Commun 1995;209:161-166. 28. Freake H: Molecular biological approaches to studying trace minerals: Why should clinicians care? J Am Coil Nutr 1993;12:294-302. 29. Maki A, Berezesky IK, Fargnoli J, et al: Role of Ca2+ in induction of c-fos, and c-myc mRNA in rat PTE after oxidative stress. FASEB J 1992;6:919-924. 30. Munro HN, Kikinis Z, Eisenstein RS: Iron dependent regulation of ferritin synthesis. In Berdanier CD, Hargrove JL (eds): Nutrition and Gene Expression. Boca Raton, FL, CRC Press, 1993, pp 525-545. 31. Padh H: Vitamin C: Newer insights into its biochemical functions. Nutr Rev 1991;49:65-70. 32. Jenkinson AM, Collins AR, Duthie SJ, et al: The effect of increased intakes of polyunsaturated fatty acids and vitamin E on DNA damage in human lymphocytes. FASEB J 1999;13:2138-2142. 33. Suttie JW: Synthesis of vitamin K-dependent proteins. FASEB J 1993;7:445-452. 34. DeLuca L: Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J 1991;5:2924-2933. 35, Mills EB, Canolty NL: Role of the time factor in protein complementation. Nutr Rep Int 1984;30:311-322. 36. Rannels DE, Pegg AE, Rannels SR,Jefferson LS:Effect of starvation on initiation of protein synthesis in skeletal muscle and heart. Am J Physiol 1978;235:EI26-EI33. 37. Wurdeman R, Berdanier CD, Tobin RB: Enzyme overshoot in starved-refed rats: Role of the adrenal glucocorticoid, J Nutr 1978; 108:1457-1464. 38. Berdanier CD, Shubeck 0: Interaction of glucocorticoid and insulin in the responses of rats to starvation-refeeding. J Nutr 1979;109: 1766-1771. 39. Bouillon 0, Berdanier CD: Role of glucocorticoid in adaptive hyperlipogenesis in the rat. J Nutr 1980;110:286-297. 40. Berdanier CD: Effects of estrogen on the responses of male and female rats to starvation-refeeding. J Nutr 1981;111:1425-1429. 41. Berdanier CD: Diabetes mellitus: A genetic disease. Nutr Today 1999;34:89-98. 42. Scearce LM, Brestelli JE, McWeeney SK, et al: Functional genomics of the endocrine pancreas. The pancreas clone set and PancChip, new resources for diabetes research. Diabetes 2002;51:1997-2002. 43. Mokdad AH, Bowman BA, Ford ES,et al: The continuing epidemics of obesity and diabetes in the United States, JAMA 2001;286: 1195-1200. 44. Breslow JL: Genetic basis of lipoprotein disorders. J Clin Invest 1989;84:373-380. 45. Cohen AM, Bavly S: Change of diet of Yemenite Jews in relation to diabetes and ischemic heart disease. Lancet 1961;2:1399-1401. 46. Cohen AM: Prevalence of diabetes among different ethnic groups in Israel. Metabolism 1961;10:50-58. 47. Breguet 0, Backo A, Fabre J, et al: Cardiovascular risk factors in headquarters staff of the World Health Organization. Schweiz Med Wochenschr 1981;111:53-60. 48. USDA Food Disappearance Data. Hyattsville, MD, Human Nutrition Information Service, 1989. 49. Krolewski AS, Warram JH: Epidemiology of diabetes mellitus. In Marble A, Krall LP, Bradley RF, et al (eds): Joslin's Diabetes Mellitus, 12th ed. Philadelphia, Lea & Febiger, 1985, pp 12-42.
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4 • Gene Expression and Nutrition
50. Libman I, Songer T, Lal'orte R: How many people in the US have 100M? Diabetes Care 1993;16:841-842. 51. Rice T, Perusse L, Bouchard C: Genetics of energy and nutrient intake. In Berdanier 0 (ed): Handbook of Nutrition and Food. Boca Raton, FL, CRCPress, 2001, pp 603-619. 52. Everts HB, Berdanier CD: Nutrient-gene interactions in mitochondrial function: Vitamin A need in two strains of rats. IUBMB-Life
2002;53:289-294.
53. EvertsHB, Claassen DO, Hermoyian CL, Berdanier CD: Nutrient-gene interactions: Dietary vitamin A and mitochondrial gene expression. IUBMB-Life 2002;53:295-301. 54. Havivi E, Bar On H, Reshef A, et al: Vitamins and trace metal status in non-insulin dependent diabetes mellitus. Int J Vit Miner Res
1991 ;61 :328-333.
II Nutritional Requirements Across Animal Species Kathryn E. Michel, DVM, MS, DACVN Lisa Freeman, PhD, DVM, DACVN
CHAPTER OUTLINE
only one portion of the animal kingdom, have evolved over 225 million years and include 4500 species.
Introduction Comparative Gastrointestinal Anatomy Comparative Digestive Processes Comparative Gastrointestinal Barrier Function Comparative Nutrient Metabolism and Requirements Water Energy Protein and Amino Acids Fat Carbohydrates Micron utrients Therapeutic Enteral Nutrition and Tube Feeding in Animals Nutritional Assessment Nutritional Plan Options for Enteral Nutrition Diets for Tube Feeding
COMPARATIVE GASTROINTESTINAL ANATOMY Mammals show an impressive variation in gastrointestinal anatomy ranging from animals with relatively short and simple gastrointestinal tracts (e.g., cats), to animals with complex stomachs (e.g., cattle), to animals with greatly enlarged large intestines (e.g., horses). The morphology of the gastrointestinal tract reflects dietary adaptation. The overall length and capacity of the various major components of the gastrointestinal tract (e.g., the stomach, small intestine, cecum, and colon) correspond to the availability and digestibility of the nutrients found in the native diet of a given species. In general, as the availability of essential nutrients and the digestibility of foodstuffs increases, the relative length and capacity of the gastrointestinal tract decreases and the relative extent of mucosal surface area increases (fables 5-1 and 5_2).1.2 Hence, mammals that feed principally on animal matter generally have a simple, undifferentiated stomach and colon, whereas mammals that feed on vegetative
INTRODUCTION _
Species evolve by developing adaptations that allow them to exploit their environmental niche. One aspect of that environment will be the type of sustenance available for nourishment. Study of the comparative aspects of nutrition is a fascinating exercise. It illuminates gastrointestinal physiology and intermediary metabolism in ways that serve to further understanding of both normal processes and dysfunction. It is also valuable to have some understanding of the comparative aspects of nutrition because so much biomedical research today relies on animal models of disease. In this chapter a brief overview of this subject will be provided with a focus principally on mammals, which, although they represent
Human Cat Dog Swine Horse Cattle
Relative Capacity (%) of the Digestive Tract of Different Mammals
Total Stomach*
Small Intestine ("A;)
17 60 59 30 9 61
66 22 28 33 30 25
Large Cecum
Intestine
2 4 16 4
17 18 11 33 45 10
*Includes the ruminoreticulum and omasum. Adapted from Table 7 in Chivers OJ, Hladik CM:Morphology of the gastrointestinal tract in primates: Comparisons with other mammals in relation to diet. J Morphol 1980;166:337-386.
43
44
5 • Nutritional Requirements across Animal Species
~ Ratio of Intestine to Body Length of _ _ Different Mammals Mammal
Ratio
Cat
4:1
Dog Swine Horse Cattle
6:1
14:1 12:1 20:1
Adapted from Table 16.1 in Argenzio RA: General functions of the gastrointestinal tract and their control and integration. In Swenson MJ, Reece WO (eds): Dukes' Physiology of Domestic Animals. Ithaca, NY: Cornell University Press, 1993,pp 325-335.
plant material (e.g., leaves or grasses) have either a complex stomach or large intestine or sometimes both. Much of the nutritive value of plant material consists of long-ehain /3-1,4-linked polysaccharides (Le., fiber). Most animal species, including mammals, lack the enzymes necessary to cleave this type of bond. Species eating
foods containing fiber rely on gut microflora to digest and utilize these compounds (see Chapter 14). Substantial variations in gastrointestinal anatomy among these herbivorous species exist, ranging from ruminants with a greatly enlarged forestomach consisting of multiple compartments (e.g., cattle, sheep, and goats) to nonruminants with a voluminous stomach that may be compartmentalized or sacculated (e.g., kangaroos, hippopotamuses, and certain primates) to mammals that have a simple stomach but an extensive cecum and colon (e.g., horse and rabbit). In between these dietary extremes are found animals that are more omnivorous in their dietary habits, including most primates. These species often subsist on seeds, fruits, and tubers-mostly the reproductive parts of plantsthat they may supplement with animal or vegetative plant material and have been classified by some as trugioory,' The morphology of the gastrointestinal tract of omnivorous species is intermediate between the carnivorous and herbivorous species and reflects the nature of the foods that forms their diet. The range of variation of gastrointestinal anatomy across mammals is illustrated in Figure 5-1.
Dog (Canis tamiliaris) Pig (Sus scrota)
oCi112o Pony (Equus cabal/us)
Sheep (Ovis aries)
oCi112o
FIGURE 5-1 . Gastrointestinal tracts of the dog, pig, horse, and sheep. (Modified from Figures 16. 1 to 16.4 in Argenzio RA: General functions of the gastrointestinal tract and their control and integration. In Swenson MJ, Reece WO (eds): Dukes' Physiology of Domestic Animals. Ithaca, NY: Cornell University Press, 1993, pp 325-335.)
45
SECTION II • Physiology of the Alimentary Tract
COMPARATIVE DIGESTIVE PROCESSES The means by which food is broken down into particles that can be absorbed in the gastrointestinal tract involves mechanical and enzymatic processes, including enzymes provided by microorganisms. The importance of mastication varies with species and is reflected in the physical structure of the oral cavity and dentition. Carnivorous species often swallow large chunks of flesh with very little mastication, whereas herbivorous animals thoroughly grind forage and larger grain kernels, although smaller seeds may be swallowed whole. Salivary secretions function principally as a lubricant, although the saliva of some animals, including swine and certain primates, also contains a-amylase, which cleaves the o-I, 4-glucosidic linkages of starches.' Species that have adapted to diets containing large amounts of plant materials through enlargement of the forestomach utilize microorganisms to breakdown cellulose and other plant cell wall polysaccharides that are resistant to hydrolysis by mammalian enzymes. These microorganisms also ferment digestible starches and, to a much lesser degree, dietary fats and proteins. Carbohydrates of all types are hydrolyzed to monosaccharides that are in turn fermented. The end products of microbial carbohydrate fermentation include the short-chain fatty acids acetate, butyrate, and propionate and gases consisting principally of methane and carbon dioxide. The proportion of these various end products formed depends on the type of foods ingested and the organisms present in the forestomach. In addition to the digestion of carbohydrates, forestomach microorganisms are responsible for the synthesis of essential nutrients including amino acids and B vitamins. All mammals have a section of the stomach in which the mucosa secretes hydrochloric acid and pepsin, thus beginning the process of protein digestion. This section, known as the "true stomach" comprises the greater part of the gastric area in animals having simple stomachs (Fig.5-2). In addition to hydrochloric acid and pepsin, the gastric mucosa of young ruminant species (e.g., calves and lambs) secretes rennin, which is an enzyme that causes milk proteins to coagulate. This process slows the release of milk from the stomach. In some mammals, notably carnivores, the gastric mucosa also secretes low levels of lipase.' In animals with enlarged forestomachs, microorganisms pass from those portions of the stomach into the true stomach in which they begin to be digested in turn and thus are utilized as food by these species.
FIGURE 5-2. Variations in the type and distribution of gastric mucosal. Stomachs are not drawn to scale. (Modified from Figure 18.4 in Argenzio RA: Secretory functions of the gastrointestinal tract. In Swenson M), Reece WO (eds): Dukes' Physiology of Domestic Animals. Ithaca, NY, Cornell University Press, 1993, PP 349-361.)
For all mammals, the small intestine is the principal site of absorption of amino acids, lipids, vitamins, minerals, and, in species having a simple stomach, carbohydrates. All mammalian species rely upon pancreatic enzymes for the further digestion of proteins and lipids. Animals with simple stomachs also utilize pancreatic amylase and brush border disaccharidases for digestion of starches; however, there can be significant variation in the level of expression of these enzymes among species (Table 5-3). For instance, the domestic cat, which is often cited as an example of an obligate carnivore, has only 5% to 10% of the amylase activity of the domestic dog, a species that, although a member of the order Carnivora, is more omnivorous in its dietary habits." The activity of the disaccharidases found in the brush border of the small intestinal epithelium also shows significant species variation. Although lactase is present in juveniles of most species, activity is greatly reduced with maturation regardless of whether milk products are fed as part of the diet," Ruminants have low levels of sucrase activity, which reflects the fact that virtually all dietary starch and simple carbohydrates undergo microbial fermentation in the forestomach."
. . . Relative Digestive Enzyme Activity of Different Mammals
Salivary Amylase Human
Cat Dog Swine Horst'
Cattle
+ +
Gastric Lipase
Pancreatic Amylase
Lactase
Sucrase
+ + + +
++
+/-
++
+
++ ++ + +
+ +
++ +
46
5 • Nutritional Requirements across Animal Species
In addition to species differences in the activity levels of the various brush border disaccharidases, there also can be differences in the ability to adapt to the presence or absence of disaccharides in the diet. These enzymes tend to be inducible in animals with omnivorous dietary habits, and activity will increase with greater intake of substrate. Other species, either that have evolved on diets mostly devoid of carbohydrates or that largely metabolize carbohydrates proximal to the small intestine, do not have the ability to adapt to different levels of intake. Ostensibly, this reflects an adaptation to conserve energy and protein by avoiding turnover of enzymes that are in minimal demand. Herbivorous animals with simple stomachs rely on microbial digestion of vegetative material in the hindgut. These species generally have a greatly enlarged cecum and colon. There, short-ehain fatty acids are released and absorbed; however, the microorganisms themselves are not available for digestion as in foregut-fermenting animals. This is also at least partly the case for the proteins and vitamins produced by these microorganisms. In comparison with ruminants, in whom short-ehain fatty acids generated by microbial fermentation are utilized for 70% to 80% of daily energy needs, in hindgutfermenting species such as the horse, 30% to 70% of their needs are met in this fashion, depending on the carbohydrate makeup of the diet. Animals with omnivorous dietary habits have much more moderate enlargement of the large intestines and derive only a limited amount of nourishment from ~-I A-linked polysaccharides. Microbial fermentation does occur in the large intestine of carnivorous species and the short-chain fatty acids produced probably have a physiologic significance although their contribution to daily energy requirements is negligible. The amount of time it takes ingesta to traverse the gastrointestinaltract understandably varies with the length and complexity of the tract and reflects the digestibility of the typical diet of the species in question. Animals consuming foodstuffs that require microbial digestion must retain food in the forestomach or hindgut for sufficient time to enable fermentation of polysaccharides and microbial growth. Table 5-4 gives the mean retention times of food in the digestive tract for some representative mammalian species.
COMPARATIVE GASTROINTESTINAL BARRIER FUNCTION The gastrointestinal barrier has both physical and immunologic attributes. Although the physical properties of the gut barrier, the epithelial surface, mucus production, peristalsis, and commensal microflora are similar among mammalian species, the immunologic aspects of this barrier show more variation. Investigation of gastrointestinal barrier-associated immune function in most animal species is preliminary in nature. Gross and microscopic anatomical differences have been described; however, the phenotypes and functions of the immune cells that populate the gastrointestinal barrier-associated lymphoid tissue are only just beginning to be characterized in the majority of species. Differences are known to exist among species in the location, numbers, and functions of Peyer's patches. For example, immature ruminants and swine have extensive numbers of Peyer's patches in the ileocecal region of the gut that are believed to function as primary lymphoid organs and involute as the animal reaches maturity.P Furthermore, 100% of the follicle-associated epithelial cells in this region of the gut are M cells in contrast to humans in whom the number is about 10%.9 Another way in which immune function differsamong mammals is the secretion of immunoglobulin (Ig) A in the bile. The IgA found in the bile of rats and rabbits, for example, represents a significant portion of the IgA produced in the intestine." For other species, including dogs, swine, and ruminants, less than 5% of the intestinal wall IgA production makes itsway into the bile." Differencesof this nature become important when data are extrapolated between species, especially when animals are used to model human disease.
COMPARATIVE NUTRIENT METABOLISM AND REQUIREMENTS
Water Body water content on a percentage basis varies with species, age, and condition, especially the degree of adiposity (fable 5-5). Percent body water decreases as animals mature and with increasing fat deposition.
DmS1!II
Mean Retention Time of Food in the _ _ Digestive Tract of Different Mammals
Mammal Human Cat Dog Swine Horse Cattle
Mean RetenUon Time (br) 46 13 23 43
29
60
Adapted from Table 3-1 in Blaxter K: Components of the energy budget: Metabolisable energy. Energy Metabolism in Animal Species. Cambridge, UK, Cambridge University Press, 1989, pp 23-37.
' . •
Body Water Content on a Percentage Basis for Different Adult Mammals (Based on Carcass Analysis)
Mammal Human Cat Swine Horse Cattle (fat)
Body Water Content ("/0)
60 62 49 61 43
Adapted from Table 2-1 in Maynard LA, Loosli JK, Hintz HF, et al: The animal body and its food. In Animal Nutrition. New York, McGraw-Hill Book Company, 1979, pp 9-20.
SECTION II • Physiology of the Alimentary Tract
Animals lose water through urinary and fecal excretion, evaporation from skin surfaces, and respiration. The impact of these different routes of water loss can vary significantly among species as a consequence of physiologic differences, diet, and environment. Major factors affecting water homeostasis in mammalian species include hibernatory or estivatory behaviors, digestibility of the diet and consequently the quantity of fecal residue, urine concentrating ability, and means of heat dissipation. For instance, for a hibernating mammal, the water produced by the metabolism of protein, fats, and carbohydrates is sufficient to meet daily water requirements. Animals that have adapted to dry, hot climates have various mechanisms for conserving water, including the ability to assume a state similar to hibernation (estivation) during periods of extreme heat and the ability to form more concentrated urine or dryer feces. For example, the domestic cat, which is believed to have evolved from a desert species, exhibits an increased threshold for the stimulation of thirst and enhanced urine concentration ability. Whereas many animals lack sweat glands, they rely on evaporative losses through respiration to dissipate heat and, therefore, still will have increased water requirements when ambient temperatures rise.
Energy The number of animal species in which energy metabolism has been investigated is a small subset of all known species and includes mainly laboratory and domesticated
47
animals. Determinations of energy expenditure have been made using various methods including direct and indirect calorimetry and energy balance studies. Investigation of minimal metabolism in animals is hampered by the fact that animals cannot be expected to comply with the same rigorously defined conditions that are used for determining basal or even resting metabolic rate in human subjects. Although this terminology is often applied to measurements of minimal metabolism in animal species, in most cases it isprobably more accurate to describe these determinations as least observed metabolic rate or fasting metabolic rate as opposed to true basal metabolic rate." Another difference that needs to be taken into consideration when one measures energy balance in herbivorous species, in particular, foregut fermenters, is the energy lost from the diet in the form of combustible gases (e.g., methane and hydrogen). Despite these challenges, careful investigations of the energy metabolism of animals with a wide range of body mass have been accomplished. From investigations of heat production by Lavoisier in the eighteenth century onward, it was recognized that small animals produced more heat per unit weight than larger ones. Later investigators, including Rubnerl- and Volt," showed that fasting metabolism in a number of species was proportional to body surface area. In the 1930s, Brody and Procter" and Kleiber" independently published their analyses of the relationship of metabolism with body mass across species in which metabolism was estimated to be proportional to a power of body mass of 0.75 (Fig. 5-3). Although there is considerable debate about which power of body mass is most appropriate to
Log. of Metabolism! Log. of Bodywelght
4.0,...---------------------------..,........., 9 8 7 6
5 4 3 2 1
3.0 9 8 7
6
5 4 3 2 1
2.0 9 8 7 6
5 4 3 2 1
1.0 9 8
7-+-r:r=r=r-=:"-"---r---.-r-r---,,,,,,:;r---r-r---.-,..,---r-""::::'T'"'"'"'T:""..,.......,r-T-'-T-''-r-r-r---r---.-,,-.--r-r-r-rl -1.01234 567 8 90.012 34 5 67 891.01 234 5 6 7 892.01 2 3456 7 8 93.0
Log W (kilograms) FIGURE 5-3. Kleiber's classic diagram showing the relation between basal metabolism and body weight. (From Kleiber M: Body size and metabolism. Hilgardia 1932;6:315-353.)
48
5 • Nutritional Requirements across Animal Species
use to express the interspecific or, in the case of species such as dog or horses that have large variations in adult body mass, the intraspecific relationship of metabolism with body mass, this allometric approach works reasonably well for describing populations of animals. The limitation of these approaches appears when one is faced with the task of estimating the energy requirements of an individual animal just as isseen with the use of populationbased equations for prediction of energy requirements of human patients.
Protein and Amino Acids Both the total amount of protein and specific amino acid requirements vary widely among animal species and are related to the diversity in dietary habits among carnivores, omnivores, and herbivores. Not surprisingly, protein requirements of carnivores are higher than those of other species. Through evolution, the high activity of hepatic gluconeogenic enzymes and the prominent role of amino acids in energy production in the cat have created a divergence from protein requirements of the dog, even though they both are in the order Carnlvora.l-" Cats are unable to down-regulate urea cycle enzymes, whereas dogs and other omnivorous species adjust the activityof these enzymes in response to changes in dietary protein intake. 16,17 This evolutionary adaptation allows cats to efficiently metabolize the nitrogenous by-products of protein metabolism that they would get from high protein meals. To slow their urea cycle during fasting, urea cycle intermediates are depleted. To put the protein requirement of the cat into a human context, the protein requirement of an adult human is 0.8 g/kg/day whereas an adult cat requires approximately 4 g/kg/day.18)fthis is expressed in metabolic body size to more accurately account for large differences in body weight, the approximate protein requirements for a 7Q-kg person would be 2 g/kgo. 75 compared with 6 g/kgo. 75 for a 5-kg cat. Protein metabolism in ruminants is distinctive as a result of the microbial fermentation that occurs in the foregut. Much of the dietary protein that these animals consume is degraded by proteases produced by rumen microorganisms before it can reach the true stomach and the small intestine. However, ruminants are unique because they can utilize nonprotein nitrogen as a source of protein and amino acids. Both of these factors dramatically affect the type and quantities of amino acids reaching the small intestine. Sources of nonprotein nitrogen, such as urea, are commonly fed to ruminants rather than standard protein sources for economic reasons. Finally, in situations of low dietary protein intake, ruminants can recycle urea by secretion into the saliva rather than into the urine. This urea is converted to ammonia in the rumen after action by microbial ureases, which then can be used for protein synthesis by rumen microorganisms. In addition to the variety of differences that exist in protein metabolism between species, there are intraspecific variations. For example, breed differences exist in the metabolism of protein by dogs. Mostspecies (except humans, nonhuman primates, and birds) including most dog breeds excrete allantoin as the end product of
purine metabolism.'? In Dalmatian dogs, however, the end product is uric acid, and this hyperuricemia can result in urate urolithiasis.!" Besides the differences in protein metabolism, requirements for individual amino acids also vary. Most species require 10 amino acids in the diet (arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine). However, certain species may require additional dietary amino acids, such as the requirement for glycine in birds or the requirement for dietary taurine in cats. Whereas most species can conjugate bile salts with either taurine or glycine, cats and dogs almost exclusively use taurine." However, cats also have a limited ability to synthesize taurine." Taurine deficiency in cats causes dilated cardiomyopathy, blindness due to central retinal degeneration, and reproductive failure.i? Certain breeds of dogs may have higher metabolic requirements for taurine. Some dogs with dilated cardiomyopathy have been found to have a taurine deficiency, and taurine supplementation may improve cardiac function in these animals." Another amino acid that is essential in dogs and cats is arginine. Cats have a higher requirement for arginine than do dogs and are particularly sensitive to arginine deficiency; ammonia toxicity can occur after just a single meal devoid of arginine." This is the result of the inability to down-regulate urea cycle enzymes.
Fat A number of differences in fat metabolism exist between species. As with many other nutrients, the cat has the most unique requirements, which have probably evolved as a result of their carnivorous, high-fat diets. Domestic cats and lions have low hepatic ~6-desaturase, and thus, a limited ability to convert "flinolenic acid (l8:3n-6) to arachidonic acid (20:4n-6).17 Similarly, cats cannot convert a-linolenic acid (l8:3n-3) to the long-chain n-3 fatty acids, eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3). Hepatic ~6-desaturase activity in dogs is intermediate between that of cats and humans and thus dogs are able to synthesize these fatty acids to a limited degree. Another interesting feature of lipid metabolism in dogs and cats is that they generally do not develop coronary artery disease. This may be the result of low circulating low-density lipoprotein concentrations and high circulating high-density lipoprotein concentrations in these species.F Exceptions are certain dog breeds that develop a primary hypertriglyceridemia (e.g., miniature schnauzers and beagles) or primary hypercholesterolemia (e.g., Briards) or lipid metabolism disorders due to endocrine diseases, such as diabetes mellitus, hypothyroidism, or hyperadrenocorticism." Fat intake is generally much lower in herbivorous species that have evolved eating a relatively low-fat diet. In ruminants, for example, a maximum of 7% fat (on a dry matter basis) can be tolerated by ruminal microorganisms, unless the fat is protected to prevent degradation in the rumen.P Higher fat intake can impair nutrient uptake and digestibility. Horses can tolerate diets with up to 15% fat (on a dry matter basis), although most equine
SECTION II • Physiology of the Alimentary Tract
diets contain low levels of fat «5%).24 Miniature horses, ponies, and donkeys are particularly susceptible to development of hypertriglyceridemia in association with obesity, a systemic illness, or food deprivation.P-" The hypertriglyceridemia (and often mild to moderate hypercholesterolemia) results in hepatic Iipidosis.25,26 Idiopathic hepatic lipidosis also occurs in cats but, unlike the equine species, cats with this disease rarely have elevated circulating lipid concentrations."
Carbohydrates As was discussed in the section on comparative digestive processes, there is great variation among mammals in the ability to digest and utilize different forms of carbohydrate. Species that utilize microorganisms in the forestomach are able to make use of fibers as well as starches as a source of energy. However, because the usable end products of microbial carbohydrate fermentation are short-ehain fatty acids, not glucose, foregut-fermenting species generally have low blood glucose concentrations and rely on gluconeogenesis to meet tissue glucose requirements. The principal gluconeogenic precursor in these species is propionate. There is also variation in carbohydrate metabolism in species in which starch digestion occurs in the small intestine. Animals for which starches and sugars form a significant portion of their natural diet, have efficient uptake and utilization of glucose and other monosaccharides from the gut. Furthermore, those species that consume large amounts of plant material in their native diet utilize microbial fermentation in the large intestine in the same way that foregut-fermenting species do to derive sustenance from fiber. Carnivorous species, such as the cat, that have evolved eating diets containing little, if any, carbohydrate, show metabolic adaptations similar to those of the foregutfermenting species. Cats and ruminants, for instance, have minimal glucokinase activity in hepatocytes or pancreatic pcells." This inducible enzyme serves to metabolize glucose efficiently during the absorptive phase and may act as a glucosensor for insulin release by the pancreatic pcells.29 Another feline adaptation to a low-earbohydrate diet is the reliance on gluconeogenesis to meet tissue glucose requirements. The gluconeogenic amino acids found in large quantity in a carnivorous diet are the major glucose precursors in this species. In the course of evolution, cats have lost the ability to down-regulate the gluconeogenic pathways, which puts them at risk for rapid protein depletion when the dietary intake of this nutrient is limited.
49
calcium and phosphorus. Even if calcium requirements are not especially high in a particular species, disorders can develop as the result of an inappropriate diet. One of the most common disorders of captive birds and reptiles is hyperparathyroidism due to a nutritional deficiency. This is the result of diets high in seed (for birds) or fruits and certain vegetables (for reptiles), all of which are low in calcium and have a low calcium to phosphorus ratio. Calcium requirements of cats and dogs are higher than those of humans. A 7Q-kg young adult man requires 1000 mg/day of calcium compared with a 7Q-kg dog that requires approximately 4600 rng/day." Conversely, rabbits have very efficient gastrointestinal absorption of dietary calcium and unlike most other species that excrete calcium through the liver, rabbits excrete excess calcium via the kidneys." High-ealcium diets in rabbits can result in hypercalcemia and mineralization of tissues. Species-specific problems with copper and zinc can occur and may be related to defects in metabolism. Certain canine breeds, such as Bedlington terriers, can develop hepatic copper accumulation and hepatotoxicity similar to Wilson's disease in humans." Arctic breeds, such as the Alaskan malamute and the Siberian husky, and other dog breeds can develop a zinc-responsive dermatosis." Vitamin requirements in cats also differ from those of other species in several ways. Cats do not have intestinal dioxygenase to convert Ikarotene to vitamin A and so require dietary retinol." Although they have the necessary enzymes, cats do not convert tryptophan to niacin as a result of competing metabolic pathways." Thus, dietary niacin requirements are higher than those for most other species. The feline vitamin B6 requirement is four times higher than that of dogs due to the high transaminase activity in the cat." Vitamin E requirements do not differ greatly between dogs and cats, but cats may require high dietary vitamin E levels because they often are fed diets high in fish and thus need increased antioxidant protection against polyunsaturated fatty acid oxidation. Both dogs and cats have low concentrations of 7-dehydrocholesterol in the skin." Therefore, conversion to active vitamin D by ultraviolet light is limited in these species. Another difference in vitamin D metabolism is that some species, such as birds, fish, reptiles, amphibians, and New World primates, do not utilize vitamin D2 efficiently, and thus require dietary vitamin D3.33 Most other species can utilize either vitamin D2 or D3 interchangeably. Finally, humans, guinea pigs, and nonhuman primates have a dietary requirement for vitamin C whereas other species synthesize adequate vitamin C endogenously."
Micronutrients
THERAPEUTIC ENTERAL NUTRITION AND TUBE FEEDING IN ANIMALS
As for the other nutrients already described, requirements for micronutrients across species depend upon the evolution and feeding behaviors of that species. Animals require all the same minerals as do humans, but the specific amounts may vary. Skeletal growth, egg production, or growth of antlers all require high concentrations of
The metabolic response to illness or injury puts critically ill patients at high risk for malnutrition and its subsequent complications, whether the patient is human, dog, cat, horse, or rabbit. The catabolism of lean body mass that occurs in ill or injured patients affects their strength, immune function, wound healing, and overall survival.
50
5 • Nutritional Requirements across Animal Species
Inadequate calorie intake in the hospitalized patient is common due to loss of appetite, an inability to eat or tolerate feedings, vomiting, or dehydration that accompanies many diseases. Because malnutrition can occur quickly in these situations, it is important to provide nutritional support by either enteral or parenteral nutrition if oral intake is not adequate. Just as in humans, the enteral route should be used whenever possible because it is the safest, most convenient, and most physiologically sound method of nutritional support.
Nutritional Assessment Nutritional assessment identifies malnourished patients that require nutritional support, and, more importantly, also identifies patients at risk for malnutrition in which nutritional support will help to prevent malnutrition. Indicators of malnutrition include weight loss, poor haircoat, muscle wasting, signs of poor wound healing, hypoalbuminemia, lymphopenia, and coagulopathies. However, these abnormalities are not specific to malnutrition and often are not present in the early stages of malnutrition. In addition, fluid shifts may mask weight loss in critically ill patients. Therefore, an assessment of factors that may predispose a patient to malnutrition is important to use as a rationale for instituting nutritional support. These factors include anorexia lasting longer than 3 days, serious underlying disease (e.g., trauma, sepsis, peritonitis, or pancreatitis) or condition (e.g., extensive gastrointestinal surgery), and large protein losses (e.g., protracted vomiting, diarrhea, or draining wounds). Nutritional assessment also identifies factors that can affect the nutritional plan, such as electrolyte abnormalities, hyperglycemia, hypertriglyceridemia, or concurrent conditions such as renal or hepatic disease or congestive heart failure. A thorough physical examination and appropriate laboratory analysis should be performed for all patients to assess these parameters.
Nutritional Plan Based on the nutritional assessment, a plan is formulated to meet energy and other nutrient requirements of the patient and at the same time, to address any concurrent condition requiring adjustments to the nutritional plan. Examples include the need for restricted fluid volumes in patients with congestive heart failure or restricted protein intake in those with severe chronic renal failure. The best route of nutrition support-enteral versus parenteral-should be determined on the basis of the underlying disease, the patient's clinical signs and laboratory parameters, and the expected duration of support. Whenever possible, the enteral route should be considered first. If enteral feedings are not tolerated or the gastrointestinal tract must be bypassed, parenteral nutrition should be considered. Tube feedings should be introduced gradually and the target rate should be achieved in 48 to 72 hours.
Just as in humans, meeting the energy, protein, and other nutritional requirements is critical in an illor injured companion animal. Energy requirements are generally calculated to meet resting energy expenditure (REE) as a starting point and then adjusted as necessary. A number of equations have been developed for calculating energy requirements in mammals; unlike the HarrisBenedict equation, they use only body weight and not height, age, or gender for the calculation. The most commonly used equation for mammals is REE =70 x (body weight in kg)o.75. Energy requirements must be reassessed often in an animal receiving enteral nutrition to avoid over- or underfeeding. Further adjustments are made on the basis of the animal's response to feeding, body weight, and changes in underlying condition. Alternatively, indirect calorimetry can be used to more accurately assess energy requirements. For species other than placental mammals, the exponential equation can still be used; however, a different constant must be included to account for differences in metabolic rate (Table 5-6).
Options for Enteral Nutrition One of the difficulties in feeding a hospitalized patient is the animal's high stress level, resulting in anorexia, particularly in cats and exotic species. "Coaxing" techniques can sometimes be helpful to increase food intake in an anorectic patient, such as warming the food or feeding it in a quiet environment. Pharmacologic agents, such as cyproheptadine or benzodiazepines, are sometimes used to initiate feeding behaviors in otherwise anorectic dogs and cats, but rarely produce reliable and adequate results and can have serious side effects. In an animal that will not or cannot consume an adequate number of calories voluntarily and that has adequate gastrointestinal function, enteral nutrition is the route of choice for providing nutritional support," Examples of situations in which tube feeding might be used include animals having anorexia from chronic diseases (e.g., chronic renal failure), animals receiving ventilatory support, animals with disorders of the oral cavity, pharynx, or esophagus (e.g., trauma or side effects of radiation therapy), or animals needing long-term nutritional support (e.g., those with myasthenia gravis,
•
Equations for Calculating Resting Energy Requirements for a Variety of Species" Equation
Species Passerine birds Nonpasserine birds Placental mammals Marsupials Reptiles
129 x 78 x 70 x 49 x 10 x
(body weight (body weight (body weight (body weight (body weight
in in in in in
kgYL75 kg)075 kg)O.75 kg)075 kg)075
* Although all these equations use (body weight in kg)O.75 as the base of the equation, a different constant must be used in each group to account for differences in metabolic rate.
SECTION II • Physiology of the Alimentary Tract
51
megaesophagus, idiopathic hepatic lipidosis, or facial fractures). Contraindications to tube feeding are vomiting or severe malabsorption. A variety of different tubes can be used and the decision of which one to use depends upon factors such as the function of the gastrointestinal tract, the patient's ability to tolerate tube placement, and the risk for aspiration." For all feeding tubes, plain radiography or fluoroscopy is generally used to confirm satisfactory placement before use.
NasoesophagealTube A nasoesophageal (Fig. 5-4) tube is placed through the nares into the distal esophagus. Placement of these tubes usually does not require sedation. Tubes should be secured in place with suture or skin glue, and, for dogs and cats, an Elizabethan collar should be used to prevent inadvertent removal of the tube. Nasoesophageal tubes typically are used only for short-term nutritional support (i.e., less than 3 to 5 days) in dogs and cats. In other species, such as horses, this is the most commonly used type of feeding tube. For dogs and cats requiring nutritional support for longer periods of time, other tubes are preferable.
FIGURE 5-5. An esophagostomy tube in an anorectic cat with hepatic failure. The tube is lightly wrapped and a specially prepared diet is being administered by slow bolus feeding.
Esophagostomy Tube Esophagostomy tubes (Fig. 5-5) are commonly used feeding tubes for dogs and cats owing to their ease of placement and use. Although they do require general anesthesia (or heavy sedation) for placement, they are excellent tubes for long-term feeding. Either red rubber tubes or specially designed silicone esophagostomy tubes can be used. Dogs and cats commonly are fed at home using esophagostomy tubes. Esophagostomy tubes also have been used in horses, turtles, and rabbits (Fig. 5-6).
Gastrostomy Tube Gastrostomy tubes (Fig. 5-7) are another type of tube that can be used for long-term nutritional support in dogs and cats. Like esophagostomy tubes, gastrostomy tubes must be placed with the animal under general anesthesia but can be placed surgically, endoscopically (percutaneous endoscopically placed gastrostomy [PEG]), or by using commercial gastrostomy tube placement devices. Gastrostomy tubes also are commonly
FIGURE 5-4. A nasoesophageal tube in a neonatal foal that is unable to nurse.
FIGURE 5-6. An anorectic turtle with an esophagostomy tube.
52
5 • Nutritional Requirements across Animal Species
FIGURE 5-7. A percutaneous endoscopically placed gastrostomy tube in a cat.
used for home tube feeding in dogs and cats. For animals requiring gastrostomy tube feeding for more than a few months, a low-profile tube can be used.
Jejunostomy Tube Jejunostomy tubes (Fig. 5-8) in dogs and cats are usually placed surgically in the mid-jejunum. Nasojejunal tubes are difficult to place and maintain in animals. Jejunostomy tubes also can be inserted transpylorically through a PEG tube into the jejunum. Generally, jejunostomy tubes are limited to in-hospital use, and commercial liquid diets are administered by continuous rate infusion.
Diets for Tube Feeding Diet selection depends upon the species, the underlying disease, and the type of tube being used." Although -3 way
stopcock
FIGURE 5-8. Placement of a jejunostomy tube in a dog. Jejunostomy tubes are placed surgically into a segment of jejunum and inserted distally 10 to 12 em. (From: Waddell LS, Michel KE: Critical care nutrition: Routes of feeding. Clin Tech Small Anim Pract 1998; 13: 197-203.)
some enteral diets are available for animal species, the selection is not as extensive as that in human medicine. Additionally, some species have very specific requirements that would be difficult to achieve with a commercial enteral diet. Neonatal dogs and cats that cannot nurse are usually fed via an orogastric tube with the mother's milk or with a milk replacer appropriate for the species. Neonatal horses requiring enteral nutritional support, however, are fed via nasoesophageal tubes using mare's milk or an appropriate milk replacer. Adult horses requiring enteral nutrition are fed using commercial human enteral diets, but because horses normally eat a very high fiber diet, they often develop diarrhea when fed with a liquid enteral diet. Younger horses requiring enteral nutrition are typically fed a gruel of water and pelleted commercial horse feed to meet their nutritional requirements. For dogs and cats, there are several commercial veterinary liquid enteral diets that can be used for tube feeding. There also are a variety of different canned therapeutic pet diets that can be mixed with water and fed through an esophagostorny or gastrostomy tube. Some therapeutic pet diets specifically designed for tube feeding are easily mixed with a small amount of water and administered through a tube, whereas others require large volumes of water, grinding with a blender, and straining to be usable for this purpose. Therapeutic diets are available for animals with a variety of underlying disorders, including renal, cardiac, and hepatic failure; gastrointestinal disease; and critical illness. Dietsavailable for critically ill dogs and cats vary among manufacturers, but they are typically high in protein, calorically dense, and supplemented with arginine, zinc, and n-3 polyunsaturated fatty acids. Human enteral diets do not meet canine and feline nutritional requirements; thus, even for short-term use, supplementation with protein, arginine, taurine, and B vitamins is necessary (Table 5-7). Supplementation with other nutrients, including calcium, zinc, and iron, would be necessary if these human products were used long term (see Table 5-7). For animals with nasoesophageal and jejunostomy tubes, liquid diets are required, whereas the larger diameter esophagostomy and gastrostomy tubes can handle diluted therapeutic pet diets. For nasoesophageal, esophagostorny, and gastrostomy tubes, diets are usually administered as a bolus three to six times per day, although animals with difficulty tolerating bolus feedings are sometimes fed more successfully by continuous rate infusion. Animals with jejunostomy tubes are almost always fed by continuous rate infusion via an enteral feeding pump. Mechanical complications of enteral nutrition, such as clogged tubes, pulmonary aspiration, esophageal erosion (for nasoesophageal and esophagostomy tubes), or inadvertent removal of the tube, are possible. Refeeding syndrome can occur after enteral nutrition is instituted. Gastrointestinal problems including vomiting, regurgitation, diarrhea, or abdominal discomfort also can occur and may require changes in diet or frequency of feeding or a switch to parenteral nutrition. Routine monitoring
-
Nutrient
Protein Taurine Arginine Fat Calcium Phosphorus Potassium Magnesium Copper Zinc Iron
SECTION II • Physiology of the Alimentary Tract
53
Comparison of Some Canine and Feline Requirements to Nutrients Supplied by a Common Human Enteral Formula Units gjlOOO kcal gjlOOO kcal gjlOOO kcal gjlOOO kcal gjlOOO kcal gjlOOO kcal gjlOOO kcal gjlOOO kcal mgj 1000 kcal mg/ 1000 kcal mgj 1000 kcal
Ensure Plus HN*
41.8 0.1 1.6 32.7 0.7 0.7 1.2 0.3 1.3 15.3 12.0
Canine Requirements
Feline Requirements
51.4
65.0 0.5 2.6 22.5 1.5 1.3 1.5 0.1 1.3 18.8 20.0
1.5 14.3 1.7 1.4
1.7 0.1 2.1 34.0 23.0
'From Ross Laboratories, Columbus, OH.
of patients with feeding tubes includes body weight; tube patency and feeding tube exit site assessment; signs of volume overload, gastrointestinal intolerance, or pulmonary aspiration; and serum electrolytes. Enteral nutritional support should be continued until the animal is able to eat adequate amounts of food on its own and the feeding tube should not be removed unless the animal is eating adequate amounts voluntarily. A variety of different tubes can be used to provide enteral nutrition for both patients seen in clinical practice and animals used in biomedical research. However, awareness of the requirements of individual species is important for provision of nutritionally complete and balanced diets. In conclusion, a comparison of gastrointestinal physiology and nutrient requirements of other mammals with those of humans is instructive. Applications of human enteral nutritional support regimens require specific modifications for a given animal species. REFERENCES 1. Chivers DJ, Hladik CM: Morphology of the gastrointestinal tract in primates: Comparisons with other mammals in relation to diet. J Morphol 1980;166:337-386. 2. Argenzio RA: General functions of the gastrointestinal tract and their control and integration. In SwensonMJ, ReeceWO (eds): Dukes' Physiology of Domestic Animals. Ithaca, NY, Cornell University Press, 1993, pp 325-335. 3. Young JA, Schneyer CA: Composition of saliva in Mammalia. Aust J Exp Bioi Med Sci 1981;59:1-53. 4. Hamosh M: Lingual and gastric lipase. Nutrition 1990;6:421-428. 5. Kienzle E: Carbohydrate metabolism of the cat. I. Activity of amylase in the gastrointestinal tract of the cat. J Anim Phys Anim Nutr 1993;69:92-101. 6. Maynard LA, Loosli JK, Hintz HF, et al: Digestive processes in different species. Animal Nutrition. New York, McGraw-Hill Book Company, 1979, pp 21-46. 7. Liebler EM,Pohlenz JF,Woode GN:Gut-associated lymphoid tissue in the large intestine of calves. I. Distribution and histology. Vet Pathol 1988;25:503-508. 8. Stokes CR, Bailey M, Wilson AD: Immunology of the porcine gastrointestinal tract. Vet Immunol Immunopathol 1994;43:43-50. 9. Liebler EM,Pohlenz JF,Woode GN:Gut-associated lymphoid tissue in the large intestine of calves. II. Electron microscopy. Vet Pathol
1988;25:509-515. 10. Tizard IA: Immunity at body surfaces. Veterinary Immunology. Philadelphia, WB Saunders, 2002, pp 222-234.
11. Blaxter K: The rmrumum metabolism. Energy Metabolism in Animal Species.Cambridge, UK, Cambridge University Press, 1989, pp 120-146. 12. Rubner M: Uber die einfluss der korpergrosse auf stoff und kraftwechsel. Z Bioi 1883;19:535-562. 13. Voit E: Uber die grossedes energiebedarfes der tiere im hungerzustande. Z Bioi 1901;41 :120-171. 14. Brody S, Procter RC: Growth and Development with Special Reference to Domestic Animals: Further Investigation of Surface Area in Energy Metabolism. University of Missouri Agricultural Experiment Station, 1932, Research Bulletin 116. 15. Kleiber M: Body size and metabolism. Hilgardia 1932;6:315-353. 16. Rogers QR, Morris JG, Freedland RA: Lack of hepatic enzymatic adaptation to low and high levels of dietary protein in the adult cat. Enzyme 1977;22:348-356. 17. MacDonald ML, Rogers QR, Morris JG: Nutrition of the domestic cat, a mammalian carnivore. Annu Rev Nutr 1984;4:521-562. 18. Association of American Feed Control Officials: Official publication. Oxford, IN: Association of American Feed Control Officials, 2002, pp 126-141. 19. Foreman JW: Renal handling of urate and other organic acids. In Bovee KC (ed): Canine Nephrology. Media, PA, Harwal, 1984, pp 135-151. 20. Pion PD, Kittleson MD, RogersQR, Morris JG: Myocardial failure in cats associated with low plasma taurine: A reversible cardiomyopathy. Science 1987;237:764-768. 21. Kittleson MD, Keene B, Pion PD, et al: Results of the multicenter spaniel trial (MUST): Taurine- and carnitine-responsive dilated cardiomyopathy in American Cocker Spaniels with decreased plasma taurine concentration. J Vet Intern Med
1997;11:204-211. 22. Bauer JE: Hyperlipidemias. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders, 2000, pp 283-292. 23. Chalupa W: The role of dietary fat in the productivity and health of dairy cows. In Naylor JM, Ralston SL (eds): Large Animal Clinical Nutrition. St Louis, Mosby Year Book, 1991, pp 304-315. 24. National Research Council: Nutrient Requirements of Horses. Washington, DC, National Academy Press, 1989, pp 3-4. 25. Moore BR, Abood SK, Hinchcliff KW: Hyperlipidemia in 9 miniature horses and miniature donkeys. J Vet Intern Med 1994;8:
376-381. 26. Watson TDG, Love S: Equine hyperlipidemia. Comp Cont Educ Pract Vet 1994;16:89-98. 27. Center SA, Crawford MA, Guida L, et al: A retrospective study of 77 cats with severe hepatic lipidosis: 1975-1990. J Vet Intern Med 1993;7:349-359. 28. Ballard FJ: Glucose utilization in the mammalian liver. Comp Biochem Physiol 1965;14:437-443. 29. Meglasson MD, Matschinsky FM: Pancreatic islet glucose metabolism and regulation of insulin secretion. Diabetes Metab Rev 1986; 2:163-214.
54
5 • Nutritional Requirements across Animal Species
30. Cheeke PR: Nutrition and nutritional diseases. In Manning PJ, Ringler DH, Newcomer CE (eds): The Biology of the Laboratory Rabbit. San Diego, Academic Press, 1994, pp 321-333. 31. Twedt DC, Stemlieb I, Gilbertson SR: Clinical, morphologic and chemical studies on copper toxicosis of Bedlington terriers. J Am Vet Med Assoc 1979;175:269-275. 32. White SD, Bourdeau P, Rosychuk RA, et al: Zinc responsive dermatosis in dogs: 41 cases and literature review. Vet Dermatol
2001;12:101-109.
33. Robbins CT: Wildlife feeding and nutrition. San Diego, Academic Press, 1993, pp 86-87. 34. Newberne PM, Conner MW: The vitamins. In Kaneko JJ (ed): Clinical Biochemistry of Domestic Animals. San Diego, Academic Press, 1989, pp 814-815. 35. Waddell LS, Michel KE: Critical care nutrition: Routes of feeding. Clin Tech Small Animal Pract 1998;13:197-203. 36. Michel KE: Interventional nutrition for the critical care patient: Optimal diets. Clin Tech Small Animal Pract 1998;1:204-210.
II Metabolism and Life Cycle: Pregnancy and Lactation Mary Hise, PhD, RD
CHAPTER OUTLINE Overview Maternal Nutritional Status and Body Weight Energy Carbohydrate Protein Fat Vitamins Minerals Conclusion
OVERVIEW Pregnancy results in significant physiologic alterations that have an impact on the function of every organ system and metabolic pathway of the mother. These metabolic changes occur in relatively small increments as gestation progresses but are profound when measured in totality over the entire gestational period. Consequently, it is critically important to both the mother and the fetus that proper nutrition is maintained and that proper maternal weight management is observed. Although a normal physiologic response, the metabolic stress that accompanies pregnancy places both mother and fetus at risk for an adverse outcome in the absence of proper nutrition and maternal weight gain. Management of proper nutrition and weight during pregnancy requires that maternal body weight as well as physiologic and biochemical values be monitored consistently throughout gestation. In this section the various metabolic changes with key importance to the health and well-being of both mother and fetus and to the mother and child after parturition that occur during pregnancy will be discussed. These changes include significant alterations in plasma volume, red blood cell, and nutrient and hormonal concentrations as pregnancy and lactation occur.
Compared with values in nonpregnant women, during gestation an approximate 50% increase in plasma volume, a 20% increase in red blood cell mass, both increases and decreases in nutrient concentrations, and increases in both estrogen and progesterone levels are seen. The increase in red blood cell mass is not, however, reflected in a concomitant increase in blood hematocrit and hemoglobin. During gestation, both hematocrit and hemoglobin mass concentrations decrease by approximately 13% on average as a result of the significant increase in plasma volume. During pregnancy, blood albumin and most nutrient concentrations decrease whereas concentrations of maternal lipids, including cholesterol, increase. The serum concentrations of several vitamins (8 6, 8 12, folic acid, and vitamin C), generally follow the decline in circulating albumin level. In contrast and with the exception of the level of vitamin A that remains essentially constant, the serum concentration of fat-soluble vitamins increases and generally follows the increase observed during pregnancy in plasma lipid concentrations. In addition to the metabolic changes that accompany pregnancy, the lactating mother requires a different nutritional regimen to meet the nutritional demands of the child while simultaneously maintaining her own proper nutrition.
MATERNAL NUTRITIONAL STATUS AND BODY WEIGHT Research data suggest that maternal nutrient deprivation in early pregnancy may have serious health consequences on the fetus later in life. The hypothesis states that inadequate nutrition during fetal development produces fetal adaptations that are beneficial to short-term survival but pose a significant long-term health risk. The result of deficiencies in fetal nutrition and endocrine status during gestation may therefore predispose an individual to cardiovascular, endocrine, and metabolic disease in adulthood. The fact that low birth weight is statistically associated with increased rates of cardiovascular disease, hypertension, and type 2 diabetes supports this hypothesis.P
57
58
6 • Metabolism and Life Cycle: Pregnancy and Lactation
BmIIII
Recommendations for Prenatal Weight Gain
Body M8lI8 Index (BMI) BMI <19.8 BMI19.8-26.0 BMI >26.0--29.0 BMI >29.0 Twin pregnancy
Recommended Weight Gain
Weight Gain per Week After 12 Weeks 0.5 kg (-lib) 0.4 kg 0.3 kg
12.5-18 kg (28-40 Ib) 11.5-16 kg (25-35 Ib) 7-11.5 kg (15-25 Ib) At least 7.0 kg (15 Ib) 15.9-20.4 kg (34-45 Ib)
0.7 kg
Adapted from Institute of Medicine: Nutrition during Pregnancy. Washington, DC:National Academy of Sciences, 1990; and Brown JE, Carlson M: Nutrition and multifetal pregnancy. J Am Diet Assoc 2000;100:343-348.
The energy demand of the many anabolic processes necessary to maintain maternal health and appropriate fetal development during pregnancy should be balanced by the energy intake of the mother. The prepregnancy nutritional status of the mother greatly influences gestational weight gain and favorable pregnancy outcomes. Additionally, prepregnancy weight influences gestational weight gain. The Institute of Medicine (10M) therefore recommends weight gain ranges during pregnancy that are determined by prepregnancy body mass index (8MI; in kilograms per square meter) measurements (Table 6-1).3 On average, women who have lower 8Mls gain more weight during pregnancy than do women who are overweight or obese at conception. However, variations in gestational weight gain relative to prepregnancy 8MI are routinely reported, which may indicate that additional and compounding factors contribute to favorable outcomes. Gestational weight gain in the second and third trimesters is an important determinant of fetal growth and development. However, factors other than gestational weight gain per se may influence these fetal outcomes. These factors include race, parity, chronologic age, income, and maternal micronutrient status, stress, and disease state. As one would predict, the influence of these and additional factors on gestational weight gain among individuals is highly variable. Consequently, the extent of the individual contribution of each factor is difficult to assess accurately. Despite the lack of clear predictive confidence, however, the current body of evidence supports the hypothesis that maternal gestational weight gain and prepregnancy weight directly influence fetal growth and have an impact on the risk of delivery of a low-birth-weight infant." Maternal nutritional demands during the second and third trimesters have been well studied. The results of these studies suggest that a low gestational weight gain increases the risk of low fetal growth in addition to the risk of giving birth to a low-birth-weight baby. The sources of gestational weight gain are deposition of both lean and fat tissue in both mother and fetus and water retention. Specifically, contributors to weight gain include the fetus, placenta, and amniotic fluid, as well as extracellular fluid, blood volume, and maternal fat stores (Table 6-2). The interaction of these factors suggests that the use of a woman's prepregnancy 8MI is a more reliable predictor of a positive birth outcome than is absolute weight alone. Thus, women may be placed into four different prepregnancy 8MI categories': (1) obese (SMI >29 kg/m''), (2) overweight (8MI >26 to 29 kg/rn") , (3) normal weight
(8MI >19.8 to 26 kg/rn"), and (4) underweight (8MI <19.8 kg/m-). Results of epidemiologic studies reveal that the effect of gestational weight gain on fetal growth is least pronounced in women in the overweight and obese categories than in thinner women. Yet, for an identical weight gain, if underweight women (8MI <19.8 kg/rrr') are compared with their higher prepregnancy 8MI counterparts, these underweight women will generally give birth to smaller babies. It has long been recognized that the risk for negative outcomes is generally higher for lower birthweight babies. As a result, the appropriate weight gain for women with a low 8MI is greater than that for women in the normal 8MI range. For example, if a woman has a prepregnancy 8Mlless than 19.8 kg/m", her weight gain should be approximately 0.5 kg (1.1 Ib) per week for the second and third trimesters compared with a weight gain of approximately 0.3 kg (0.7 Ib) per week for a woman with a prepregnancy 8MI greater than 26 kg/m". Therefore, appropriate gestational weight gain is lower for women who are overweight and obese prepregnancy than for their thinner counterparts. Women with prepregancy 8MI greater than 29 kg/rn'' should be counseled not to gain more than 1104 kg of weight throughout the total pregnancy because excessive weight gain increases the chance of weight retention postpartum."
ENERGY Energy requirements increase during pregnancy due to the metabolic demands of fetal maintenance and the increased workload required for cardiovascular and pulmonary function. Total energy needs for pregnant women range between 2500 and 2700 kcal/day':
DmID
Distribution of Weight Gain During _ _ Pregnancy
Weight Gain (kg)
Location
3.4-3.86 3.4 1.8 1.22 0.9 0.8 0.68 0.45 12.7-13.2
Fetus Fat and protein stores Blood Tissue fluids Uterus Amniotic fluid Placenta and umbilical cord Breast tissue Total weight gain
SECTION III • Nutrient Metabolism
however, significant variations in need may occur due to BM[, activity, age, and stress level. Basal energy expenditure (BEE) accounts for a significant portion of the increased energy requirements during pregnancy. However, variations in BEE may be influenced by maternal prepregnancy energy status, energy intake during pregnancy, and fetal size." Because there is little metabolic demand in the first trimester, BEEdoes not increase linearly throughout pregnancy. In the last trimester, approximately 50% of the increase in BEE may be attributed to fetal demand alone," The new Dietary Reference Intakes (DR[s) for energy published by the Institute of Medicine include the term estimated energy requirement (EER).8 EER is defined as "the dietary energy intake that is predicted to maintain energy balance in healthy, normal weight individuals of a defined age, gender, weight, height and level of physical activity consistent with good health." Calculations for energy requirements for adolescent and adult females are shown in Table 6-3. This EER value may be used to determine total energy requirements in pregnancy. The EER in pregnancy is derived by using the EER of a woman (nonpregnant state) plus a median increase of 8 kcallwk for the second and third trimesters (20 and 34 weeks, respectively) plus the energy deposition required for maternal adaptation and fetal growth and development. The theoretical energy cost of tissue deposition during pregnancy including fetus, placenta, amniotic fluid, and maternal tissues (uterus, breasts, blood, extracellular fluid, and amniotic fluid) has been estimated to be 38,852 total kcal or a mean of 180 keel/day." Therefore, additional energy requirements for a 19- to 50-year-old pregnant woman are 340 kcal during the second trimester and an additional 452 kcal during the third trimester. Estimated energy requirements for pregnancy in adolescents (14 to18 years of age) or adult women (19 to 50 years of age) are shown in Table 6-4. Additional energy intake is recommended only during the second and third trimesters because fetal energy needs and weight gain do not generate a significant demand during the first trimester. _
. •
Estimated Energy Requirements (EERs) for Adolescent and Adult Females
EER for Women 19 Years and Older EER = 354 - 6.91 x age [y] + PA x (9.36 x weight [kg] + 726 x height [m]) Where PA is the physical activity coefficient: PA = 1.00 if PAL is estimated to be ~1.0 <1.4 (sedentary) PA = 1.12 if PAL is estimated to be ~1.4 <1.6 (low active) PA = 1.27 if PAL is estimated to be ~1.6 <1.9 (active) PA = 1.45 if PAL is estimated to be ~1.9 <2.5 (very active) EER for Girls 9 through 18 Years EER = 135.3 - 30.8 x age [y] + PA x (10.0 x weight [kg] + 934 x height [m]) + 25 (kcal for energy deposition) Where PA is the physical activity coefficient: PA = 1.00 if PAL is estimated to be ~1.0 <1.4 (sedentary) PA = 1.16 if PAL is estimated to be ~1.4 <1.6 (low active) PA = 1.31 if PAL is estimated to be ~1.6 <1.9 (active) PA = 1.56 if PAL is estimated to be ~1.9 <2.5 (very active) Adapted from Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Available at www.nap.edu. PAL, physical activity level.
•
Estimated Energy Requirements (EERs) for Pregnancy in Adolescent and Adult Females
14-18 years 1st trimester
2nd trimester 3rd trimester 19-50 years Ist trimester 2nd trimester 3rd trimester
59
EER =adolescent EER + pregnancy energy deposition Adolescent EER + 0 (pregnancy energy deposition) Adolescent EER+ 160 kcal (8 kcal(wk x 20 wks) + 180 kcal Adolescent EER + 272 kcal (8 kcal/wk x 34 wks) + 180 kcal EER =adult EER + pregnancy energy deposition Adult EER + 0 (pregnancy energy deposition) Adult EER + 160 kcal (8 kcal(wk x 20 wks) + 180 kcal Adult EER + 272 kcal (8 kcal/wk x 34 wks) + 180 kcal
Adapted from Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Available at www.nap.edu.
Basal energy requirements for lactation are based on the EER for adolescent or adult women plus energy requirements for milk output and mobilization of maternal tissue reserves (fable 6-5). In well-nourished women, energy requirements are met during the first 6 months of lactation by both diet and mobilization of maternal tissue. Although this mechanism is not obligatory, on average, most well-nourished women experience a mild postpartum weight loss, averaging a deficit of 0.8 kg/mo or approximately 170 kcal/day.v'? Postpartum milk energy output increases during the first 6 months and averages 500 kcallday, whereas milk energy output in the second 6 months is more variable. Average estimates of milk energy output during the second 6 months of lactation were set at 400 kcal/day."
CARBOHYDRATE Carbohydrate metabolism during pregnancy is highly complex. Energy demands of the fetus and mother are interwoven and quantification of dietary carbohydrate
•
14-18 years 1st 6 mo
2nd 6 mo 19-50 years 1st 6 mo 2nd 6 mo
Estimated Energy Requirements (EERs) for Lactation in Adolescent and Adult Females EER = adolescent EER + milk energy output weight loss Adolescent EER + 500 - 170 (milk energy output - weight loss) Adolescent EER + 400 - 0 (milk energy output - weight loss) EER = adult EER + milk energy output weight loss Adult EER + 500 - 170 (milk energy output - weight loss) Adult EER + 400 - 0 (milk energy output - weight loss)
Adapted from Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Available at www.nap.edu.
60
6 • Metabolism and Life Cycle: Pregnancy and Lactation
intake requirements from exogenous sources is not only difficult to determine but also is highly variable. What is known is that energy requirements increase during pregnancy: the mothers energy stores meet some of these requirements; others are met by exogenous uptake and a diet rich in carbohydrate to support desired fetal development and maternal health. During normal pregnancy, high-earbohydrate meals result in postprandial hyperglycemia. However, because of the glucose demand of the fetus, the mothers fasting blood sugar levels decline throughout pregnancy. Additionally, pregnancy is associated with insulin resistance and compensatory hyperinsulinemia. The increase in glucose utilization during pregnancy results in high respiratory quotients for both basal metabolic rates and total energy expenditure compared with those in the postpartum period.!':" Metabolic stress and/or gestational diabetes may result in sustained elevations in maternal glucose levels. A high maternal blood glucose level is reflected in fetal hyperglycemia and hyperinsulinemia. Women with impaired glucose tolerance during pregnancy have an increased risk for poor pregnancy outcomes. Poor maternal glycemic control is associated with macrosomia, congenital anomalies, perinatal mortality, and prematurity. 13 Additionally, maternal complications increase significantly with high glucose concentrations and may include caesarean delivery and clinical chorioamnionitiS. 14 It is recommended that in women with preexisting diabetes a level of hemoglobin Ale less than 1% above normal should be achieved and maintained. Some recommendations for pregnant women with gestational diabetes are that fasting blood glucose levels should not exceed 90 mg/dL and 2-hour postprandial values should not exceed 120 mg/dL.I5-17 Conversely, in the absence of adequate glucose intake during pregnancy, maternal ketosis may occur. Although ketone bodies may be metabolized to some extent by the developing fetus and circulating ketoacids are common in pregnant women, severe maternal ketonemia and ketonuria are believed to have a generally negative effect on the fetus. To assure adequate glucose provision as a fuel source to both maternal and fetal brains, the Recommended Dietary Allowance eRDA) for carbohydrate during pregnancy is 175 g/day,"
protein turnover rates during gestation have been shown to influence fetal growth." The RDAs for protein and for lactation during the second and third trimesters of pregnancy are equivalent at 1.1 or 25 g/day of additional protein," Supplemental protein in excess of 25 g/day may be required for illness or twin births. In severe stress states, protein requirements may be substantially increased but should not exceed 2 g/kg/day.2o In conjunction with overall protein requirements, the RDAs for essential amino acids in both pregnancy and lactation have also been published (Table 6-6). Requirements for these amino acids are used to develop reference amino acid patterns to aid in evaluation of protein quality of diets. Because limited data exist for amino acid requirements during pregnancy, essential amino acid determinations reflect the RDAincrease in protein requirements during pregnancy. Amino acid requirements for lactation are based upon the average amounts of individual amino acids secreted in human milk during the first 6 months of lactation for an adult woman of standard reference weight.
FAT Lipid metabolism in pregnancy is influenced by endocrine status, dietary intake, and nutrient transfer to the fetus. Lipid metabolism during gestation is characterized by elevations in free fatty acids, triglyceride, and cholesterol values compared with those seen in a nonpregnant state. Serum triglyceride values progressively increase 200% to 400% above normal, peaking at the 40th week of gestation. Cholesterol values gradually increase between 25% and 40% throughout pregnancy." Maternal fat stores are predominately gained between the 10th and 30th weeks of gestation. In late pregnancy, there is an acceleration of fat utilization by the fetus and accelerated breakdown of maternal fat depots. Maternal adiposity gains provide an energy reserve of approximately 30,000 kcal." Fatty acids in the n-6 and n-3 families are extremely important in pregnancy. Polyunsaturated fatty acids in the n-6 family are required during pregnancy and
• . ••
PROTEIN Protein metabolism is enhanced during pregnancy and supports the synthesis of maternal and fetal tissues. However, because of variations in protein turnover rates, protein synthesis rates during pregnancy are not constant. Alterations in protein metabolism during late pregnancy favor nitrogen retention. Concurrently, the maternal blood concentration of plasma amino acids declines by 15%to 25% during late pregnancy, reflecting increased placental amino acid transfer and fetal uptake. 18 Serum albumin levels decline by 8% to 10% in the first 10 weeks of pregnancy and return to normal by 9 to 10 weeks postpartum. Additionally, maternal visceral lean body mass and
•
Recommended Dietary Allowances (RDAs) for Amino Acids for All Ages in Pregnancy and Lactation
Amino Acid (mg/kg/day) Histidine Isoleucine Leucine Lysine Methionine + cysteine Phenylalanine + tyrosine Threonine Tryptophan Valine
Pregnancy
lactation
18
19 30
25 56 51
25 44
62 52 26
26
51 30
7 31
9 35
Adapted from Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatly Acids, Cholesterol, Protein and Amino Acids. Available at www.nap.edu.
SECTION III • Nutrient Metabolism
lactation for cellular membrane synthesis and serve as substrates for eicosanoid production. Approximately 85% to 90% of n-6 fatty acids consumed in the diet are in the form of linoleic acid. n-3 fatty acid requirements in pregnancy are increased; specifically docosahexaenoic acid (DHA) is required for membrane synthesis of neuronal synapses and retina development as evidenced by the high levels of DHA that accumulate in fetal gray matter of the cerebral cortex and in the fetal retina. Dietary a-linolenic acid may be converted to DHA in the liver; however, it appears that conversion is limited and dietary DHA results in higher fetal accretion than does the synthesis of DHA from a-linolenic acid. Olsen and associatesf suggested that dietary supplementation of n-3 fatty acids may prolong the duration of gestation. Additionally, researchers have suggested that a dietary source of DHA may increase visual acuity, motor skills, and language development in premature infants.23•24 Daily intakes for a-linolenic acid, linoleic acid, and DHA in pregnant Canadian women have been reported to be 1.6 g/day, 11.2 g/day, and 160 mg/day, respectively." Because of the lack of evidence to establish precisely the requirements for a-linolenic acid and linoleic acid in pregnancy, an Adequate Intake (AI) level has been set that is based on the median intake of a-linolenic and linoleic acid in the United States." Al levels for linoleic acid in pregnancy and lactation are set at 13 g/day. Al levels for a-linolenic acid have been determined to be 1.4 and 1.3 g/day for pregnancy and lactation, respectively. For these essential fatty acids, the fetus depends solely on maternal fatty acid status and dietary intake." Therefore, the diet during pregnancy should contain sufficient essential polyunsaturated fatty acids to meet both maternal and fetal demands.
VITAMINS Growth and development of the fetus depend on an adequate maternal supply of micronutrients. Vitamin metabolism in pregnancy may be influenced by maternal age and prepregnancy nutritional state, smoking, parity, and socioeconomic status. In industrialized countries, micro-nutrient supplementation during pregnancy is common. However, health providers recommend caution with the indiscriminate use of any single or high-dose vitamin supplement because of possible adverse effects and the limited benefit in well-nourished populations. Conversely, single and multiple vitamin deficiencies have been reported in all trimesters of pregnancy in women taking prenatal vitamins although no adverse fetal or neonatal outcomes were associated with reduced levels." The DRls for vitamins in pregnant and lactating women are shown in Table 6-7. Percent increases in DRls for all vitamins compared with those of nonpregnant or nonlactating women range from 0% (vitamin D) to 86% (vitamin A). During pregnancy, the vitamin with the largest increase in requirement is folate (50%) and during lactation it is vitamin A (86%). Requirements are increased during pregnancy and lactation for riboflavin,
61
thiamin, and niacin owing to increased energy demands of the fetus and mother." In pregnancy, there is a gradual rise in serum vitamin D and E levels. Vitamin D requirements can usually be met with adequate exposure to sunlight and, with the exception of high-risk women living in northern latitudes or women who have little or no sun exposure, need not be supplemented.P Compared with requirements in nonpregnant or nonlactating women, vitamin D or vitamin K requirements for pregnancy and lactation are unchanged. Additionally, there is no increase in the vitamin E requirement for pregnancy above that for adult, nonpregnant women. Serum ascorbic acid concentrations decrease in pregnancy because of hemodilution and fetal tissue demands. Compared with the RDA for vitamin C in adult women, vitamin C requirements increase by 13% and 60% during pregnancy and lactation, respectively. The recommendation is that vitamin C intake should not exceed 2g/day owing to the risk of osmotic diarrhea and isolated reports of potential risks to the fetus.31}-32 Folate requirements increase by 50% during pregnancy compared with those for nonpregnant females of childbearing age, primarily because of increased maternal and fetal demands for cellular division. Folate RDAs are expressed in dietary folate equivalents, which take into account the greater bioavailability of synthetic folic acid compared with naturally occurring folate found in food. An AI value for choline was set by the 10M in 1998.28 Data for choline requirements during pregnancy and lactation are limited, however based on human and animal data it appears that pregnancy increases the requirements due to depletion of maternal stores and fetal and placental accumulation values." Because of the high choline content of human milk, choline requirements increase by approximately 30% in lactation compared with the AI for nonpregnant women. Tolerable Upper Intake Levels (ULs) have not been set for pantothenic acid, riboflavin, thiamin, vitamin B12, and vitamin K due to lack of data on adverse effects. However, the lack of ULs does not mean that excessive intakes of these nutrients are necessarily safe. The following paragraphs focus on several vitamins, for which an association of supplementation, lack of sufficient dietary intake, and risk for adverse outcome have been definitively demonstrated. Serum vitamin A concentrations have been directly correlated with hemoglobin status. In developing countries, vitamin A deficiency during pregnancy is associated with night blindness and anemia, and supplementation trials have resulted in decreased maternal morbidity and mortality.F" In contrast, high-dose preformed vitamin A intake in early pregnancy is associated with teratogenic risk. Intakes greater than 4800 mg of preformed vitamin A from all sources have been suggested as the threshold at which risk for fetal malformations substantially increases." No adverse effects have been demonstrated at supplementation doses up to 3000 mg/day, which is the established UL for vitamin A in both women of child-bearing age (> 19 years) and pregnant and lactating women (>19 years)."
400 425
450 450
550 550
3,000 3,500
25 30
30 30
35 35
NDt
NO
AI
AI
Choline (mgfday)
800 1,000
17
500 500
30 35
17
18 18
14 14
RDA
Niacin (mgfday)
600 600
400 400
RDA
Folate (}!g/day)
NO
ND
7 7
6 6
5 5
AI
NO
ND
1.6 1.6
1.4 1.4
1.0 1.1
RDA
Riboflavin (mgfday)
ND ND
1.4 1.4
1.4 1.4
1.0 I.l
RDA
Thiamine (mgfday)
2,800 3,000
1,200 1,300
750 770
700 700
RDA
Vitamin A {J.tg/day)
80 100
2.0 2.0
1.9 1.9
1.2 1.3
RDA
~
(mgfday)
Vitamin
ND ND
2.8 2.8
2.6 2.6
2.4 2.4
RDA
Vitamin B 12 (J..1g/day)
2,000
I,BOO
115 120
80 85
65 75
RDA
Vitamin C (mg/day)
50 50
5 5
5 5
5 5
AI
Vitamin D (}!g/day)
BOO 1,000
19 19
15 15
15 15
RDA
Vitamin E (mgfday)
ND ND
75 90
75 90
75 90
AI
{J.tg/day)
K
Vitamin
maximum level of daily nutrient intake that is likely to pose no risk of adverse effects. Unless otherwise specified, the UL represents total intake from food, water, and supplements. tND, not determinable because of a lack of data on adverse effects in this age group. Source of intake should be from food only to prevent high levels of intake. Adapted with permission from the Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1997); Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6 , Folate, Vitamin B12 , Pantothenic Acid, Biotin, and Choline (1998); Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000) and Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington, DC, National Academy Press, 2001.
a UL, the
RDA/AI Females Sl8yr 19-50 yr Pregnancy S18yr 19-50 yr Lactation S18yr 19-50 yr Tolerable upper level (UL)8 for pregnancy or lactation S18yr 19-50 yr
Biotin (}!g/day)
Pantothenic Acid (mgfday)
. . Dietary Reference Intakes (DRls) for Vitamins in Pregnancy and Lactation Compared to Recommended Daily Allowances (RDAs) or Adequate Intake Levels (Als) for Nonpregnant, Nonlactating Females
<:5"
;;,
III
III
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Vitamin A supplementation has been investigated as a relatively low-cost treatment to inhibit human immunodeficiency virus (HIV) transmission from HIVinfected pregnant women to their unborn children and to improve overall pregnancy outcomes. However, in a recent review of clinical trials, Shey and associates" concluded that there is insufficient evidence to support recommendations of vitamin A supplementation to prevent HIV transmission from an HIV-infected woman to her child. Additionally, Fawzi'" found no maternal or fetal benefit with vitamin A supplementation in HIVinfected women for improving pregnancy outcomes; however, multivitamin supplementation in this population decreased the risk of fetal death, low birth weight, and preterm birth. Periconceptual folic acid supplementation is often recommended as standard prenatal care. Clearly, folate supplementation programs in both developing and developed countries show clear benefits for reduction of risk of poor pregnancy outcomes. The consistent association of reduced neural tube defects in the offspring of women with increased folate status" resulted in the fortification of grains in the United States with folic acid (140 mgllOO g of grain)." It was also recommended that women capable of child bearing take a folic acid supplement of 400 mg/day beyond intake of folate from food." Plasma folate and total homocysteine concentrations were improved," and the occurrence of neural tube defects at birth dropped 19% after supplernentation.f Although it is difficult to measure the exact increase in folate intake achieved by grain fortification, estimates are almost double the goal increment in intake.f Because both serum and red blood cell folate concentrations are significantly lower in pregnant women who smoke." intervention trials with periconceptual folate supplementation in these women are indicated to measure the potential outcome of reduction in fetal anomalies associated with smoking.
MINERALS The conditions of pregnancy and lactation significantly alter the nutritional requirements for mineral micronutrients. Generally, higher intakes of most minerals are needed to prevent adverse outcome and to maintain proper pre- and postnatal nutrition.P'" See Table 6-8 for a summary of these data. The 10M recommends that for women aged 19 to 50 years, the RDAs for copper (900 mg/day) and zinc (8 mg/day) increase approximately 11 % and 37.5%, respectively, during pregnancy and approximately 44% and 50%, respectively, during lactation. Such increased nutritional demands for all minerals are not, however, constant for both conditions. Within the same age range, the 10M recommends that the RDA for iron (18 mg/day) increase approximately 50% during pregnancy but decrease approximately 50% during lactation." For some minerals, such as calcium, the 10M recommends no change in Als during pregnancy or lactation (1000 mg/day) relative to the requirements for a healthy nonpregnant or lactating female
63
(1000 mg/day). The variation in recommended RDAs and/or Als for different minerals reflects the physiologic changes during pregnancy and lactation that lead to higher compensatory absorption rates or the increased demand for these minerals. Because of these increased demands and/or the requirement to maintain mineral intake, it is possible for deficiencies to occur. Such deficiencies may arise as a result of underlying diseases that lead to malabsorption, certain cultural dietary restrictions and/or the availability of these minerals within the diet. The following paragraphs focus upon several minerals for which an association between lack of sufficient dietary intake and risk for adverse outcome has been definitively demonstrated. An increased need for iron results from the increased demand for erythrocyte production (red blood cell hemoglobin) owing to the increased physiologic requirement for adequate oxygenation of maternal and fetal tissues. The most significant expansion of hemoglobin mass occurs during the second and third trimesters; however, the exact timing of the increase remains unclear. Low hemoglobin and hematocrit levels may be used to assess iron deficiency, whereas high hemoglobin levels may indicate poor blood volume expansion in the second trimester. Hemoglobin and hematocrit levels less than 11 mg/dL and 33% in the first and third trimesters and less than 10.5 mg/dL and 32% in the second trimester may indicate a possible iron deficiency." Additionally, normal development of the placenta and fetus requires increased iron availability. Depending upon the amount of usable iron available in the diet, different levels of dietary increase are recommended. The RDA for iron recommended by the 10M for healthy nonpregnant women 19 to 50 years of age is 18 mg/day and for similarly aged pregnant or lactating women is 27 mg/day. In contrast, the RDA for high bioavailable iron recommended for nonpregnant or nonlactating women aged 19 to 60 years by the Food and Agriculture Organization of the United Nations/World Health Organization is 11 mg/day and for similarly aged pregnant or lactating women is between 31 and 61 mg/day." There is substantial evidence that iron deficiency is the main cause of anemia in women who live in most developing and in many developed countries. Use of iron supplementation either corrects or prevents anemia. Clearly, there is an overall health benefit associated with proper iron intake. However, it is much less clear what effect mild to moderate anemia may have on pregnancy outcomesf and, consequently, what actual benefit will be received from iron supplementation. What is clear is that severe anemia can lead to maternal mortality and harm to the fetus. Because anemia may be caused by factors other than dietary iron deficiency, it is important to recognize that iron supplementation alone may not provide a successful reproductive outcome. Nonetheless, supplementation of iron during pregnancy is justified, regardless of dietary or other indicators, because of the overall general health benefits of maintaining adequate iron stores.' The Centers for Disease Control and Prevention recommend at least 30 mglday of iron supplement for all pregnant women that should begin after the first prenatal visit."
2,500 2,500
NDt ND
44 45
29 30
24 25
8,000 10,000
1,300 1,300
1,000 1,000
900
890
RDA
(j..lg/day)
Copper
10 10
3 3
3 3
3 3
AI
fluoride (mg/day)
900 1,100
290 290
220 220
ISO 150
RDA
Iodine (j..lg/day)
45 45
10 9
27 27
IS 18
RDA
Iron (mg/day)
350' 350'
360 310-320
350-360
400
360 310-320
RDA
Magnesium (mg/day)
11
9
2.6 2.6
2.0 2.0
1.6 1.8
AI
Manganese (mg/day)
1,700 2,000
50 50
50 50
43 45
RDA
Molybdenum (j..lg/day)
3,500 3,500
1,250 700
1,250 700
1,250 700
RDA
Phosphol1Ul (mg/day)
400
400
70 70
60 60
55 55
RDA
34 40
13 12
11
12
9 8
RDA
Selenium Zinc (j..lg/day) (mg/day)
*UL, the maximum level of daily nutrient intake that is likely to pose no risk of adverse effects. Unless otherwise specified, the UL represents total intake from food, water, and supplements. tND, not determinable because of lack of data of adverse effects in this age group. Source of intake should be from food only to prevent high levels of intake. 'The ULs for magnesium represent intake from a pharmacologic agent only and do not include intake from food and water. Adapted with permission from the Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride (1997); Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000); and Dietary Refemce Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington, DC, National Academy Press, 2001.
19-50 yr
~18yr
1,300 1,000
1,300 1,000
1,300 1,000
AI
AI
Tolerable upper level (UL)* for pregnancy or lactation
19-5Oyr
~18yr
Lactation
19-5Oyr
~18yr
Pregnancy
19-5Oyr
~18yr
RDA/AI Females
Chromium (j..lg/day)
Calcium (mg/day)
. . Dietary Reference Intakes (ORis) for Minerals in Pregnancy and Lactation Compared with Recommended Daily Allowances (RDAs) or Adequate Intake Levels (Als) for Nonpregnant, Nonlactating Females
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SECTION III • Nutrient Metabolism
There are more than 300 different enzymatic reactions that require either copper or zinc as enzyme cofactors that must function during pregnancy and after birth. Connective tissue development and maintenance, utilization of iron and possible specific aspects associated with central nervous system function are dependent upon copper-requiring systems. Additionally, several activities associated with DNA function (i.e., gene expression) are significantly dependent upon proteins that require zinc. Consequently, both of these minerals significantly influence the appropriate expression of normal cellular processes that develop and maintain cells, tissue, and organ system function. [t has, however, been difficult to determine the precise human dietary requirements for these two minerals during pregnancy. The 10M reported that there were no data available to provide an estimated average requirement (EAR) during pregnancy for copper. As a result, the [OM states that the EAR is "based on estimates of the amount of copper that must be accumulated during pregnancy to account for the fetus and products of pregnancy.?" For copper requirements during lactation, estimates are based on amounts required for normal adolescent girls and women in addition to the amount of copper lost through secretion on a daily basis in human milk. There is evidence from animal studies that copper absorption increases during lactation; however, similar data are not yet available for humans. During pregnancy, the total amount of zinc that accumulates in maternal plus fetal tissues ranges from 0.08 rng/day during the first quarter to 0.73 mg/day during the fourth quarter." Consequently, sufficient zinc intake to account for normal maintenance and increased need during pregnancy is recommended. Zinc is lost by secretion during lactation, but the amount declines from 4 mg/l, at 2 weeks postpartum to 1.2 mg/L at 24 weeks postpartum.tv" This decline in zinc secretion along with the release of zinc postpartum owing to blood volume decrease and uterine changes led to an increased requirement for absorbed zinc during lactation estimated to be 1.35 mg/day. The effects of zinc and copper deficiency on adverse reproductive outcomes have not yet been clearly defined.' Whereas experimental animal data show that zinc deficiency results in fetal growth retardation and developmental defects, similar data are not conclusive for humans. In a study of more than 3400 pregnant women, there was no correlation between zinc blood levels and pregnancy outcomes.50 However, other human studies suggest that adverse pregnancy outcomes are associated with zinc deficiencies." One important consideration involves the interactions of iron, copper, and zinc with one another. In 1990 the [OM recommended that if an iron supplement of greater than 30 rug/day is taken, zinc should also be supplemented.' Because zinc is known to inhibit copper absorption, if a zinc supplement is used, a concomitant supplement of 2 mg/day copper is recommended. lt is important to keep in mind, however, that whereas there are no data indicating adverse reactions between zinc and other micronutrients when zinc is supplied by food, there are data showing adverse nutrient interactions when zinc is supplied
65
as a supplement. Consequently, the effect on copper status is used to generate the ULs of zinc from food, water, and supplements. The recommended UL values of 40 mg/day for zinc for pregnant and lactating women are the same as those for nonpregnant and nonlactating
women." The importance of calcium during pregnancy and lactation is clear. Calcium within teeth and bones accounts for approximately 99% of total body calcium and represents up to 2% of total body weight. The dynamic activity of bone tissue via osteoclast-driven bone resorption and osteoblast-driven bone formation results in relatively constant flux of bone calcium deposition. As a consequence, proper skeletal development and maintenance are critically dependent upon calcium adequacy. Additionally, calcium is required for various cellular processes including nerve signal transmission, muscle contraction, and intracellular signals required for cellular activation and response to other physiologic systems. With the exception of foods high in oxalic acid and/or phytic acid, most food sources of calcium provide this mineral equally well and therefore differ primarily in their available calcium content availability rather than bioavailability. Up to 30 g of calcium are transferred to the fetus during pregnancy.' The majority of this transfer occurs during the third trimester, the source of which is the increased intestinal absorptive capacity of calcium by the mother. A possible explanation for this increase in absorptive capacity is the increase in the amount of activated vitamin D and vitamin D binding protein that occurs during pregnancy.52-54 Total serum calcium levels decrease during pregnancy; however, serum ionized calcium levels decrease only slightly and remain in the physiologic range throughout gestation." One concern is that the maternal skeleton serves as a reserve for fetal calcium requirements. Although there are some conflicting data, on the basis of bone density and other studies, the 10M feels that the concern that maternal bone mass may be used as a reservoir for fetal calcium needs is unwarranted.v-" Consequently, as long as the amount of dietary calcium is sufficient to provide nonpregnant women with appropriate bone accretion, the AIof calcium need not be increased during pregnancy, remaining at 1000 mg/day of calcium for pregnant and nonpregnant women aged 19 to 50 years." In contrast to findings during pregnancy, most studies reveal that neither serum 1,25-dihydroxyvitamin D nor the intestinal absorptive capacity of calcium increase during lactation." Maternal calcium intake is not associated with milk calcium concentrations during lactation.F Instead, in the early months of lactation, calcium is lost from the maternal skeleton, averaging 3% to 5% decreases in the spine and hip. This loss is not altered by an increase in dietary calcium intake. Recovery of bone loss associated with lactation occurs during the last months of lactation and after weaning." Consequently, the 10M finds no evidence to support an increase in AI of calcium because of lactation. Consequently, the 10M recommendations for the Als for calcium for lactating and nonlactating women aged 19 to 50 years are 1000 mg/day.t"
66
6 • Metabolism and Life Cycle: Pregnancy and Lactation
Calcium deficiency is rarely seen during pregnancy. However, in the presence of allergies to milk and/or other dairy products or because of physiologic dysfunctions that impair calcium utilization, it is possible for a calcium deficiency to occur. Relative deficiencies in calcium intakes have been suggested to contribute in part to the development of preeclampsia, and low urinary calcium to creatinine ratios may be a screening mechanism for women at greatest risk.58.59 Given the potential risk factors and the impact upon fetal skeletal development during pregnancy, a calcium and vitamin D supplement might be warranted.'
CONCLUSION Nutritional adequacy during pregnancy and lactation is essential for positive pregnancy outcomes and infant development. Routine nutritional assessment is vital to identify individuals at risk and to provide timely nutritional interventions. Nutritional goals should include optimization of prep regnancy nutritional status, appropriate weight gain for each trimester of pregnancy, and appropriate macro- and micronutrient supplies to support demands of the fetus and lactation requirements. Proper nutritional support during pregnancy with early and regular prenatal care reduces risk and promotes positive pregnancy outcomes. REFERENCES I. Godfrey KM, Barker DJP: Fetal programming and adult health. Public Health Nutr 2001;4:611-624. 2. Godfrey KM, Barker DJP: Maternal nutrition in relation to fetal and placental growth. Eur J Obstet Gynecol Reprod BioI 1995;61:15-22. 3. Institute of Medicine: Nutrition During Pregnancy. Part I: Weight Gain. Part II: Supplements. Washington, DC, National Academy Press, 1990. 4. Cogswell ME, Serdula MK, Hungerford DW, et al: Gestational weight gain among average-weight and overweight women-What is excessive? Am J Obstet Gynecol 1995;172:705-712. 5. Kaiser LL, Allen L: Nutrition and lifestyle for a healthy pregnancy outcome-Position of ADA. J Am Diet Assoc. 2002;102:1479-1490. 6. King JC, Butte NF, Bronstein MN, et al: Energy metabolism during pregnancy: Influence of maternal energy status. Am J Clin Nutr I 994;59(suppl):439s-445S. 7. Hytten FE: Nutrition. In Hytten FE, Chamberlain G (eds): Clinical Physiology in Obstetrics, Oxford, UK, Blackwell Scientific, 1991. 8. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Energy,Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Washington, DC, National Academy Press, 2002. 9. Butte NF, Wong WW, Hopkinson JM: Energy requirements of lactating women derived from doubly labeled water and milk energy output. J Nutr 2001;131:53-58. 10. Butte NF, Hopkinson JM: Body composition changes during lactation are highly variable among women. J Nutr 1998;128(suppl): 3815-385S. II. Assel B, Rossi K, Kalhan S: Glucose metabolism during fasting through human pregnancy: Comparison of tracer method with respiratory calorimetry. Am J Physiol 1993;265:E351-E356. 12. Kalhan SC, Oliven A, King KC, et al: Role of glucose in the regulation of endogenous glucose production in the human newborn. Pediatr Res 1986;20:49-52. 13. Tallarigo L, Giampietro 0, Perino G, et al: Relation of glucose tolerance to complications of pregnancy in nondiabetic women. N Engl J Med 1986;315:989-992.
14. Scholl TO, Sowers M, Chen X, et al: Maternal glucose concentrations influences fetal growth, gestation, and pregnancy outcomes. Am J EpidemioI2001;154:514-520. 15. American Diabetes Association: Preconception care of women with diabetes. Diabetes Care 2001;24(suppl):66s-68S. 16. American Diabetes Association: Gestational diabetes mellitus. Diabetes Care 2001;34(suppl):775-79S. 17. Jovanovic-Peterson L, Peterson CM: Dietary manipulation as a primary treatment strategy for pregnancies complicated by diabetes. J Am Coli Nutr 1990;9:320-325. 18. King JC: Physiology of pregnancy and nutrient metabolism. Am J Clin Nutr 2000;71 (suppl):121Bs-1225S. 19. Duggleby SL, Jackson AA: Relationship of maternal protein turnover and lean body mass during pregnancy and birth length. Clin Sci 2001;101:65-72. 20. Matarese LE, Gottschlich MM: Pregnancy. Part V: Nutrition support throughout the life cycle. Contemporary Nutrition Support Practice, 2nd ed. Philadelphia, WB Saunders, pp 337-343. 21. Hachey DL: Benefits and risks of modifying maternal fat intake in pregnancy and lactation. Am J Clin Nutr 1994;59(suppl):454S464S. 22. Olsen SF, Sorensen JD, Secher NJ, et al: Randomized controlled trial of effect of fish oil supplementation on pregnancy duration. Lancet 1992;339:1003-1007. 23. OConner Dl, Auestad N, Jacobs J: Growth and development in preterm infants fed long-ehain polyunsaturated fatty acids: A prospective randomized controlled trial. Pediatrics 2001;108: 359-372. 24. SanGiovanni JP, Parra-Cabrera S, Colditz GA, et al: Meta-analysis of dietary essential fatty acids and long chain polyunsaturated fatty acids as they relate to visual resolution acuity in healthy preterm infants. Pediatrics 2000;105:1292-1298. 25. Innis SM, Elias SL: Intakes of essential n-6 and n-3 polyunsaturated fatty acids among pregnant Canadian women. Am J Clin Nutr 2003;77:473-478. 26. Al MD, van Houwelingen AC, Hornstra G: Long-ehain polyunsaturated fatty acids, pregnancy, and pregnancy outcomes. Am J Clin Nutr 2000;71 (suppl) 2855-291S. 27. Baker H, DeAngelis B, Holland B, et al: Vitamin profile of 563 gravidas during trimesters of pregnancy. J Am Coli Nutr 2002; 21:33-37. 28. Institute of Medicine: Dietary Reference Intakes. Thiamin, Riboflavin, Niacin, Vitamin B6 , Folate, Pantothenic Acid, Biotin and Choline. Washington, DC, National Academy Press, 1998. 29. Ladipo OA: Nutrition in pregnancy: Mineral and vitamin supplements. Am J Clin Nutr 2000;72(suppl):2805-290S. 30. Ballin A, Brown EJ, Doren G, et al: C-induced erythrocyte damage in premature infants. J Pediatr 1988;113:114-120. 31. Powers HJ, Loban A, Silvers K, et al: Vitamin C at concentrations observed in premature babies inhibits the ferroxidase activity of ceruloplasmin. Free Radic Res 1995;22:57-65. 32. Institute of Medicine: Dietary Reference Intakes. Vitamin C, Vitamin E, Selenium and Carotenoids. Washington, DC, National Academy Press, 2000. 33. West KP, Katz J, Khatry SK, et al: Double blind, cluster randomized trial of low dose supplementation with vitamin A or B-carotene on mortality related to pregnancy in Nepal. Br Med J 1999;318:570-575. 34. Suharno D, West CE, Muhilal, et al: Supplementation with vitamin A and iron for nutritional anemia in pregnant women in West Java, Indonesia. Lancet 1993;342:1325-1328. 35. Rothman KJ, Moore LL, Singer MR, et al: Teratogenicity of high vitamin A intake. N Engl J Med 1995;333:1369-1373. 36. Institute of Medicine: Dietary Reference Intakes. Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine. Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc. Washington, DC, National Academy Press, 2001. 37. Shey WI, Brocklehurst P, Sterne JA: Vitamin A supplementation for reducing the risk of mother-to-ehild transmission of HIV infection. Cochrane Database SystRev 2002;CD003648. 38. Fawzi WW, Msamanga G, Spiegelman D, et al: Randomized trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-l-infected women in Tanzania. Lancet 1998;351: 1477-1482. 39. Lumley J, Watson L, Watson M, et al: Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev 2001;CD001056.
SECTION III • Nutrient Metabolism 40. U.S. Department of Health and Human Services, Food and Drug Administration: Folic acid; proposed rules. Fed Regist 1993;21: 53293-53294. 41. Jacques PF, Selhub J, Bostom AG, et al: The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-1454. 42. Honein MA, Paulozzi LF, Matthews TJ, et al: Impact of folic acid fortification of the USfood supply on the occurrence of neural tube defects. JAMA 2001;285:2981-2986. 43. Quinlivan EP, Gregory JF: Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 2003;88: 221-225. 44. McDonald SD, Perkins SL, Jodouin CA, et al: Folate levels in pregnant women who smoke: An important gene/environment interaction. Am J Obstet GynecoI2002;187:62Q-625. 45. Yip R: Significance of an abnormally low or high hemoglobin concentration during pregnancy: Special consideration of iron nutrition. Am J Clin Nutr 2oo0;72(suppl):272S-279S. 46. Centers for DiseaseControl and Prevention: Recommendations to prevent and control iron deficiency in the United States. MMWR 1998;47:1-36. 47. Swanson CA, King, JC: Zinc and pregnancy outcome. Am J Clin Nutr 1987;46:763-771. 48. Krebs NF, Reidinger CJ, Hartley S, et al: Zinc supplementation during lactation: Effects on maternal status and milk zinc concentrations. Am J Clin Nutr 1995;61:1030-1036. 49. Krebs NF: Zinc supplementation during pregnancy. AM J Clin Nutr 1998;68(suppl):509S--512S.
67
50. Tamura T, Goldenberg RL,Johnston KE, et al: Maternal plasma zinc concentrations and pregnancy outcome. Am J Clin Nutr 2000;71: 109-113. 51. King J: Determinants of maternal zinc status during pregnancy. Am J Clin Nutr 2000;71 (suppl):1334S-1343S. 52. Bouillon R, Van Assche FA, Van Baelan H, et al: Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxy vitamin D3• Significance of the free 1,25-dihydroxy vitamin D3 concentration. J Clin Invest 1981;67:589-596. 53. Cross NA, Hillman IS, Allen SH, et al: Calcium homeostasis and bone metabolism during pregnancy, lactation and postweaning: A longitudinal study. Am J Clin Nutr 1995;61:514-523. 54. Wilson SG, Retallack RW, Kent JC, et al: Serum free 1,25-dihydroxy vitamin D and the free 1,25-dihydroxyvitamin D during a longitudinal study of pregnancy and lactation. Clin Endocrinol 1990;32:613-622. 55. Prentice A: Calcium in pregnancy and lactation. Annu Rev Nutr 2000;20:249-272. 56. Institute of Medicine: Dietary reference intakes. Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC, National Academy Press, 1997. 57. Laskey MA, Jariou L, Dibba B, et al: Does maternal calcium intake influence the calcium nutrition of the breast-fed baby? Proc Nutr Soc 1997;56:6A. 58. Kazeroni T, Hamze-Nejadi S: Calcium to creatinine ratio in a spot sample of urine for early prediction of pre-eclampsia. Int J Gynecol Obstet 2003;80:279-283. 59. Alexander S: On the prevention of preeclampsia: Nutritional factors back in the spotlight? Epidemiology 2002;13:382-383.
• Nutrient Metabolism in Children Theresa L. Han-Markey, MS, RD
CHAPTER OUTLINE Introduction Protein Fat Carbohydrate Macronutrient Requirements Protein Requirements Fat Metabolism Carbohydrate Metabolism
INTRODUCTION The pediatric age group spans from preterm infants to adolescence. Nutrient metabolism and subsequent enteral nutrition support for this wide age span is broken down into three broad age categories: preterm infant, term infant, and child aged 1 through 10 years; enteral nutrition products and delivery systems are tailored to the needs of these specified groups. Clinicians must keep in mind the fact that infants and children are not "just little adults." This population is unique because of their increased calorie, protein, and fluid requirements for growth. Digestion, absorption, and metabolism of protein, fat, and carbohydrate may be affected during these growth and development stages.
PROTEIN Dietary protein digestion begins in the stomach. Inactive pepsinogens-proenzymes-are synthesized and released by the gastric chief cells, which playa major role in protein digestion.' Pepsinogens are secreted very early during fetal development. Pepsinogen secretions are also regulated by numerous hormones such as cholecystokinin, acetylcholine, gastrin, and cytokines.' The hydrochloric
68
acid of the stomach changes these proenzymes into the active form called pepsin. A summary of macronutrient enzymes is presented in Table 7-1. Pepsin cleaves dietary polypeptides into amino acids and shorter chain polypeptides. Via peristalsis, these broken-down proteins are transported to the small intestine for further digestion and absorption. Although pepsinogen is detected in early fetal development, gastric proteolysis is low in the neonate.' In preterm infants, postprandial pepsin output is very small compared with that of an adult. Recently, gastric proteolysis was measured in 29-week gestational age infants with a postnatal age of 5 to 6 weeks.' Infants were fed either breast milk or premature infant formula and approximately 15% of dietary protein was digested. Protein hydrolysis did not differ between breast milk and formula, which indicates the contrast in dietary fat digestion between the two substrates. Basal and postprandial pepsin and lipase activity and output were measured in 28 preterm infants and healthy adults. The pepsin enzyme activity and output of the infants were 21% and 18% of adult levels, respectively. Dietary protein digestion continues in the small intestine. Pancreatic proteases such as trypsinogen and chymotrypsinogen are secreted as inactive zymogens. These enzymes are endopeptidases rather than pancreatic carboxypeptidases, which are metalloenzymes that depend on trypsin for activatton.' These inactive zymogens are activated by enterokinase, an enteropeptidase originating from the small intestinal mucosa. The pancreas also secretes elastase, an enzyme capable of digesting elastin and other connective tissue proteins. Its role in the protein digestion of the neonate is minimal because activity levels run low. After pancreatic secretion of endopeptidases and carboxypeptidases, dietary polypeptides are cleaved into peptides and amino acids for absorption. These pancreatic enzymes are detectable at 3 months' gestation, and secretion has been noted to begin at 5 months' gestation." Activation of trypsin and chymotrypsin increases after birth for both preterm and fullterm infants. Subsequent dietary protein absorption is quite complete as a result of intestinal digestion.
... Protein
Fat
Carbohydrate
SECTION III • Nutrient Metabolism
69
Macronutrient Digestive Enzymes
Enzyme
Origin
Site of Action
Full-Term Newborn Activity
Pepsin Enteropeptidase Trypsin Chymotrypsin Elastase Carboxypeptidase Lipase-colipase
Stomach Intestine Pancreas Pancreas Pancreas Pancreas Pancreas
Scant Adequate Adequate Adequate Low Adequate Low
Gastric lipase Pancreatic lipase Milk bile salt-dependent lipase Carboxyl ester lipase Salivary amylase Pancreatic amylase Milk amylase Glucoamylase Sucrase-isomaltase Lactase
Stomach Pancreas Milk
Stomach Intestinal lumen Intestinal lumen Intestinal lumen Intestinal lumen Intestinal lumen Duodenum (with bile salts) Stomach Intestine Intestine (with bile salts) Intestine Stomach, Intestine Intestine Intestine Intestine Intestine Intestine
Pancreas Salivary glands Pancreas Milk Intestine Intestine Intestine
High Unknown High Unknown Moderate Scant High High High High
Adapted from Hamosh M: Digestion in the newborn. Clin PerinatoI1996;23:191-209.
The brush border of the small intestine hydrolyzes peptides in preparation for absorption. Microvilli peptidases, such as enteropeptidase, activates pancreatic enzymes for further peptide cleavage. Enteropeptidase plays a critical role in pancreatic enzyme activation and has been studied extensively in the past. This enzyme has been detected in intestinal mucosa at 24 weeks' gestation.' Amino acids, dipeptides, and tripeptides are absorbed into mucosal cells where intestinal peptidases cleave small peptides into amino acids. True protein digestibility in infants has been measured by using labeled N-protein. Traditionally, protein digestion and absorption are estimated by nitrogen intake and fecal nitrogen output. By using a radioactive tracer, measurement of small bowel flow of N-protein indicates nearly complete dietary protein digestion and absorption.' Shulman and associates fed labeled glycine (0.5% of first feeding only) in five feedings per day for 11 days to nine healthy male infants, aged 3 to 5 months. The difference between the isotopic enrichment of urine nitrogen and fecal nitrogen output represents the isotopic dilution by unlabeled dietary nitrogen. With these methods, the true digestibility was more than 95% with cereal feeding in these subjects. Nonprotein components in the diet have an impact on rates of protein digestion and absorption. Numerous studies have demonstrated this concept and, recently, investigators have examined the impact of nonprotein energy sources on postprandial protein metabolism. The consumption of complete meals versus protein alone meals produced less marked differences in postprandial leucine metabolism." Two types of protein studied, whey and casein-dominant, have different digestion rates." Intrinsically labeled bovine milk proteins were produced for subject consumption to most accurately represent the metabolic fate of labeled tracer. The two major milk proteins, casein and whey, were isolated and purified. These two types of protein tracers were used in
a study of healthy adults ingesting either whey- or caseinlabeled protein. Digestion of leucine derived from whey was faster and more transient than that of leucine derived from casein. Whey protein digestion is considered "fast" compared with that of casein, which is considered "slow." From these studies, the protein digestion rate is an independent regulating factor of postprandial protein retention and has implications for maximizing protein retention." Dietary patterns of eating may also have an impact on protein accretion, whether one is feeding with a slowly digested versus a fast digested protein. In addition, these changes are age-dependent, and this concept of differing rates of protein digestion that depend on protein source may have further applications in pediatric clinical practice. 11
FAT Fat digestion also begins in the stomach. Gastric lipase is a 379-amino acid polypeptide, is resistant to an acidic environment and to gastric protease action, and can function in the absence of bile salts or other cofactors.' Long-chain polyunsaturated fatty acids and mediumchain fatty acids is preferentially released by gastric lipase in newborns. Numerous studies using milk substrate to study lipid digestion and absorption indicate that gastric lipase can penetrate the milk fat globule for digestion and pancreatic lipase cannot." Additionally, milk-derived bile salt-dependent lipase is also unable to penetrate milk fat for digestion. In the newborn stomach, 30% to 60% of milk fat is digested, and gastric lipase hydrolyzes milk fat in preparation for intestinal digestion. Gastric lipase activity in preterm infants matches that in adults. In fact, when gastric lipase activity is determined by biopsy, no significant changes occur in the age range of 3 months to 26 years." The products of gastric fat digestion are diacylglycerol and free fatty acids. 14
70
7 • Nutrient Metabolism in Children
Regulation of gastric lipase secretion has been extensively studied in animal models but has yet to be thoroughly elucidated in humans. Species differences, cellular localization of lipase, and the diversity of experimental models make the study of gastric lipase regulation difficult, and results are inconclusive at this time. I For future study, it is important to develop more physiologic human tissue and cell cultures that contain both pepsinogen and gastric lipase, because these enzymes are expressed simultaneously in human gastric chief cells. Intestinal digestion of fat is aided by numerous Iipases originating from the pancreas. Carboxyl ester lipase is identical to milk bile salt lipase. Pancreatic carboxyl ester lipase and Iipase-eolipase cleave glycerides from the n-l and n-3 positions of the triglyceride to further yield two monoglycerides and free fatty acids." In the adult, pancreatic Iipases are the major digestive lipase but, in the infant, pancreatic lipase activity is minimal or absent. Bile salt-dependent lipase found in human milk, along with gastric lipase, compensates for the lack of pancreatic lipase activity in the neonate. Pancreatic cholesterol ester hydrolase hydrolyzes cholesterol esters into free fatty acids and cholesterol." Cholesterol ester hydrolase may also assist in the digestion of triglycerides containing long-ehain polyunsaturated fatty acids such as docosahexaenoic acid and arachidonic acid. Bile salt-dependent lipase is important to human milk long-chain polyunsaturated fatty acid digestion too. Free fatty acids and monoglycerides form bile micelles, combine with phospholipids, and pass through the unstirred water layer to be absorbed. Lipids can be re-esterfied into triglycerides or phospholipids and then transported as chylomicrons. Chylomicrons travel via the lymphatic system whereas medium-ehain fatty acids can be absorbed through the stomach after hydrolysis by gastric lipase."
isomaltose and a-limit dextrins; sucrase hydrolyzes sucrose; and maltose and glucoamylase hydrolyze glucose oligomers." Hydrolyzed lactose, isomaltose, maltose, and sucrose yield fructose, glucose, and galactose. The uptake of galactose and glucose from the small intestinal brush border depends on sodium-dependent glucose transporter-I, an active transport system. Fructose uptake occurs via facilitated diffusion using two different carriers in the brush border and basilateral membranes of enterocytes, glucose transporter-5, and glucose transporter-a." In preterm and term infants, carbohydrate malabsorption is rare, despite low levels of amylase activity. The majority of carbohydrate fed in infancy is lactose and lactase activity is fully developed by 36 to 40 weeks gestation. The level present at this time is equivalent to that of l-year-old children.'? In preterm infants of 26 to 31 weeks gestational age, at 31 to 37 weeks postconception age, lactose digestion and breath hydrogen excretion were measured. Lactose digestion was approximately 79 ± 26%, and the percentage of lactose not absorbed but fermented in the colon averaged 35 ± 27%.20 In fact, colonic salvaging of these undigested carbohydrates by absorption of bacterial fermentation products results in an additional calorie source. Brush border glycohydrolases appear to be genetically determined. Provision of lactose or the presence of milk does not induce lactase activity. For example, lactase is present in high amounts before birth and subsequent exposure to lactose. Neither prolonged ingestion of lactose nor elimination of lactose alters lactase activity. In preterm infants, early exposure to lactose-eontaining nutrients may induce lactase. However, this induction effect may be due to changes in small intestinal surface area or motility." After weaning, lactase activity progressively declines. A physiologic reduction of lactase activity occurs in 80% to 90% of Asians, African Americans, and most other ethnic groups except Northern Europeans."
CARBOHYDRATE MACRONUTRIENT REQUIREMENTS Dietary carbohydrate digestion begins with secretion of amylase by the salivary glands, and in the infant, the site of action for this enzyme is the stomach. In humans, salivary and pancreatic amylases have similar structures. However, the synthesis of pancreatic amylase is very low in the newborn and salivary and breast milk amylases become essential to carbohydrate digestion." Pancreatic amylase levels develop slowly in the newborn and are 0.2% to 0.5% of adult levels before the age of 6 months." Salivaryamylase is active in the stomach and was detected in amniotic fluid of 16-week fetuses. 15% to 40% of salivary amylase is found in the duodenum of adults. As a result of amylase activity, starch is hydrolyzed to maltose, maltotriose, and a-limit dextrins. The end products of starch digestion and dietary disaccharides are further digested in the small intestine. n-Glucosidases such as sucrase, isomaltase, and glucoamylase and ~alactosidase, or lactase, are found in the brush border enterocytes. These enzymes are substrate specific: lactase hydrolyzes lactose; isomaltase hydrolyzes
The Dietary Reference Intakes (DRIs) for protein, amino acids, fat, and carbohydrate have been published recently.P The DRI represents the Recommended Dietary Allowances (RDAs), Adequate Intakes (AIs), and Acceptable Macronutrient Distribution Range (AMDR). Both the RDAs and Als may be used by clinicians in individualized nutrition care plans; the AMDR is the range of intake that is associated with reduced risk of chronic disease while providing intakes of essential nutrients. See Table 7-2 for the current pediatric references.
PROTEIN REQUIREMENTS Protein requirements in pediatrics are calculated to meet the child's maintenance needs for protein turnover and support the child's growth. Calculation of these needs is difficult and remains controversial owing to methodology differences and assumptions used. In general,
... Ufe Stage Group Infants 0-6 mo 7-12 mo Children 1-3 yr 4-8 yr Males 9-13 yr 14-18yr Females 9-13 yr 14-18 yr
SECTION III • Nutrient Metabolism
71
DRls for Protein, Amino Acids, Fat, and Carbohydrate RDA/AI/AMDR Protein (g/day)
Fat (g/day)
n-6 Unolelc Acid (g/day)
0-3 a·Uoolenlc Acid (g/day)
Carbohydrate (g/day)
9.l/ND 13.S/ND
31 30
4.4/ND 4.6/ND
O.S/ND O.S/ND
60/Not determinable (ND) 9S/ND
13/5-20 19/10-30
/30-40 /25-35
7/5-/0 /0/5-/0
0.7/0.6-/.2 0.9/0.6-/.2
13045-65 13045-65
34/10-30 52/10-30
/25-35 /25-35
/2/5-/0 /6/5-/0
/.2/0.6-/.2 /.6/0.6-/.2
13045-65 130/45-65
34/10-30 46/10-30
/25-35 /25-35
/0/5-/0 ///5-10
/.0/0.6-/.2 /.1/0.6-/.2
130/45-65 130/45-65
Adapted from Reference 22. RDA is recommended dietary allowance, presented in bold print. ADMR is acceptable macronutrient distribution range, presented as underlined.
protein requirements depend upon the digestibility of the protein, absorption rate, and concurrent nonprotein energy intake. As stated earlier, frequency and quantity of protein intake may affect absorption rates. The influence of nonprotein calorie delivery on dietary protein retention and subsequent growth has been studied extensively. In preterm infants, 21 studies of feeding were reviewed by Bell23 who concluded that there was a relationship between calorie intake and stored energy. Increasing the amount of nonprotein calories in this population without simultaneously increasing protein intake can lead to increased fat deposition. In earlier studies of protein/energy ratios, the conclusion was that ratios less than 2.1 g of protein/ 100 cal in preterm formula leads to a higher percentage of fat deposition." In 2002 the minimum ratio recommended by the Expert Panel to promote fetal rates of growth is 2.5 g of protein/lOO cal. 24 This ratio provides for a weight gain of no more than 25% fat, which does not appear to be harmful. As a maximum, the Panel recommends 3.6 g of protein/lOO cal based on studies of Kashyap and co-workers.P For term infants, an Expert Panel in 1998 summarized their recommendations for formula." Their minimal recommendation for protein/energy ratios, 1.7 g of protein/ 100 cal, is based on true protein values and does not include other nonprotein nitrogen sources, unlike the recommendations for preterm infant formula. However, the maximum of 3.4 g/lOO cal of "crude" protein or total nitrogen x 6.25 is calculated differently than the minimum. This value of 3.4 g is a revision downward from the Code of Federal Regulations due to the potential impact on renal solute load. Again, these recommendations summarize data defining protein/energy needs to support growth and obligatory protein turnover. Protein requirements have been calculated in infants and children using two primary methods: the factorial approach and the observed approach. Typically, the factorial approach accounts for losses from feces, urine,
skin, and hair. These obligatory losses are calculated while the subject is consuming a protein-free diet. A growth factor is added to these loss factors and a requirement is established. Fetal and infant growth has been estimated from values for reference infants, which assist in determining requirements for energy and protein as well. There remain questions about the relationship between measured total body potassium and body protein levels. Also, the relationship between infant and adult body composition is a continued area of research." The observed, or empirical, approach measures outcome variables such as anthropometries, nitrogen balance, biochemical indices, plasma amino acid patterns, and isotope nitrogen studies while subjects are fed varying quantities of protein and energy. Nitrogen balance is a crude measurement for which assumptions concerning protein synthesis and degradation are made. For example, a positive nitrogen balance, implying an anabolic condition, could result from four possible scenarios: (1) an increase in the synthesis rate and a decrease in breakdown; (2) a decrease in both synthesis and breakdown; (3) an increase in synthesis and breakdown; and (4) an increase in synthesis and no change in breakdown." With a balance technique, protein requirements are higher owing to undermeasurement of body losses. Isotope nitrogen studies include arteriovenous difference measurements and measurements of the concentration of amino acids entering an organ and the concentration of amino acids leaving the organ. This measure gives some indication of organ extraction of amino acids for synthesis. Because of limitations in methodology, amino acid uptake measured by arteriovenous difference can only measure large interorgan flux.29 There are three general guidelines that form the background for amino acid flux measurements. (1) Proteins are not stored in the body; therefore, homeostatic protein synthesis occurs and excess protein intake is catabolized. (2) Most amino acids are glucogenic and the liver
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7 • Nutrient Metabolism in Children
and kidney are the major organs for gluconeogenesis. Therefore, a large amino acid flux is measured at these organs. (3) Lastly, the liver is the only site for urea synthesis, a necessary by-product from amino acid catabolism and excretion. Again, flux of amino acids across the liver would be high." Nonprotein nitrogen compounds, such as nucleotides, are also supplemented in infant formula. Nucleotides are low molecular weight intracellular compounds that contain three characteristic components: a nitrogen base; a pentose; and one or more phosphate groups." Found in human milk and diet, they have a role as active precursors of DNA and RNA, adenosine triphosphate, and coenzymes. They also have a role in the growth and differentiation of the gastrointestinal tract and positively affect the immune system." Lastly, dietary nucleotides may increase plasma levels of long-ehain polyunsaturated fatty acids of the n-6 and n-3 series and increase the level of plasma high-density lipoproteins. Today, both preterm and term infant formulas are supplemented at levels approximating those in human milk.
FAT METABOLISM The nutritional requirements for humans are set to prevent essential fatty acid deficiency (EFAD). Thus, 4% to 5% is the estimated amount of the diet needed to be composed of the essential fatty acids, linoleic acid (l8:2n-6) and a-linolenic acid (l8:3n-3). To review the nomenclature of fatty acids, the first number, e.g., "18," defines the carbon chain length. The second number, e.g., "2" or "3," describes the total number of double bonds in the carbon chain. Lastly, "n-" describes the position of
the first carbon of the double bond relative to the methyl terminal of the carbon chain." Essential fatty acids are necessary for growth and maintenance of skin and hair. One of the most sensitive diagnostic indicators of essential fattyacid deficiency is the triene (n-9)/tetraene (n-6) ratio. The triene is the product from the n-9 series of fatty acids and is a nonessential fatty acid. When this ratio is below 004, the dietary intakes of these fatty acids are adequate. Figure 7-1 shows the metabolic pathways of linoleic (l8:2n-6) and a-linolenic (l8:3n-3) acids. Through a series of desaturase (insertion of additional double bonds) and elongase enzymes, these fatty acids are transformed into biologically important products such as arachidonic and docosahexaenoic acids. 24 The dietary intake of n-3 and n-6 polyunsaturated fatty acids decreases triene formation because n-3 and n-6 fatty acids compete with the desaturase and elongase enzymes of the n-9 series. n-3 and n-6 fatty acids products such as arachidonic and docosahexaenoic acids can be enzymatically transformed into leukotrienes, prostaglandins, and thromboxanes, collectively known as eicosanoids. Eicosanoids can alter a number of body reactions such as immune, cardiovascular, and pulmonary functions." During the last trimester of pregnancy, fetal growth is rapid. On autopsy of deceased infants and fetuses, the presence of arachidonic and docosahexaenoic acids has been documented in the brain, retina, and other tissues." Studies have also shown preferential placental transfer of arachidonic and docosahexaenoic acids. Isotopically labeled precursor fatty acids are given and plasma levels of the metabolites are measured. It appears that more enzyme activity via desaturases and elongases is seen in preterm than in term infants. However, the
Linoleicand a-linolenic metabolicpathways
FIGURE 7-1. Metabolic pathways for linoleic acid and a-linolenic acid. (Adapted from Klein C]: Nutrient requirements for pre term infant formula. j Nutr 2002; 132[suppl 1J: 13955-15775.)
SECTION III • Nutrient Metabolism
exact quantities in tissues are not known because this type of study is limited to plasma.P The Expert Panel has determined the minimum and maximum levels of both n-6 linoleic acid and n-3 a-linolenic acid for both preterm and term infant formulas. Linoleic acid should comprise 8% of the total fatty acid content of both term and preterm formulas. No data support making the levels of preterm infant formula lower than those of term infant formulas. The maximum level established for preterm infant formula is not to exceed 25%, and there are several reasons to support this recommendation. The level in human milk, which reflects maternal diet, does not exceed 25% and currently available preterm formulas contain medium-ehain triglycerides and, therefore, do not contain greater than 25% linoleic acid. Term infant formulas do have a higher maximum content level of 35%. Historically, these formulas have delivered more than 35%of the fatty acids as linoleic acid and have not been associated with side effects." The minimum and maximum levels of n-3 a-linolenic acid for both preterm and term infant formulas are the same. The Expert Panel has determined that a minimum content of 1.75% of total fatty acids and a maximum content of 4% of total fatty acids shall be a-linolenic acid." The ratios of linoleic to linolenic acids were also considered by the Panel. The minimum ratio for both term and preterm formula is 6:1, and the maximum is 16:1. Excess provision of linoleic acid, in relation to linolenic acid, may negatively impact docosahexaenoic acid production." Currently, infant formula is supplemented with both arachidonic and docosahexaenoic acids. The quantities provided in these formulas closely approximate levels found in human breast milk. In general, formulas contain 0.3% to 0.6% arachidonic acid and 0.2% to 0.4% docosahexaenoic acid from sources such as marine oils, microalgal and fungal oils, and egg yolk-derived lipids." In general, the literature supports such supplementation. Conflicting results do exist for the efficacy of these supplemented fatty acids and their impact on cognitive development, growth, and irnrnunocompetency." These differences may be related to dosage of fatty acids, duration of supplementation, small sample size, and varying measurement methodology. Recent meta-analysis does show benefits in visual acuity for both preterm and term infants fed docosahexaenoic acid-supplemented formulas compared with those fed unsupplemented formula.36,37
CARBOHYDRATE METABOLISM Carbohydrate provides a major source of calories for growing children and adults. Glucose, the predominant end product of carbohydrate digestion, is the main energy source for the human brain and the RDAs are set at a level to meet the needs of this organ." Actual glucose utilization rates have not been measured in preterm and term infants but have been measured in children using isotope methodology. However, rates of glucose utilization can be calculated from other published data.
73
Through autopsy, brain weight with age has been documented; a linear relationship exists between body weight and brain weight. Up to the age of 4 to 5 years, a rapid increase in brain weight occurs for both sexes; by age 7 to 8 years, the brain has reached adult size. Therefore, a correlation between measured glucose utilization rates in children and brain size data can be seen." Potential differences in measured brain glucose utilization rates may exist. Studies using positron emission tomography document lower rates in normally developing infants and children." These differences may be due to population variances between these studies, but at this time remain to be fully explained. The current recommendations for carbohydrate, with brain glucose utilization rates as a component, are based on the measured isotope data correlated with brain size. Carbohydrate must be provided in quantities to promote growth in infants and children. Also, enough carbohydrate should be absorbed and metabolized to prevent gluconeogenesis." The recommendation assumes that adequate protein and total energy are being consumed by the child and the source of carbohydrate is absorbable and nonalcoholic. Lastly, safety factors are added to the recommendations to account for glucose utilization by nonbrain organs and unaccounted for recycled gluconeogenic carbon. The Expert Panel has established guidelines for the minimum and maximum carbohydrate content for both preterm and term infant formulas. For the preterm formula, 9.6 gllOO kcal has been determined to provide adequate energy for brain needs and growth. The maximum level is 12.5 gl100 kcal and is based on the minimum fat and protein requirements. For term formula, the minimum and maximum levels are 9 and 13 glIOO kcal, respectively. The quantity of lactose as a carbohydrate source in preterm infant formula is currently being studied. A previous study showed that lactose in formula was associated with improved absorption of calcium." However, more recent work contradicts this finding. Using lactosefree preterm formulas with higher calcium supplementation, calcium absorption, in addition to absorption of nitrogen and magnesium, is irnproved.f Infants consuming low-lactose formula also show improved weight gain and decreased feeding intolerance. In a randomized trial involving 306 preterm infants, a decrease in the number of days before full enteral feedings and decreased gastric residuals, leading to better weight gain, occurred in infants fed a low-lactose «1% carbohydrate formula content) formula." Because conflicting evidence exists in the literature on preterm infant formulas, the Expert Panel based their recommendations on current clinical practice using preterm formulas and not on the literature. The minimum and maximum levels for lactose are 4 glIOO calor 40% of the carbohydrate intake and the maximum levels would meet the entire carbohydrate requirement of 12.5 gllOO cal. Recently, investigators compared lactose-free versus lactose-eontaining term infant formulas." Both calcium and zinc absorption was measured using a multitracer isotope technique. Infants who received the lactose-eontaining
74
7 • Nutrient Metabolism in Children
formula absorb calcium, but not zinc, in higher quantities than those receiving the lactose-free diet. However, the calcium needs of term infants were met with both types of feeding. REFERENCES I. Mennard D, Basque J: Gastric digestive function. In Deluca EE,
Lentz MJ (eds): Gastrointestinal Functions. Baltimore, Nestec Ltd, Lippincott Williams & Wilkins, 2001, p 147. 2. Serrano MT, LanasAI, Lorenke S, et al: Cytokine effectson pepsinogen secretion from human peptic cells. Gut 1997;40:42-48. 3. Britton JR, Koldovsky 0: Gastric luminal digestion of lactoferrin and transferrin by preterm infants.Early Hum Dev1989;19:127-135. 4. Henderson TR, Hamosh M, Armand M, et al: Gastric proteolysis in preterm infants fed mother's milk or formula. Adv Exp Med Bioi 200I;50I:403-408. 5. Hamosh M: Digestion in the newborn. Clin Perinatol 1996;23: 191-209. 6. Lebenthal E: Concepts in gastrointestinal development. In Lebenthal E (ed): Human Gastrointestinal Development. NewYork, Raven Press, 1989. p 4. 7. Shulman RJ, Gannon N, Reeds PJ: Cereal feeding and its impact on the nitrogen economy of the infant. Am J Clin Nutr 1995;62: 969--973. 8. Gibson NR, Fereday A, Cox M, et al: Influences of dietary energy and protein on leucine kinetics during feeding in healthy adults. AmJ Physiol 1996;270: E282-E291. 9. Boirie Y, DanginM, Gachon P, et al: Slowand fast dietary proteins differently modulate post-prandial protein accretion. Proc Natl Acad Sci USA 1007;94:14930-14935. 10. DanginM, Boirie Y, GuilletC, et al: Influence of the protein digestion rate on protein turnover in young and elderlysubjects. J Nutr 2002;132:32285-3233S. 11. Fruhbeck G: Protein metabolism: Slow and fast dietary proteins. Nature 1998;391:843-845. 12. Hamosh M: Gastric and lingual Iipases. In Johnson JR (ed): Physiology of the Gastrointestinal Tract. New York Raven Press, 1994, p 1239. 13. Dipalma J, Kirk CL, Hamosh M, et al: Lipaseand pepsin activity in the gastric mucosa of infants, children and adults.Gastroenterology 1991;101:116--120. 14. Ramirez M, Amate L, Gil A: Absorption and distribution of dietary fatty acids from different sources. Early Hum Dev200I;65:S95-S101. IS. CarlierH,BernardA,Caselli C:Digestion and absorption of polyunsaturated fatty acids. Reprod NutrDev 1991;31:475-500. 16. Lebenthal E, Lee PC: Development of functional response in human exocrine pancreas. Pediatrics 1980;66:556--560. 17. KienCL: Digestion, absorption, and fermentationof carbohydrates in the newborn. Clin Perinatol 1996;23:211-228. 18. Wright EM: Human intestinal nutrient transporters. In Deluca EE, LentzMJ (eds): Gastrointestinal Functions. Baltimore, Nestec Ltd, Lippincott Williams & Wilkins, 2001, p 77. 19. Antonowicz I, Lebenthal E: Developmental pattern of small intestinal enterokinase and disaccharidase activitiesin the human fetus. Gastroenterology. 1977;72:1299--1303. 20. Kien CL, McClead RE, Cordero L Jr: lactose digestion in preterm infants. AmJ ClinNutr 1996;64:700-705. 21. Shulman RJ, Schanler RJ, Lau C, et al: Early feeding, feeding tolerance and lactase activity in preterm infants. J Pediatr 1998; 133:645-649. 22. Available at www.nap.edu. Accessed May 30,2003.
23. Bell EF: Diet and body composition of preterm infants. Acta Paediatr Suppl 1994;405:25-28. 24. Klein CJ: Nutrient requirements for preterm infant formula. J Nutr 2002;132(suppl 1):I3955-1577S. 25. Kashyap S, Schulze KF, Ramakrishnan R, et al: Evaluation of a mathematical model for predicting the relationship between protein and energy intakes of low-birth-weight infants and the rate and composition of weight gain. Pediatr Res 1994;35: 704-712. 26. Raiten DJ, Talbot JM, Waters JH (eds.): LSRO Face Report: Assessment of nutrient requirements for infant formulas. J Nutr 1998; 128(11 suppl): 21105-2127S 27. Fomon S: Body composition of the male and female reference infants.Annu Rev Nutr2002;22:1-17. 28. Matthews D: Protein and amino acids. In Shils M, Olson JA, Shike M, RossAC (eds): Modem Nutrition in Health and Disease, 9th ed. Baltimore, LippincottWilliams & Wilkins, 1999, pp 11-48. 29. Brosnan JT: Interorgan amino acid transport and its regulation. J Nutr2003; 133:20685-2072S. 30. Gil A: New additions to infant formulas. In Lifschitz CD (eds): Pediatric Gastroenterology and Nutrition in Clinical Practice. NewYork, Marcel Dekker, 2002, pp 113-135. 31. Jones PJH, KubowS: Lipids, Sterols, and Their Metabolites. In Shils M, Olson JA, Shike M, Ross AC (eds): Modem Nutrition in Health and Disease, 9th ed. Baltimore, Lippincott Williams & Wilkins, 1999, pp 11-48. 32. Koletzko B:Lipids. In Lifschitz CD (ed): Pediatric Gastroenterology and Nutrition in Clinical Practice. New York, Marcel Dekker, 2002, pp 31-73. 33. Uauy R, Mena P, Wegher B,et al: Longchain polyunsaturated fatty acid formation in neonates: Effect of gestational age and intrauterine growth. Pediatr Res 2000;47:127-135. 34. Carver JD: Advances in nutritional modifications of infant formulas. AmJ Clin Nutr2003;77(suppl):15505-1554S. 35. Motil KJ: Infantfeeding:Acritical look at infant formulas. CurrOpin Pediatr 2000;12:469-476. 36. SanGiovanni JP, Parra-Cabrer S, ColditzGA, et al: Meta-analysis of dietary essential fatty acids and long-chain polyunsaturated fatty acids as they relate to visual resolution acuity in healthy preterm infants. Pediatrics 2000;105:1292-1298. 37. SanGiovanni JP, BerkeyCS, DwyerIT, et al: Dietary essential fatty acids, long-chainpolyunsaturated fattyacids, and visual resolution acuity in healthy full term infants; a systematic review. EarlyHum Dev2000;57:165-188. 38. Kalhan SC, Kilic I: Carbohydrate as nutrient in the infants and child: Range of acceptable intake. Eur J Clin Nutr 1999;53(suppl): S94-S100. 39. Chugani HT: Positronemission tomographyscanning: Applications in newborns. Clin Perinatol 1993;20:395-409. 40. Bier DM, Brosnan JT, Flatt JP, et al: Report of the IEDCG Working Group on lower and upper limitsof carbohydrate and fat intake. EurJ Clin Nutr 1999;53:S177-5178. 41. Ziegler EE, Fomon SJ: Lactose enhances mineral absorption in infancy. J Pediatr Gastroenterol Nutr 1983;2:288--294. 42. Moya M, Lifschitz C, Ameen V, et al: A metabolic balance study in term infants fed lactose-containing or lactose-free formula. Acta Paediatr 1999;88:1211-1215. 43. Griffin MP, Hansen JW: Can the elimination of lactose from formula improve feeding tolerance in premature infants? J Pediatr 1999;135:587-592. 44. AbramsSA, Griffin IJ, DavilaPM: Calciumand zinc absorption from lactose-containingand lactose-free infant formulas. AmJ ClinNutr 2002;76:442-446.
II Metabolism in the Life Cycle: Aging Melanie Berg, MS, RD Gordon Jensen, MD, PhD
CHAPTER OUTLINE Introduction Organ System Changes with Aging Changes in Body Composition Nutrient Requirements Macronutrients Micronutrients Fluid Requirements
to a reduction in the number of neurons in the myenteric plexus. Clinically significant impairment of esophageal motility is usually observed only in the setting of pathologic conditions such as diabetes mellitus or neurologic
-
Summary of Aging Effects on Organ Systems
O rgan System
Aging Effects
Skin
Dryness Wrinkling Mottled pigmentation Loss of elasticity Dilatation of capillaries Poor dentition Xerostomia Altered taste perception Decreased olfactory discrimination Esophagus-decreased motility Gastric-delayed emptying/atrophic gastritis Small intestine-largely intact structure and function Colon/rectum-increased constipation and incontinence Thickening of heart wall Increase in presence of collagen and rigidity Differing opinions on effect on actual heart size Stiffening of tissue Decreased vital capacity Decreased Vo2max Decreased breathing capacity Decreased glomerular filtration rate Decreased renal blood flow Decreased daily urinary creatine excretion Decreased sodium concentration Decreased renal concentrating ability Alterations in circulating hormone levels and actions Decreased sensory perception Decreased muscle response to slimuli Decreased cognition and memory Loss of brain cells
Conclusion
Oropharyngeal
INTRODUCTION The number of older persons IS Increasing, reflecting dramatic changes in health and longevity. There is a growing interest in all aspects of the aging process, including changes in nutritional status. During the later years of the life cycle there are significant alterations in organ system functions and body composition that have an impact upon nutrient metabolism and requirements. These changes will be highlighted in this portion of the chapter.
Gastrointestinal
Cardiovascular
Pulmonary
ORGAN SYSTEM CHANGES WITH AGING Aging is accompanied by a wide variety of organ system changes. A summary of these changes is presented in Table 8-1. Changes in oral and gastrointestinal functions are particularly important in relation to nutrition. Poor dentition is common, and the number of oral health problems experienced by an individual is a strong predictor of involuntary weight loss. 1 Altered taste perception and decreased olfactory discrimination may contribute to decreased oral intake.' Esophageal motility may be affected by alterations in contraction that relate
Renal
Endocrine Nervous
Adapted from McGee M, Jensen GL: Nutritionin the elderly. J Clin Gastroenterol 2000;30:372-380.
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8 • Metabolism in the Life Cycle: Aging
disease.' Gastric emptying is similarly well-preserved except with disease processes that affect autonomic nervous system function." Atrophic gastritis is relatively common among older persons and is associated with decreased acid secretion that may diminish secretion of intrinsic factor and vitamin BI2 absorption.Y Unless there is an underlying pathologic condition, the motility and absorptive functions of the small intestine appear to be well-preserved with aging, as are pancreatic exocrine functions.S" Evidence suggests that bile acid synthesis and excretion may be reduced in older adults presumably because of decreased gallbladder contractility associated with aging." Constipation is a common complaint among aging persons. Constipation and laxative use are reported more often by older women than men. 8•9 Studies of colonic transit time have yielded conflicting results.'? Mechanical changes in the rectum including reduced rectal wall elasticity and an increase in rectal pressure threshold contribute to increased occurrence of fecal incontinence among older persons.v"
CHANGES IN BODY COMPOSITION Body composition changes occur with aging and may also affect nutrient requirements. There is a characteristic decline in skeletal muscle mass, called sarcopenia. 12- 14 It is associated with a loss of strength and decreased protein reserves that increase risk for functional decline and disability. The loss of lean body mass due to sarcopenia is approximately 45% from age 30 to 80 years." Biopsy studies found a reduction in the number and size of type II fibers, whereas type I fibers were spared." Whether the loss of lean body mass is an inexorable part of aging or an as yet unrecognized contributing factor is unclear. Suggested pathogenic factors include altered cytokine regulation, a decline in endogenous growth hormone production, decreased androgen and estrogen secretion, and a loss of ex motor neurons from the spinal column." Suboptimal protein intake and sedentary lifestyle may also be factors. Experimental approaches that have increased skeletal muscle mass in older persons have included administration of trophic factors such as growth hormone and testosterone and resistance strength training.":" The potential utility of protein or other nutrient supplementation awaits further investigation. For many older persons, the decline in skeletal muscle mass occurs with an increase in total body fat mass. In particular, an increase in the deposition of intraabdominal (visceral) fat is a risk factor for hypertension, dyslipidemia, coronary artery disease, and insulin resistance. The surging incidence of obesity (body mass index ~30 kg/m") now extends to older persons in their 60s and 70S. 22 Contributing factors probably include lifestyle factors such as diet and physical inactivity, along with estrogen and androgen withdrawal. Untoward outcomes associated with obesity include impaired functional status, increased health care resource use, and increased mortality.23-25 It is not yet clear whether intervention should focus upon weight
loss or weight maintenance for obese older persons, but it is evident that further weight gain is associated with undesirable outcomes.
NUTRIENT REQUIREMENTS
Macronutrients The original Recommended Dietary Allowances (RDAs) were established by the National Academy of Sciences as the amounts of nutrients necessary to prevent deficiency. The 1989 RDAs were based almost entirely on extrapolations from studies conducted in young, healthy adults. They did not include any further age breakdown beyond age 51 years because of the lack of available research information for older adults at that time. The physiologic features and health status of those aged 50 to 60 can be quite different from those of individuals aged 80 years and older. 26In addition, more recently the focus has shifted from preventing nutrient deficiency to decreasing the risk of chronic disease and optimizing intake. Thus, the new Dietary Reference Intakes (DRls) were established and include four categories: Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA), Adequate Intake (AI), and Upper Intake Level (UL).27 The DRlsare a more complete set of values that are used for diet assessment as well as planning, and they include nine life stage categories including separate categories for adults aged 51 to 70 and older than 70 years (Table 8-2). Although the expectation is that energy needs would be less among elderly persons, it had been previously suggested that micronutrient needs would be unchanged from younger to older adulthood. The latest recommendations highlight a number of important changes in macronutrient and micronutrient needs. The loss of muscle mass that occurs with aging is associated with a reduction in basal metabolic rate. Basal metabolic rate is a major component of total energy expenditure; thus, energy requirements for older adults must be adjusted. The presence of chronic disease and degree of physical activity should also be considered. The DRIs for energy and macronutrients were recently updated by the Food and Nutrition Board of the National Academy of Sciences (Table 8-3). The DRls for energy for aging adults may be extrapolated from those for younger adults by subtracting 10 kcal/day for males and 7 kcal/day for females for each year of age above 19 years." Aging is often characterized by a reduction in glucose tolerance." It is unclear whether the impairment is partly a direct result of the aging process or is largely due to confounding lifestyle or other variables. Abdominal adiposity and dietary factors such as consumption of excessive dietary fat, alcohol, and carbohydrates may further contribute to glucose intolerance. Lactose intolerance associated with relative lactase deficiency can result in reduced intakes of milk or milk-products by older persons. Marginal calcium and vitamin D intakes may result and are common among older persons.
.-
77
SECTION III • Nutrient Metabolism Changes in Recommended Dietary Allowances for Persons Older Than 50 Years
Nutrient Calcium* Phosphorus Magnesium Vitamin D*
Fluoride" Thiamin Riboflavin Niacin Vitamin B,; Folate Vitamin B I2 Pantothenic acid* Biotin* Choline* Vitamin C a-Tocopherol Selenium
Male 51-70 yr
Male >70 yr
1200 700 420 10 4 1.2 1.3 16 1.7 400 2.4 5 30 550 90 15 55
1200 700 420 15 4 1.2 1.3 16 1.7 400 2.4 5 30 550 90 15 55
Female 51-70 yr 1200 700 320 10 3 1.1 1.1 14 1.5 400 2.4 5 30 425 75 15 55
Female >70 yr
Change Reftected
1200 700 320 15 3 1.1 1.1 14 1.5 400 2.4 5 30 425 75 15 55
Increase Decrease Increase Increase New Increase for females Decrease Increase Decrease Increase Increase New New New Increase Increase Decrease for males
*Adequate Intakes (AI), not Recommended Dietary Allowances (RDA). Adapted from: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC, National Academy Press, 1997; Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC, National Academy Press, 1999; and Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids, Washington, DC, National Academy Press, 2000.
The recommended adequate intake for dietary carbohydrates is 130g/day. It is recommended that adults should consume 45% to 65% of total calories from carbohydrates. No more than 25% of total calories should come from added sugars. The recommendation for total fiber intake for adults older than age 50 is 30 g/day for men and 21 g/day for women. Dietary protein requirements for elderly persons have been controversial. Recent Food and Nutrition Board recommendations left protein requirements for older persons at 0.8 g/kg of body weight per day, the same as those for younger adults." In addition, the recommendation was that dietary protein should comprise 10% to 35% of total calories. Others have suggested protein requirements of 1.0g/kgof body weight per day or higher
to help maintain muscle mass." Protein needs may be further elevated to 1.5g/kg of body weight per day during times of injury, stress, inflammation, and infection. The presence of certain diseases that result in renal or hepatic insufficiency may necessitate protein restriction. Lipid metabolism may also be affected by reduced fat oxidation associated with aging. This leads to increased availability of free fatty acids and thus increased serum levels,which promote hyperinsulinemia and insulin resistance. The development of an atherogenic lipid panel increases the risk for cardiovascular disease. Aerobic physical activity increases fat oxidation and can decrease lipid levels and truncal adiposity. The recommended adequate intake for dietary fat is 30 g/day (see Table 8-3). Total fat should comprise 20% to 35% of total calories.
_.[)i!t!'ryReference Intakes for Macronutrients by Sex and Age Women
Men Nutrient Energy (kcaljday)* Carbohydrates (gjday)* Fiber (gjday)* Protein (g/day)" Fat (gjday)' n-6 PUFA (g/day)! n-3 PUFA (g/day)! Saturated fat trans-Fatty acids Cholesterol
51-70 yr 2557-2747 130 30 56 30 14 1.6 ND ND ND
>70 yr <2557 130 30 56 30 14 1.6 ND ND ND
51-70 yr 2046-2179 130 21 46 30 11 1.1 ND ND ND
>70 yr <2046 130 21 46 30
11 1.1 ND ND ND
*Recommended Dietary Allowance (RDA). 'Adequate Intake (AI). PUFA. polyunsaturated fatly acid; ND, not determinable. Adapted from Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Washington, DC, National Academy Press, 2002.
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8 • Metabolism in the Life Cycle: Aging
Recommendations for n-6 and n-3 fatty acids have also been established. Values for saturated fatty acids, transfatty acids, and cholesterol have not been established because they have no beneficial role in preventing chronic disease."
Micronutrients The requirements for various micronutrients including calcium; vitamins D, B12, and B6; folate, and iron may be altered with aging. Atrophic gastritis can affect the bioavailability of calcium owing to a decreased ability of calcium to dissociate from foods. Inadequate gastric acid can also have an adverse impact on calcium absorption. Vitamin D status can further affect calcium absorption. Findings reveal that 25-hydroxyvitamin D levels are lower in older than in younger persons.f Contributing factors may include poor dietary intake, compromised absorption due to a decrease in intestinal vitamin D receptors, and reduced exposure to sunlight. The ability to make vitamin D with ultraviolet radiation exposure is also impaired in elderly persons. Vitamin D status is further compromised in elderly women with osteoporosis because of a relative inability to convert 25-hydroxyvitamin D to the most active form, 1,25-dihydroxyvitamin D.26 Homocysteine levels are increased with vitamin BI2 or B6 or folate deficiencies because of a reduced ability to convert homocysteine to cystathione. Elevated homocysteine levels have been implicated in the increased risk for coronary artery disease, stroke, and dementia." Vitamin BI2 deficiency is common among older persons. Oropharyngeal changes with aging such as xerostomia and poor dentition may contribute to compromised intake of meats, a rich source of vitamin B12. Atrophic gastritis may further contribute to vitamin B12 deficiency by interfering with the dissociation of BI2 from foods and by decreasing the binding of the vitamin to intrinsic factor for absorption. The reduced acid defenses may also contribute to bacterial overgrowth resulting in uptake of vitamin BI2 by bacteria in the stomach and small intestine. Inadequate dietary intakes of vitamin B6 have been detected among community-dwelling populations of older persons.P Atrophic gastritis may also contribute to an increased need for vitamin B6 in elderly persons by interfering with its absorption. Several medications commonly used by aging adults including antacids, diuretics, and anti-inflammatory agents affect both absorption and utilization of tolate.P Supplementation of folate at a population level of women with child-bearing potential has recently been undertaken to reduce risk of neural tube defects among newborns. Increasing epidemiologic evidence suggests that excessive iron may be a factor in development of atherosclerosis and ischemic heart disease. High levels of stored iron as indicated by elevated serum ferritin levels have been associated with increased risk of coronary heart disease.f Dietary iron has been positively correlated with coronary heart disease among men and women aged 60 years and 01der.35 Suggested mechanisms include the role of iron in catalyzing the formation of free radicals and thus enhancing oxidation of
lipoproteins. Postmenopausal women have reduced need for iron with the cessation of menses.
FLUID REQUIREMENTS Decreased perception of thirst, impaired response to serum osmolarity, and reduced ability to concentrate urine after fluid deprivation lead to increased risk of dehydration among older persons." Dehydration is the most common fluid and electrolyte disorder in the longterm care population and among community-dwelling older persons. Dehydration may be accompanied by decreased urine output, elevated body temperature, mucosal dryness, and changes in skin turgor and mental status. Fluid needs of older persons may be generally met with consumption of 30 mUkg of body weight per day or 1 mUkcal. The presence of fever or infection and use of diuretic or laxative medications may increase fluid needs. Derangements in fluid status, either overhydration or underhydration, may affect anthropometric and biochemical measurements, confounding nutritional assessments.
CONCLUSION Notable alterations in organ system functions and body composition occur with aging that have an impact on nutrient metabolism and requirements. Lifestyle factors and chronic diseases that affect older persons are also important considerations. New micronutrient and macronutrient guidelines for older persons have been released by the Food and Nutrition Board of the National Academy of Sciences. Food guide pyramids modified for older persons that incorporate many of the new recommendations have been developed from the U.S. Department of Agriculture food pyramid." Recommendations for fluid and fiber intake are made and supplementation of calcium, vitamin D, and vitamin BI2 are suggested. Practitioners who undertake nutritional assessment and care of older persons should familiarize themselves with the important differences between younger and older adults.
REFERENCES I. Sullivan DH, Moriarty MS, Chernoff R, et al: Patterns of care: An analysis of the quality of nutritional care routinely provided to elderly hospitalized veterans. JPEN J Parenter Enteral Nutr 1989; 13:249--254. 2. Doty RL,Shaman P, Applebaum SL,et al: Smell identification ability: Changes with age. Science 1984;226:1441-1443. 3. Russell RM: Changes in gastrointestinal function attributed to aging. Am J Clin Nutr 1992;55:12035-1207S. 4. Lovat LB: Age related changes in gut physiology and nutritional status. Gut 1996;38:306--309. 5. Lipski PS, Bennet MK, Kelly PJ, et al: Aging and duodenal morphometry. J Clin Pathol 1992;45:450-452. 6. Gullo L, Priori P, Daniele C, et al: Exocrine pancreatic function in the elderly. Gerontology 1983;29:407-411. 7. Holt PR, Balint JA: Effects of aging on intestinal lipid absorption. Am J Physiol 1993;264:GI-06.
SECTION III • Nutrient Metabolism 8. Harari D, Gurwitz JH, Avorn J, et al: Bowel habit in relation to age and gender. Arch Intern Med 1996;156:315--320. 9. Towers AL, Burgio KL, Locher JL, et al: Constipation in the elderly: Influence of dietary, psychological and physiological factors. J Am Geriatr Soc 1997;45:1140. 10. Meier R, Beglinger C, Dederding JP, et al: Influence of age, gender, hormonal status and smoking habits on colonic transit time. Neurogastroenterol Motil 1995;7:235-238. 11. McHugh SM, Diamant NE: Ellect of age, gender and parity on anal canal pressures, contribution of impaired anal sphincter function to fecal incontinence. Dig Dis Sci 1987;32:726-736. 12. Evans WJ, Campbell WW: Sarcopenia and age-related changes in body composition and functional capacity. J Nutr 1993;123 (2 Suppl):465-468. 13. Kehayias J, Heymsfield S (eds): Symposium: Sarcopenia: Diagnosis and mechanisms. J Nutr 1997;127:989S. 14. Lexell JL, Dutta C (eds): Sarcopenia and physical performance in old age. Proceedings of a workshop. Muscle Nerve 1997;20:5--9. 15. Kurpad AV, Vaz M: Protein and amino acid requirements in the elderly. Eur J Clin Nutr 2000;54:S131-S142. 16. Lexell 1: Human aging, muscle mass, and fiber type composition. J Gerontol A Bioi Sci Med Sci 1995;50:No:II-6. 17. Rudman D, Feller AG, Nagraj HS, et al: Ellects of human growth hormone in men over 60 years old. N Engl J Med 1990;323:1-6. 18. Fiatarone MA, O'Neill EF, Ryan ND, et al: Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994;330:1769-1975. 19. Papadakis MA, Grady D, Black D, et al: Growth hormone replacement in healthy older men improves body composition but not functional ability. Arch Intern Med 1996;124:708-716. 20. Sih R, Morley JE,Kaiser FE,et al: Testosterone replacement in older hypogonadal men: A 12-month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661-1667. 21. Snyder PJ, Peachey H, Hannoush P, et al: Ellect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999;84:2647-2753. 22. Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among U.S. adults, 1999-2000. JAMA 2002:288: 1723-1727.
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23. Galanos A, Dieper C, Coroni-Huntley J, et al: Nutrition and function: Is there a relationship between body mass index and functional capabilities of community-dwelling elderly? J Am Geriatr Soc 1994;42:368-373. 24. Jensen GL, Kita K, Fish J, et al: Nutrition risk screening characteristics of rural older persons: Relation to functional limitation and health care charges. Am J Clin Nutr 1997;66:819-828. 25. Stevens J, Cai J, Pamul ER, et al: The ellect of age on the association between body mass index and mortality. N Engl J Med 1998:338:1-7. 26. Russell RM. New views on the RDAs for older adults. J Am Diet Assoc 1997:97:515-518. 27. Barr SI, Murphy SP, Poos MI: Interpreting and using the dietary reference intakes in dietary assessment of individuals and groups. J Am Diet Assoc 2002;102:780-788. 28. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Washington, DC, National Academy Press, 2002. 29. Elahi D, Muller DC: Carbohydrate metabolism in the elderly. Eur J Clin Nutr 2oo0;54:S112-S120. 30. Campbell WW, Crim MC, Dallal GE, et al: Increased protein requirements in elderly people: New data and retrospective reassessments. Am J Clin Nutr 1994:60:501-509. 31. Phillips PA, Rolls BJ, Ledingharn JG, et al: Reduced thirst after water deprivation in healthy elderly men. N Engl J Med 1984;311: 753-759. 32. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: An independent risk factor for vascular disease. N Engl J Med 1991;324:1149-1155. 33. Tucker K: Micronutrient status and aging. Nutr Rev 1995;53:S9-S15. 34. De Valk B, Marx JJM: Iron, atherosclerosis, and ischemic heart disease. Arch Intern Med 1999;159:1542-1548. 35. Tzonou A, Lagiou P, Trichopoulou A, et al: Dietary iron and coronary heart disease risk: A study from Greece. Am J Epidemiol 1998: 147:161-166. 36. Russell RM, Rasmussen H, Lichtenstein AH: Modified Food Guide Pyramid for people over seventy years of age. J Nutr 1999:129: 751-753.
Metabolism in Acute and Chronic Critical Illness Mark Nunnally, MD Patrick Neligan, MA, MB, BcH, FCARCSI Clifford S. Deutschman, MS, MD, FCCM
CHAPTER OUTLINE Introduction The Acute Stress Response Time Course of the Response Metabolic Changes Protein Catabolism Carbohydrate-Glucose Delivery Lipid Clinical Relevance Neuroendocrine Modulation Clinical Significance Metabolism and Chronic Critical Illness Epidemiology Malnutrition of Chronic Critical Illness Neuroendocrine Dysfunction in Chronic Critical Illness Metabolic Bone Disease and Chronic Critical Illness Fluid and Electrolyte Abnormalities in Chronic Critical Illness Neuromuscular Disease in Chronic Critical Illness Conclusion
feedback dysregulation, or genetic variability, becomes pathologic. This prolonged hyperinflammatory state is referred to as the systemic inflammatory response syndrome (SIRS), sepsis, and, in the presence of overt, clinically evident signs and symptoms, the multiple organ dysfunction syndrome (MODS).! Sepsis, SIRS, and MODS also present with a characteristic metabolic picture that differs from what is observed after simple injury and requires specific approaches to metabolic support." After a period of time, a third pattern may emerge. This is a poorly characterized state that is currently referred to as chronic critical illness. Although it is convenient to think of these processes as distinct, in reality they occupy a continuum and the transition from one state to another is rarely clear-cut. In addition, the distinction between adaptive and pathologic processes may be nebulous. In this chapter, we will discuss the metabolic changes observed in acute and chronic critical illness. For completeness, we will mention the characteristic changes of sepsis, SIRS, and MODS, although these are well covered elsewhere. Descriptions in this chapter come from various basic science and clinical investigations and are derived from different models of stress.
THE ACUTE STRESS RESPONSE INTRODUCTION Recovery from a severe bodily insult is a massive, dynamic process, involving functional changes in nearly every organ system and a reprioritization of resources for survival and healing. In general this response is adaptive, with characteristic metabolic changes that are designed to facilitate recovery. This has important implications for nutritional support. However, the adaptive response to injury represents only one of a number of related disorders that confront the critical care physician. There are instances in which the process, because of a prolonged inflammatory stimulus, an overexuberant response,
80
The stress response is a complex, orchestrated neuroendocrine-humoral response to tissue Injury.l lt is mediated through the tissues of the body by a series of signals. Familiarity with this response has profound implications for the nutritional and metabolic management of critically ill patients.' Because the spectrum of human disease is varied in breadth and depth so too are the downstream effects of tissue injury. Thus, the stress response can take on a variety of forms. It is useful to conceptualize the process as being initiated by an insult or injury ("stress"), mediated by a complex signaling network, and effected by end-organ responses.
SECTION III • Nutrient Metabolism
A multitude of insults may initiate the stress response. These include tissue injuries from ischemia, infection, toxins, burns, and trauma. Each has the potential to initiate the response, but it is possible that the mechanisms involved differ, depending on the insult. What is common to each is a perturbation of healthy tissue function that leads to a series of events, both local and global, that activate the stress response. A variety of mediators, including cytokines, neural impulses, hormones, and coagulation factors, may be activated by tissue injury and may lead to clinically important downstream effects. Some of these mediators follow a stereotypical inflammatory pattern. Others constitute a parallel anti-inflammatory response. Still others are capricious, defying attempts to quantify or categorize their behavior. These may represent an effort to keep the response discreet, avoiding collateral damage to healthy tissue. Inflammatory mediators can exert both local and systemic effects. The characteristic response increases activity in pulmonary, cardiovascular, hepatic, renal, central nervous, endocrine, gastrointestinal, and immune systems. These responses result in clinically evident signs and symptoms. Details of these end-organ responses will follow in our description of the stress response and its time course. The stress response is an adaptive phenomenon, representing a mechanism for survival and recovery from large injury. It does not just describe certain aspects of the healing process; it is the healing process. Clinically, this response is both predictable and appropriate.
Time Course of the Response Investigation of the temporal changes associated with a stressor has led to recognition of progressive phases of the stress response (Fig. 9-1). Cuthbertson and Tilstone' divided the stress response into ebb and flow phases, characterized initially by generalized hypometabolism and impaired global perfusion (the "ebb" phase) followed by hypermetabolism and circulatory hyperdynamism (the "flow" phase). This model provides an excellent framework upon which
Time FIGURE 9-1. The "stress" response: altered metabolism in response to a noxious stimulus.
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empiric evidence may be accrued to flesh out the metabolic, immunologic, hematologic, endocrinologic, and histologic features of tissue response to injury. The ebb of the stress response is classically viewed as a period of shock, defined clinically by all the physiologic responses described in an organism with circulatory insufficiency. The sympathetic "fight or flight" response is activated, and cardiac output is preferentially shunted to the most vital organs-the heart, lung, and brain-at the expense of the remaining tissues. The presumption is that the inciting insult, or stressor, will be short-lived. Either the body will be able to recover, or the injury will be lethal. Clinically, the ebb phase manifests by acute decompensation in the patient recently beset by tissue injury, and its length is often determined by the time to systemic resuscitation. This period is characterized by the signs of shock. Systemic end-organ perfusion is poor. Cardiac output drops, the peripheral circulation becomes compromised, surface temperature decreases as blood is shunted from the periphery, and mechanisms to conserve salt and water are activated. The impaired perfusion can exacerbate or extend tissue damage, increasing the extent of repair required during the hypermetabolic phase. The transition from hypo perfusion to hypermetabolism marks a shift in priority from survival and preservation to healing and repair. The stress response, as described in the remainder of this chapter, will deal with the flow phase. Flow, or hypermetabolism, is a description of all the energy needs, growth requirements, and signal modulation that underlie the recovery of the organism from injury. Although a classic time course will be described, it is important to recognize that significant interpatient variability exists. Preexisting conditions, secondary events, and successful and unsuccessful therapies alter the trajectory of illness. Further, new injury can occur at any time during the response. This may lead to ongoing tissue and organ dysfunction, or worse, trigger de novo inflammatory disease and worsen the clinical state. As the patient begins to recover from the initial impact of a major insult, the body mobilizes substrate to repair injury and combat ongoing tissue damage. Resuscitation need not be complete at the onset of flow. In the initial two or three days after injury, there is a progressive increase in various indices of metabolism in the recovering patient. Temperature, oxygen consumption, and carbon dioxide production increase, as do cardiac output, minute ventilation, and substrate mobilization. By day two, in the absence of ongoing resuscitation, the process has peaked and subsequently a gradual decline in metabolism occurs, which is complete by day six. After hypermetabolism subsides, a longer process of anabolism begins. This phase lasts from weeks to months and encompasses a period of restoration of depleted endogenous substrate stores of protein, fat, and glycogen. During flow, elevated cardiac output is distributed over a multitude of tissue beds as a result of peripheral vasodilation of arterioles. It may seem that this would result in enhanced delivery of oxygen to all tissues, but the low resistance of the circulation results in diminished flow to restricted beds, such as the kidney,
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9 • Metabolism in Acute and Chronic Critical Illness
watershed areas of the splanchnic circulation, or any vascular bed affected by atherosclerotic disease. Although regional perfusion may be impaired, evidence points to defects in oxygen and substrate utilization that probably contribute to the metabolic abnormalities that are described below.
Metabolic Changes Hypermetabolism in early healing is a result of the activities of white blood cells. Tissues associated with the highest oxygen utilization and glucose metabolism are those with the highest levels of leukocytes.V Oxygen uptake is augmented not just for intrinsic metabolism but also for the production of reactive oxygen species.' Leukocyte function includes control of infection, modulation of inflammation, clearance of necrotic and apoptotic cellular debris, and preparation of damaged tissue for repair. With healing, metabolic activities shift from inflammation to tissue regeneration and repair. These include angiogenesis, which permits delivery of substrate to the wound. Angiogenesis may be the determinant of the time course of the response with simultaneous hypercatabolism to mobilize metabolic substrate for tissue repair. It is convenient to compare the stress response to starvation metabolism. Although clinically both processes are marked by metabolic reprioritization and often reduced caloric intake, they are fundamentally very different. Starvation is a conservative process during which scarce resources are redirected toward vital organs. Metabolism is restricted. Reserves are broken down and mobilized in a specific order: glycogen and then fat and protein. Ketosis is common as a way of providing energy from fat stores. Glucagon and insulin mediate substrate provision and limit it to that needed for survival. Insulin effects wane with ketosis. The stress response is dramatically different. Tissue damage drives hypermetabolism. Catecholamines, cortisol, glucagon, and cytokines all stimulate rampant degradation of tissue substrate stores. This is reflected in muscle degradation, glycogenolysis, gluconeogenesis, and even aerobic glycolysis. As a result of elevated serum glucose levels, insulin secretion increases and ketosis is inhibited. Glucose, amino acids, and lactate all circulate in abundance during acute stress. These provide a ready source of fuel for the leukocytes and other tissues involved in repair. This increase in serum nutrient macromolecule concentration permits diffusion of these substances into damaged tissue, where the microvascular supply may have been disrupted. The presence of elevated lactate does not necessarily represent anaerobic metabolism or the absence of sufficient oxygen delivery: lactate production is an up-regulated metabolic pathway in stress." The order of substrate utilization appears to reflect the preferences of the most metabolically active tissue types. Glucose uptake is diminished in non immune tissues and is preferentially shunted to leukocytes for metabolism. Amino acids are mobilized from muscle and visceral stores. Glutamine and branched chain amino acids are oxidized preferentially
rather than phenylalanine and aromatic amino acids, especially in muscle and liver.10,1 I Fatty acids provide the bulk of the substrate for visceral function.l-" The liver plays a central role in stress metabolism. Gluconeogenesis from mobilized peripheral amino acid stores and triglyceride-derived glycerol is up-regulated in stress and takes place in the liver.14.15 Fatty acid reesterification also occurs. Integral to the stress response is the mobilization of metabolic substrate from the periphery to the circulation for hepatic modification, redistribution, and consumption. This process results in a reduction in tissue mass, principally muscle, and augmentation of centrally circulating nutrients.
Protein Catabolism Protein stores are preferentially degraded during the stress response. Muscle provides a large portion of the mobilized amino acids, but other tissues contribute as well. Amino acids are released into the circulation and can be extracted and used by the liver for gluconeogenesis or acute-phase protein synthesis. In addition, they can be taken up by injured tissue and used to synthesize enzymes or structural proteins. In severe stress, an ominous finding is impairment of hepatic synthesis.'?" Amino acid metabolism is reflected by increased urea production and increased urine urea nitrogen excretion. Peripheral tissues significantly decrease anabolic protein activities," and skeletal muscle amino acid uptake is reduced." There appears to be an oxidative preference for glutamine for metabolism, and glutamine depletion has been demonstrated in muscle tissue.'? Furthermore, the enzyme glutamine synthetase is up-regulated in lung tissue," suggesting a possible pulmonary role in substrate provision.
Carbohydrate-Glucose Delivery As mentioned, glucose demand to provide substrate for mobilized leukocytes is one of the hallmarks of stress. Commonly, hyperglycemia is encountered in the stressed patient, and this is simplistically described as glucose intolerance. In fact, hyperglycemia may represent an adaptive response to deliver substrate to damaged tissue by mass action and diffusion. To support this hypothesis, increased glucose uptake has been demonstrated in animal models20,21 as has increased glucose oxidation 2o,22 and aerobic glycolysis. This activity appears to correlate with the metabolic activities of leukocytes, the major agents of tissue repair and infection control. A large portion of the elevated serum glucose is derived from hepatic gluconeogenesis. Substrate for glucose is provided by lactate, from the Cori cycle, from amino acids via the alanine-glucose cycle, and from glycerol via triglyceride catabolism. Although glucose availability is high and total body uptake increases, many tissues attenuate their uptake. Skeletal muscle gluconeogenesis is dimlnished-v" as is uptake of glucose into adipose and cardiac tissues.25,26 Functional insulin
SECTION III • Nutrient Metabolism
receptor modification by cytokines is one mechanism described." However, increased levels of glucagon and [3-adrenergic stimulation" probably contribute most to this phenomenon. The continued ability of insulin to suppress ketogenesis suggests that modulation of its effects occurs downstream of the insulin receptor in the cellular signaling pathway.
Lipid Lipid metabolism is dramatically altered in the stress response. The hypermetabolic state is often associated with fatty infiltration of tissues, hypertriglyceridemia, and elevated circulating levels of fatty acids. Such findings can be confused with impaired f3-0xidation of available fat. The actual disposition of body lipid is substantially more complex. Fat oxidation produces a large amount of usable energy by mass and does so at a favorable respiratory quotient, decreasing ventilatory requirements. These properties undoubtedly help account for the presence of fatstores in many tissues of the body. Stored fat is usually in the form of triglyceride within adipocytes, hepatocytes, and muscle, as well as other peripheral tissues. The total body storage of fat is therefore divided into several distinct pools. These pools provide substrate for local metabolism or redistribution via the circulation to other tissues. Lipid is stored as triglyceride in the cell and may be mobilized by intercellular lipases, the most prominent of which is hormone-sensitive lipase. Lipolysis produces free fatty acids and glycerol. Fatty acid can be esterified to triglyceride for storage, oxidized for energy, or converted to ketone bodies for systemic release and metabolism. Glycerol is available for oxidation as well as conversion to amino acid or glucose. The various metabolic pathways shift according to the needs of the organism. Release into the circulation is via breakdown. Glycerol and free fatty acid may freely circulate to the liver or other peripheral tissue sites for uptake. The liver is capable of releasing triglyceride as lipoproteins; lipoprotein lipase on the extracellular adipocyte membrane converts these to fatty acids and glycerol for uptake. In the ebb phase, reprioritization of circulation and decreased tissue metabolism limit fatty acid availability. Uptake of fatty acid is high in tissues with ongoing metabolism. Owing to poor perfusion, adipose stores do not necessarily mobilize. Serum lipid levels may be high or low. As hypermetabolism begins, mobilization and uptake increase. Hormone-sensitive lipase activity is stimulated via the ~2 receptor." Tumor necrosis factor ~ and interleukin (lL)-1 ~ have been demonstrated to increase lipolysisin animal models," and glucagon, cortisol, and vasopressin also stimulate lipolysis. Hepatic and peripheral tissues increase fatty acid and glycerol catabolism from circulating and local stores. A substantial portion of the lipolytic products in peripheral tissues is oxidized locally. Another portion is cyclically re-esterified while a third transfers to the circulation. The net result is an increase in serum fatty acid concentrations.
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Although caloric intake is often inadequate during the stress response, ketogenesis is not seen." Elevated serum insulin inhibits this pathway. Unlike with starvation, ketone bodies are not a common substrate in stress." The reduction of [3-hydroxybutyrate to acetoacetate is impaired,31,32 and the ratio of the two has been used as an early diagnostic marker for sepsis. Hepatic reesterification of fatty acid to triglyceride continues.W' and lipids cycle between the periphery and the liver. Diminished lipoprotein lipase activity in adipose tissue limits uptake.f and serum triglyceride levels increase. Partly as a consequence of elevated free fatty acids, fatty infiltration of tissues may be seen. 17,35 Hepatic steatosis is a common finding.36,37 This may represent an imbalance between uptake and re-esterification, impairment in transport protein, or both.
Clinical Relevance The significance of increased circulating substrate is poorly understood. Elevated fatty acid levels could contribute to hepatic dysfunction by steatosis and may also increase the risk of pancreatitis. Hormone binding to circulating globulins may be diminished. Changes in drug pharmacokinetics are possible as a result of alterations in binding, volume of distribution, or receptor interactions. Protein wasting is a well-recognized consequence of serious illness and may lead to weakness and diminished function. Loss of respiratory motor reserve is a common reason for prolonged ventilator dependence. Patients who survive critical illness and the stress response often face years of rehabilitation to regain a normal level of muscular function. Changes in circulating proteins affect hormone and drug binding. Adequate healing of surgical wounds is impaired. Myopathies and neuropathies commonly found in critically ill patients are at least in part related to protein wasting. One objective of metabolic support in critical illness is to attenuate this loss. Provision of nutrition early in the course of the stress response can spare some protein catabolism, but the process has, in general, been refractory to therapeutic intervention.
Neuroendocrine Modulation Because so many complex changes occur in the stressed organism, itshould be of no surprise that they occur in the context of a very complex system of signaling pathways. Not only do inflammatory mediators such as cytokines and arachidonic acid metabolites affect aspects of the stress response, but also various changes are influenced through adrenergic and endocrine signaling. Neuroendocrine pathways are important in the regulation of metabolism and cellular function in both health and illness. The pituitary gland is responsible for releasing many stimulating hormones that affect different endocrine axes in the body. The gland is under control from the hypothalamus, via secretagogues, and the periphery, via feedback mechanisms.
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Growth hormone (GH) is secreted from the pituitary gland under hypothalamic control. It mediates multiple anabolic and catabolic functions, many through insulinlike growth factors (IGFs). Thyrotropin (TSH) stimulates thyroid secretion of thyroxine (T4). This hormone is peripherally converted to either triiodothyronine (T3),or reverse T3 (rT3), a hormone with uncertain activity. T3 is associated with increased catabolism. Adrenocorticotropic hormone (ACTH) is the pituitary hormone of the adrenal endocrine axis. Its release is stimulated by corticotropin-releasing hormone (CRH) and arginine vasopressin. Itstimulates cortisol, and to a smaller degree, aldosterone release. Adrenal androgens such as dehydroepiandrosterone are stimulated by ACTH. Cortisol stimulates peripheral catabolic activity and helps maintain cardiovascular tone. High levels suppress arginine vasopressin, CRH, and ACTH. In the acute stress response, several hypothalamic pathways are altered. The alterations result from descending neural signaling and cytokine action. There are many descriptions of increased production of CRH38-41 as one of several influences on increased cortisol production. Thyrotropin-releasinghormone (TRH)secretion, however, is decreased.w" The prolactin level is elevated," probably as a result of the interactions of cytokines, vasoactive intestinal peptide, oxytocin, and dopamine.tv" This hormone has a known immunostimulatory role.46-49 In the pituitary gland, hypothalamic influences as well as peripheral feedback lead to additional endocrine changes. Corticotropin levelsare increased,38-41 probably as a consequence of increased CRH and a direct cytokine effect. GH synthesis is augmented. 44,so,51 This manifests as an increase in the number of secretory pulses, as well as in interpulse concentrations.f TSH levels are typically in an unstressed "normal" range. GH exerts effects peripherally, acting to increase lipolysis, to antagonize the effects of insulin, and to augment inflammatory responses. The peripheral response to this hormone may be altered; it is believed that the overall response shifts from anabolism to catabolism.P Peripheral hormone effects are altered. The activities of GH are mediated by other hormones and the activity of these substances may be altered. The activity of IGF-I is decreased,53-55 and the activity of IGF binding protein 3 may be increased52.56 or decreased along with its acid labile subunit. 54,57 IGF-I is associated with tissue anabolism, and the activities of the binding protein both augment its effects and increase the duration of its activities in plasma. The binding protein is a bloodstream carrier for IGF. IGF binding protein 3 protease activity is also increased in acute stress.54,58 The activities of this protease probably account for the decreased levels of its substrate and may represent a mechanism for increase in unbound IGF at the local level. Changes in endocrine signaling are carried out in the various peripheral glands as well as by enzymatic modification of circulating hormone. TSH mediates thyroid activity that is normal or low for unstressed organisms. This mediation occurs despite low levels of circulating active hormone.v-" There are several proposed mechanisms behind this, including decreased amounts of TRH,42,43 a direct cytokine effect,42,60-62 the effects of
administered dopamine, and the effects of endogenous thyroid hormone analogues. 63,64 Serum T4 activity is normal or slightly low, and serum T3 activity is markedly low, characteristic of the euthyroid sick syndrome. Conversion of T4 to T3 is reduced because of diminished enzymatic activity." The relative balance of T4 degradation to T3 and rT3 is tilted toward the latter pathway. Serum T3 breakdown is increased." Because the same enzyme is responsible for both the conversion of T4 to T3 and the degradation of rT3, levels of serum rT3 rise. In addition, the disposition of circulating thyroid hormone is affected by reduced binding globulin, impaired hormone-toprotein binding, and transport and uptake of circulating hormone." It is postulated that this may be due to the effects of elevated serum free fatty acid or elevated serum bilirubin levels commonly seen in the stress response.
Clinical Significance In uncomplicated stress, the neuroendocrine response is adaptive and facilitates repair. In general terms, most of the endocrine changes observed are consistent with a general shift from anabolism to catabolism. Cortisol and GH effect substrate mobilization. Upstream and downstream endocrine signals, such as CRH and IGF-3, do so as well. In a milieu of elevated catecholamine and inflammatory mediator levels, the effect is broadened. An understanding of the role of the characteristic changes of sepsis, SIRS, and MODS is harder to derive. For perceived deficiencies, attempts to study specific replacement therapies have resulted in mixed results. Notable exceptions may be made for vasopressin and, quite possibly, steroid therapy. Vasopressin, in physiologic doses, has proven to be a useful adjunct to hemodynamic support. A reduction in exogenous vasopressor requirements has been demonstrated in clinical trials.68,69 Glucocorticoid and mineralocorticoid replacement, in modest doses, may also benefit patients in septic shock. 70.71 As with any complex process, a reduction to individual elements offers the opportunity for insights, but this approach is prone to oversimplification. What is clear is that the constellation of changes in stress is the result of an elaborate network of signals and responses. Individual roles are less well defined.
METABOLISM AND CHRONIC CRITICAL ILLNESS Although the human body has evolved a series of immune-hormonal responses to acute injuries manifest by the stress or systemic inflammatory response, in some cases the response becomes exaggerated. That is, the characteristic response, geared toward repair of damaged tissue via activation and metabolic support of leukocytes exceeds what is actually required (Fig. 9-2). Malignant hyperinflammation is the basis of SIRS, sepsis, or MODS. The latter occurs when the uncontrolled
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Time
85
Time
FIGURE 9-2. Prolonged hypermetabolism: the development of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS).
FIGURE 9-3. The development of "chronic" critical illness: decreased metabolism and endocrine "burnout."
response evolves to produce clinically recognizable abnormalities in organ function. These take the form of lung injury (the acute respiratory distress syndrome), ileus and malabsorption, renal insufficiency, hepatic synthetic failure, coagulopathy, myopathy and neuropathy, encephalopathy, refractory vasodilatation, and myocardial depression. The metabolic changes that accompany this syndrome are similar to those we have already described. They include glucose and lipid intolerance, increased reliance on amino acids and lactate for peripheral metabolism, and progressive acidosis. Ultimately, patients develop immune paralysis and acquire infections involving organisms that are not normally pathogenic. Despite these myriad abnormalities, modern technology is such that support of this state is possible. Part of this evolution involves metabolic support. In recent years, it has become clear that with current methods we are unable to meet the metabolic demand of these hyperinflammatory states. Thus, from a caloric point of view, patients are purposely underfed. Aggressive attempts to meet demand with protein alone have been marginally successful. Attempts to modify metabolic support, using (0-3 fatty acids, glutamine, modified amino acid formulas, nucleic acids, and hormonal supplementation have shown some promise. However, none has been fully effective. Nonetheless, the ability to sustain patients in this severely compromised state has led to the emergence of a subgroup of critically ill patients that enter a chronic, relatively stable, but highly pathologic, phase of illness. This has been termed prolonged or chronic critical illness (CCI) (Fig. 9-3). As stated, it is convenient to view the acute stress response, systemic inflammatory response, and CCI as a continuum. In this context, the stress response is a defined reproducible, adaptive paradigm (see Fig. 9-1). SIRS or MODS represents the response to ongoing inflammation or, perhaps, an overly exuberant response to an initial insult (see Fig. 9-2). In contrast, CCI must be regarded as an abnormal and, indeed, futile, process (see Fig. 9-3). This is a group of patients who, without the assistance of modern intensive care interventions, would not have survived critical illness. A teleologic
origin of CCI is thus unlikely. It is unclear why a specific subgroup of critically ill patients develop this syndrome. Genetic predisposition has been suggested.F" CCI is characterized by failure to be weaned from mechanical ventilation, immobilization, hypoalbuminemic (kwashiorkor-like) malnutrition, neuroendocrine exhaustion, metabolic bone disease, myopathy, and neuropathy. There is chronic depletion of physiologic reserve, akin to accelerated aging. Patients with CCI remain in intensive or intermediate care units for a prolonged period, consume scarce resources, and often die of infectious complications." Survival is associated with significant morbidity." These patients represent a huge challenge to physicians in terms of therapeutics, ethics, and resource utilization." In this section we will explore the paradigm of CCI in terms of metabolic and neuroendocrine regulation.
Epidemiology There is no specific definition of CCI. In general, the term CCI is used to refer to patients who remain in intensive or intermediate care units for weeks to months." The majority of patients with this syndrome fail to be weaned from mechanical ventilation." Many are in the "recovery" phase of MODS due to sepsis. 79,8o Other characteristics of CCI include prolonged stay in the hospital (14,21, and 29 days or more), the requirement for tracheostomy (unrelated to face, neck, or mouth procedures), and the inability to restore "normal" levels of serum albumin." Regardless of the perspective, these patients represent 5% to 10% of the population in intensive care units (ICUS).81.82 Two series by Spicher and White83 and Gracey and colleagues" shed light on the typical profile of patients with CCI. Such patients are more likely to be elderly and male and have had cardiac or abdominal surgery. There is a significant association with a history of lung disease. MODS often has complicated the primary illness. Patients requiring mechanical ventilation for neurologic problems or after surgery have better prognoses than those with cardiac or pulmonary disease.
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FIGURE 9-4. Mean (+SE) change in weight from base line among patients with the acute respiratory distress syndrome at the time of discharge from the intensive care unit and at 3, 6, and 12 months. (From Herridge MS, Cheung AM, Tansey CM, et al: One-year outcomes in survivors of the acute respiratory distress syndrome. N Eng) J Med 2003;348:683-693.)
There is no specific method of predicting the development of CCI.85,86 Indeed, the etiology is probably multifactorial and includes premorbid status, lack of complete source control, number of failed organ systems, and genetic variance. Trauma victims and postoperative patients have better outcomes, and these improve inversely with age. 84 Of patients who survive critical illness, an average of 18% of premorbid body weight is lost" (Fig. 9-4). Parallel with the aging population and earlier more aggressive critical care treatment, the absolute and relative number of patients with CCI is increasing.'" This has significant implications for future health care resource utilization." Wong and colleagues 85 determined that patients with CCI (>14 days stay), represented 7.3% of admissions, but accounted for 43.5% of total days in the ICU. Higgins and colleagues" investigated risk factors for prolonged critical illness in 34 ICUs in 1998 (Project IMPACn. Infection and mechanical ventilation at 24 hours after admission were the main risk factors, along with lack of an intensive care specialist and prolonged ward stay before admission to the ICU. Interestingly, severity of illness was not a factor. This was also seen in other studies.86 Because these scoring systems control for both acute illness and physiologic reserve, the implication is that CCI results from therapeutic failure,80 inadequate critical care,89 provision of parenteral nutrition to inappropriate patientsf" or preoperative malnutrition."
Malnutrition of Chronic Critical Illness McClave and colleaguesf evaluated 180 patients treated with parenteral nutrition over a 12-month period. Of these patients, 25%had a marasmus, a form of malnutrition characterized by normal serum albumin levels and a reduction in body weight. This type of malnutrition is commonly associated with starvation and is rarely seen in ICUs. Patients rapidly respond to delivery of adequate nutrition.
Conversely, 45% of patients in the study were described as having kwashiorkor-like (hypoalbuminemic) malnutrition. Kwashiorkor-like malnutrition is a common feature of CCI. This appears to result from prolonged activation of the stress response, with persistence of hyperadrenergic catabolism." There is futile substrate cycling and inadequate utilization of carbohydrates and fats with concomitant depletion of visceral and muscular protein. Kwashiorkor-like malnutrition is characterized by hypoalbuminemia, due to the persistence of hepatic protein reprioritization (toward inflammatory mediators and acute phase proteins) and continued "capillary leak." In this circumstance, hypoalbuminemia represents a nonspecific marker of severity of illness." Lack of restoration of normal serum albumin levels is a good indicator of failure of weaning from mechanical ventilation'" and indeed of CCI.96,97 There is significant loss of skeletal muscle mass with preservation of body fat content. Patients develop significant muscle weakness, and this contributes to failure to wean them from mechanical ventilation." The amount of weight loss is unusual, owing to increased body water (anasarca) and maintenance of body fat deposits. Patients with CCI are thus hypercatabolic, not hypermetabolic. This results in loss of diaphragmatic muscle mass and loss of respiratory muscle strength. Feeding of patients with CCI should be focused on supporting body protein mass." It is not possible for these patients to be converted to an anabolic state with nutritional therapy alone. Feeding strategies should be focused on nitrogen retention rather than total calorie load. Thus 1.5 to 2.0 g/kg of protein should maintain muscular mass, whereas 20 to 35 g/kg of nonprotein calories will meet metabolic demands.P Therapy is targeted toward positive, or at least less negative, nitrogen balance. Patients with CCI are vulnerable to both overfeeding and the refeeding syndrorne.l'" Although the enteral route is preferred to maintain gut mucosal integrity'?' and to avoid the infectious complications associated with parenteral feeds,102 often this route is inaccessible or the patient is intolerant. Complications include high gastric residuals, abdominal distension, nausea and vomiting, aspiration pneumonitis, and diarrhea.P" If absorption of enteral feeds is questionable, supplemental parenteral nutrition may be used."
Neuroendocrine Dysfunction in Chronic Critical Illness Acute and chronic critical illness should be seen as separate neuroendocrine paradigms. In the acute phase response there is hypersecretion of pituitary hormones, with peripheral insensitivity, presumably to favor the catabolic effects of hormones and maintain substrate delivery. Conversely, in CCI, there is restoration of peripheral hormonal sensitivity, but loss of central drive. From this perspective, CCI should be considered a state of neuroendocrine exhaustion. Clearly, neuroendocrine dysfunction is a key, perhaps causative, element of CCI (Fig. 9-5).
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Acute phase
Chronic phase
87
Recovery phase
FIGURE 9-5 Simplified concept of the pituitary-dependent changes during the course of critical illness. In the acute phase of illness, anterior pituitary hormonal secretions increase, but there is peripheral resistance to anabolic activity. In chronic critical illness, anterior pituitary secretion is uniformly reduced. Cortisol levels are maintained by a peripheral drive, but this may ultimately fail. The onset of recovery is characterized by restored sensitivity of the anterior pituitary to reduced feedback control. (Adapted from Van den Berghe GH, de Zegher F, Bouillon R: Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83: 1827-1834.)
Hypothalamus-Pituitary-Adrenal axis The activation of the hypothalamus-pituitary-adrenal (HPA) axis is considered the key neuroendocrine response to acute stresses. Cortisol has multiple physiologic roles in this circumstance; one is that of shifting metabolism toward substrate delivery. This helps explain an elevated rate of hepatic gluconeogenesis, increased free fatty-acid release from adipose tissue, and amino acid release from body proteins inhibiting adipose tissue glucose uptake.'?' This cascade provides energy to cells for immediate immunologic response and tissue repair. Cortisol also helps maintain normal vascular tone. This hormone is a cofactor for vascular smooth muscle responsiveness to epinephrine, norepinephrine, and angiotensin II. Further it acts as a positive inotrope. Acute deficiency of cortisol is associated with cardiovascular collapse manifest by vasodilated shock resistant to catecholamines.P' Cortisol has immunosuppressive effects at every level in the immune axis. This appears to be an immune self-regulatory effect. During the normal recovery from acute stress, the HPA resets itself, and serum ACTH and cortisol levels return to normal, facilitating tissue anabolism. In a minority of patients the system failsto reset, and HPAactivity realigns to favor peripheral activation. In CCI, ACTH levels are low, but cortisol levels remain elevated. The factors responsible for persistent cortisol release are unclear, although this release most likely relates to continued production of tissue cytokines due, for example, to unresolved infection. There is a decrease in dehydroepiandrosterone production in CCI, with paradoxically increased renin levels but decreased aldosterone levels, suggesting reprioritization of glucocorticoid over mineralocorticoid production. Although glucocorticoids are required for maintenance of normal vascular tone, it is unclear what benefit, if any, is
derived from persistent hypercortisolemia in CCI. Indeed the immunosuppressive and catabolic effects of glucocorticoids may prolong critical illness further. Conversely, there exists a subgroup of patients with absolute or relative adrenal insufficiency.l'" This represents a potentially devastating loss of physiologic reserve. In critical illness, adrenal insufficiency is usually diagnosed after a failure to wean from vasopressor medications despite control of the infective source. The overall incidence of adrenal insufficiency as quoted in the literature is variable, depending on the population of patients studied and the diagnostic criteria. Rivers and colleagues.l'" using a 0.25 Ilg cosyntropin stimulation test, diagnosed adrenal insufficiency (serum cortisol concentration <20 ug/dl, at all time points, with Acortisol [60 minutes after ACTH minus baseline] of <9 Ilg/dL) in 8.9%of 104vasopressor-dependent patients. Barquist and Kirton107prospectively screened patients in a surgicallCU over a 9-month period. Although the overall incidence of adrenal insufficiency was 0.66%, this rose to 6% for patients who remained in the ICU for 14 days; 11 % if those patients were older than 55 years. Some authors have suggested that these studies may have underestimated the incidence of adrenal insufficiency. lOS, 108 Marik and Zaloga 109 investigated 59 patients with septic shock, comparing outcomes (steroid responsiveness) after baseline (cortisol) to 1 to 250 Ilg ACTH stimulation tests. Of these patients, 22% showed steroid responsiveness (vasopressors were stopped within 24 hours of starting hydrocortisone therapy). A random cortisol concentration of more than 25 ug/dl, was the most sensitive indicator of steroid responsiveness. Annane and colleagues'? demonstrated a 10% absolute risk reduction (63% vs. 53% hazard ratio, 0.67; 95% confidence interval, 0.47 to 0.95; P=.02) for death and for adrenal insufficiency (diagnosed by the cosyntropin test) in
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patients treated with gluco- and mineralocorticosteroids. Thus, restoration of physiologic levels of adrenal hormones improves outcomes in critically ill patients.
Somatrophic Axis In the acute stress response there is a loss of GH pulsatility, an increase in interpulsile levels, and a concomitant decrease in the serum levels of IGFs (Fig. 9-6). The amounts of GH binding proteins decrease, as do those of certain IGF binding proteins. This peripheral resistance to GH reflects inhibition of its indirect anabolic effects and predominance of its direct catabolic effects. In CCI, again reduced pulsatility is seen. However, the peaks are lower and the troughs are higher than normal or those seen in acute critical illness. I09•11O GH release is erratic, but levels are low normal. Conversely, levels of IGFs, particularly IGF-1, and GH binding protein are reduced. This appears to reflect a relative deficiency of GH, which may explain the cachectic wasting illness so prevalent in this patient population. It is tempting to believe that relative or absolute deficiency of GH is responsible for the prolonged catabolism associated with CCI. There is some evidence that high-dose GH increases protein synthesis in a variety of perioperative and critical care settings.'!"!" Many intensive care specialists believed that GH therapy would reduce ventilatory times, shorten the duration of stay in ICUs, and improve outcomes. This approach was controversial, however.!" Therapeutic use of ---Health - - - Critical illness acute phase - - - Critical illness chronic phase
recombinant GH was attempted in the 1990s.Takala and colleagues!'? undertook a multicenter randomized, controlled trial of 527 intermediate-stay ICU patients. Unfortunately, this high- dose GH therapy was associated with an absolute increase in mortality of between 19% and 26%. This doubling of the mortality rate in the investigational group was associated with progressive multiorgan failure associated with overwhelming sepsis. A number of criticisms of this study have been published. These relate primarily to the dose of GH administered (0.07 to 0.13 mg/kg). This dose resulted in very high levels of IGF-1 and may have led to a hypermetabolic state, triggering cellular apoptosis'P that aggravated fluid retention, insulin resistance, hypoadrenalism, and hypothyroidism.P' Undoubtedly, negative feedback control was obliterated, because the agent is direct acting, and this may have contributed to adverse outcomes. Van den Berghe and colleagues!" suggested that apparent pituitary failure during CCI most likely reflects an abnormality of hypothalamic origin. Consequently, the use of GH secretagogues, such as growth hormonereleasing hormone (GHRH) and growth hormonereleasing peptide (GHRP), is more likely to restart the somatotrophic axis, while maintaining endogenous control of GH release. Thus, when continuous infusions of GHRH and GHRP were administered to patients with CCI,123.124 there was a 6- to lO-fold increase in GH pulsatility, with a dramatic increase in plasma levels of IGFs and IGF binding proteins. When combined with TRH, there was evidence not only of this increased pulsatility and reactivation of peripheral response, but also of the presence of active feedback inhibition loops, preventing overtreatment. 125 Clearly, reactivation of the GH axis remains a priority in the management of patients with CCI. To date, there is little support for the use of recombinant GH for this purpose. The use of GH secretagogues appears promising but requires rigorous examination in a randomized, controlled trial.
Thyroid Axis
Time FIGURE 9-6. Illustrative serum concentration profiles of growth hormone (GH), comparing levels in a healthy individual with those in patients in the acute phase and the chronic phase of critical illness within an intensive care setting. (Adapted from Van den Berghe GH, de Zegher F, Bouillon R: Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83: 1827-1834.)
The euthyroid sick syndrome is characteristic of acute critical illness. T3 levels are reduced owing to reduced peripheral conversion of T4 to T3 and increased T4 to rT3 conversion. TSH levels are generally normal. With recovery, T3 rises progressively. In contrast, during CCI, T3 and T4 levels remain depressed. TSH levels are either low or normal. 110 Although nocturnal TSHsecretion declines dramatically, this pattern appears to be related to hypothalamic failure, because the thyroid axis can be reactivated by intravenous administration of TRH.126 There is a resultant drop in markers of hypercatabolism and urea production and bone degradation. Thyroid hormone deficiency appears, then, to contribute to prolonged catabolism and postponed anabolism in CCI. Brent and colleague'" studied the administration of T4 to patients with low T4 levels in a medical ICU. Compared with control subjects, the treatment group had increases
SECTION III • Nutrient Metabolism
in T3 and T4 levels, with a concomitant decrease in TSH. Mortalitywas similar in both groups. Van den Berghe and colleagues'" proposed that combining thyrotropin and somatropin secretagogues would stimulate anabolism and prevent overstimulation (catabolism) and production of rT3. This synchronous administration appears to optimally increase circulating levels of thyroid hormones, IGFs, and binding proteins, while preserving negative feedback mechanisms. Again, these data require confirmation by a large clinical trial.
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The administration of LH-releasing hormone (LHRH), in combination with somatotropes and thyrotropes, would be expected to reactivate the array of anabolic hormone systems. This has been studied in 33 men with CCI by Van den Berghe and colleagues.!" LHRH alone appeared to have little effect; however, when combined with GHRP-2 and TRH, there was significant improvement in target organ responses and anabolism, as evidenced by reduced ureagenesis and increased osteocalcin levels. This study demonstrates that hypothalamuspituitary dysfunction affects all of the anabolic hormones in CCI, and reactivation of pituitary activity requires replacement of each of the hypothalamic-tropin hormones. Previously, attempts were made to use peripheral hormonal therapy, with GH or thyroxine, which was proved to be ineffective-" or dangerous.I'? because the nature of hormonal deficiency was misunderstood.
Other Hormone Systems in CCI Testosterone is known to be an essential anabolic hormone. Virtually every catabolic state is associated with reduced serum testosterone levels.P' In acute chronic illness, the testosterone level is reduced despite normal luteinizing hormone (LH) levels. In CCI, both testosterone and LH levels are reduced.'!" This hypogonadotropic hypogonadism has a significant impact on the prolongation of hypercatabolism in critical illness. It is known that restoration of the somatotropic axis using secretagogues often requires coadministration of androgens.!" Hypogonadism may result from persistent cytokine activity, pain, opiate, and dopamine administration. Thus, reactivation of the gonadotropic axis would be predicted to reduce catabolism.
Metabolic Bone Disease and Chronic Critical Illness The majority of patients with CCI develop metabolic bone disease, principally osteomalacia and bone hyperresorption.!" This results from prolonged immobilization, vitamin D deficiency, malnutrition, malabsorption, and renal and liver dysfunction (Fig. 9-7). Secondary hyperparathyroidism is present, 132 In addition, iatrogenic
Stress disease immobilization
Decreased Vitamin D intake and/or absorption Hepatic 25-D formation Renal 1.25-D formation
Decreased GI calcium absorption
FIGURE 9-7. Diagram of proposed metabolic pathways that lead to bone hyperresorption with elevated urine N-telopeptide(NTx) levels.GI,gastrointestinal; PTH, parathyroid hormone. (From Nierman OM, Mechanick JI: Biochemical response to treatment of bone hyperresorption in chronically critically ill patients. Chest 2000; 118: 761-766.)
Increased PTH
Osteoclast activation
Increased Increased bone resorption ----+ urinary NTx
I+--
Increased bone resorption
Increased extracellular calcium
Decreased PTH
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osteopenia is common owing to glucocorticoid and heparin administration. Renal failure accelerates secondary hyperparathyroidism, hypocalcemia, and hyperphosphatemia. Metabolic bone disease may mirror neuroendocrine dysfunction as described above. CCI is associated with elevated levels of circulating cytokines.P' such as IL-l and [L-6, which affect bone rnetabolism.P" [L-6 is a major inducer of osteoclast production and mediator of pathogenic bone resorption.P' Nierman and Mechanick!" investigated 49 patients with CC[ (median hospital stay before admission was 30 days) in a respiratory stepdown unit for evidence of metabolic bone disease. Of these patients, 92% had increased urinary levels of Ntelopeptide, signifying bone hyperresorption. Nineteen patients (42%of total patients) had elevated parathyroid hormone (PTH) levels consistent with a predominant vitamin D deficiency, 4 patients (9%) had suppressed PTH levels consistent with predominant hyperresorption from immobilization, and 22 patients (49%) had normal PTH levels consistent with an overlap of both vitamin D deficiency and immobilization. In a follow-up study.P' the same authors studied the biochemical response of bone hyperresorption in patients with CC[ to treatment with either calcitriol (activated vitamin D) alone or calcitriol and pamidronate (an antiresorptive biphosphonate agent). Calcitriol alone failed to halt bone hyperresorption; however, the drug combination significantly reduced Ntelopeptide levels, but not PTH levels. This suggests that bone resorption for many patients with CCI is PTH independent (see Fig. 9-7). Hyperphosphatemia is a common problem in CCI, resulting from malnutrition, vitamin D deficiency, malabsorption (particularly of calcium, fat, and fat-soluble vitamins), refeeding syndrome, the use of antacids (which bind phosphate), dialysis, and therapeutic use of insulin. Phosphate is an essential factor for nucleic acid (and thus protein) production and cellular energetics. Hypophosphatemia is associated with profound muscular weakness, lethargy, and cardiovascular and hematologic dysfunction.l'" Meticulous attention should be paid to serum phosphate levels in critically ill patients, particularly those in whom feeding has been delayed.I'"
Fluid and Electrolyte Abnormalities in Chronic Critical Illness Electrolyte and acid-base abnormalities are common in CCI. Hypematremia occurs because of free water loss. Patients with CC[ are particularly vulnerable to insensible water loss from open wounds, pressure ulcers, and prolonged mechanical ventilation, particularly when the ventilation liberation strategy involves spontaneous breathing ("trach-eollar" trials). Liberal use of loop diuretics, in an attempt to reduce anasarca, is associated with hypematremia, hypochloremia, and hypokalemia. This frequently causes neuromuscular weakness and metabolic alkalosis. Inappropriate diuresis commonly follows acute renal failure, hyperuricemia, (associated with overfeeding) and depletion of calcium and potassium.
Hyponatremia may be associated with a syndrome of inappropriate anti diuresis or cerebral salt wasting, due to neurologic dysfunction, mechanical ventilation, opiates, and antidepressants. This also occurs with inappropriate use of hypotonic intravenous fluids in patients with renal dysfunction. Delayed resolution of body water expansion is ubiquitous in CCI.136 This is easily observed as anasarca. It results from tissue fluid sequestration associated with the stress response. Clark and colleagues'" demonstrated in a group of 21 septic patients that total body and extracellular water were 13 and 9 L above predicted normal at the end of resuscitation. At 21 days, water levels in these patients remained 8 and 5 L above normal. Critically ill patients routinely exhibit depletions of potassium, magnesium, and phosphorus. These are associated with fluid sequestration, refeeding, diarrhea, high ostomy outputs, diuretic usage, and inadequate electrolyte repletion. The importance of these elements for restoration of neuromuscular function and intracellular energetics cannot be overstated.I" Deficiencies are associated with cardiac arrhythmias, muscular weakness, and failure to be weaned from mechanical ventilation. Aggressive repletion of these electrolytes to high normal values is strongly recommended. Metabolic alkalosis is common. One major cause is the depletion of the total weak acid pool, principally albumin and phosphorus, leading to urinary chloride wasting. Clearly nutritional strategies for patients with CC[ must include meticulous measurement of requirements and losses of fluids, electrolytes, and trace metals. This can be very challenglng." Malnourished patients, with deficiencies of essential electrolytes and trace elements, particularly zinc and vitamin C, are particularly prone to show poor wound healing and to develop pressure ulcers. A large French study of supplementary nutrition in elderly critically ill patients'P revealed a decrease in the incidence of such sores compared with the incidence in control subjects.
Neuromuscular Disease in Chronic Critical Illness Muscular atrophy is universally seen in prolonged critical illness due to hypercatabolism. Muscular weakness, leading to a prolonged need for mechanical ventilation, may result from this and other mechanisms.F'" These disorders, typically labeled critical illness myopathy and critical illness polyneuropathy (C[P),71 do not respond to nutritional therapy. C[Prepresents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously when the critical illness resolves.l'? De Jonghe and colleagues!" studied recovering critically ill patients for what they termed "[CU-acquired paresis" (lCUAP). Among 95 patients who achieved satisfactory awakening (for examination), the incidence of [CUAP was 25.3% (95% confidence interval, 16.9% to 35.2%). All patients with ICUAP had a sensorimotor axonopathy, and all patients who underwent a muscle biopsy had
SECTION III • Nutrient Metabolism
specific muscle involvement not related to nerve involvement. Garnacho-Montero and colleagues'" studied ClP in a cohort of septic patients with multiorgan failure. Of 73 patients enrolled, 46 had evidence of C[P as demonstrated on electrophysiologic studies. Interestingly, there was a significant association between hyperosmolar syndromes and the development of C[P: this included hypernatremia, hyperglycemia, and parenteral nutrition. In a small study, Fletcher and colleagues'< found evidence of C[P in 95% of survivors of critical illness. ln other series, between 70% and 80% of patients with CC[ developed C[P.140 Herridge and colleagues" followed 109 survivors of critical illness in the year after hospital discharge. Most of the patients had significant postmorbid disability, of which profound muscular weakness was the most prevalent. Among the critical illness myopathies, three main types have been identified: a non-necrotizing "cachectic" myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments (thick filament myopathy), and an acute necrotizing myopathy of intensive care."? Clinical manifestations of both critical illness myopathies and C[P include delayed weaning from mechanical ventilation, muscle weakness, and prolongation of the mobilization phase. The pathogenesis of these neuromuscular complications is incompletely understood." In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers.140.143 No specific strategies have been discovered to prevent or treat critical illness myopathy and C[P, except source control and avoidance of risk factors-high-dose steroids, neuromuscular blockers (particularly when used together), hyperosmolar syndromes, and hyperglycemia.
CONCLUSION Critical illness occurs as a result of a maladaptive systemic inflammatory response. Without interventions, aimed to support vital organ systems, the patient would not survive. This acute illness syndrome manifests as prolongation of the "normal" response, which the body has developed to deal with acute stress. Metabolically a persistent catabolic state exists, paralleled by activation of the hypothalamus-pituitary axis, with peripheral inactivation of anabolic hormones. The majority of patients, with appropriate supportive care and control of the source of the problem, emerge from critical illness, albeit with some reduction in physiologic reserve. A smaller subset of patients will fail to recover, entering a relatively stable state of dependence. This chronic critical illness syndrome is associated with persistence of catabolism, changes in body water and electrolyte composition, and loss of central neuroendocrine drive. The patient appears to enter a phase of accelerated aging, which no specific intervention has been proven to slow. To date, combinations of hypothalamic secretagogues have been the most promising interventions introduced experimentally to halt this state of neuroendocrine exhaustion. We await, keenly, the results of further investigation.
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101. Kompan L, Kremzar B, Gadzijev E, Prosek M: Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failureafter multiple injury. Intensive Care Med 1999;25:157-161. 102. Heyland OK, MacDonald S, Keefe L, DroverJW: Total parenteral nutrition in the critically ill patient: A meta-analysis. JAMA 1998; 280:2013-2019. 103. Hwang TL, Lue MC, Nee YJ, et al: The incidence of diarrhea in patients with hypoalbuminemia due to acute or chronic malnutrition during enteral feeding. Am J Gastroenterol 1994;89: 376-378. 104. Pilkis 51, Granner OK: Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol 1992; 54:885-909. 105. Cooper MS, StewartPM: Corticosteroid insufficiency in acutely ill patients. N Engl J Med2003;348:727-734. 106. Rivers EP, Gaspari M, Saad GA, et al: Adrenal insufficiency in highrisksurgicaliCU patients. Chest2001;119:889-896. 107. Barquist E, Kirton 0: Adrenal insufficiency in the surgical intensive care unit patient. J Trauma 1997;42:27-31. 108. Marik PE, Zaloga GP: Adrenal insufficiency in the critically ill: A new look at an old problem. Chest2002;122:1784-1796. 109. Marik PE, Zaloga GP: Adrenal insufficiency during septic shock. CritCare Med 2003;31:141-145. 110. Van den BergheGH, de Zegher F, Bouillon R: Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms.J ClinEndocrinol Metab 1998;83:1827-1834. 111. Manson JM, Smith RJ, Wilmore OW: Growth hormone stimulates protein synthesis during hypocaloric parenteral nutrition. Role of hormonal-substrate environment. Ann Surg 1988;208:136-142. 112. Gore DC, Honeycutt 0, Jahoor F,et al: Effect of exogenous growth hormone on glucose utilization in burn patients. J Surg Res 1991; 51:518-523. 113. Jeevanandam M, Ali MR, Holaday NJ, Petersen SR: Adjuvant recombinant human growth hormone normalizes plasma amino acids in parenterallyfed trauma patients.JPEN J Parenter Enteral Nutr1995;19:137-144. 114. ZieglerTR, Rombeau JL, Young LS, et al: Recombinant human growth hormone enhances the metabolic efficacy of parenteral nutrition: A double-blind, randomized controlled study. J Clin Endocrinol Metab 1992;74:865-873. 115. Ponting GA, Halliday 0, Teale JD, Sim AJ: Postoperative positive nitrogen balance with intravenous hyponutrition and growth hormone. Lancet 1988;1:438-440. 116. Voerman HJ, van Schijndel RJ, Groeneveld AB, et al: Effects of recombinant human growth hormone in patients with severe sepsis. Ann Surg 1992;216:648-655. 117. Voerman81,Strackvan Schijndel RJ, GroeneveldAB, et al: Effects of human growth hormone in critically ill nonseptic patients: Results from a prospective, randomized, placebo-controlled trial. CritCare Med 1995;23:665-673. 118. Pichard C, Kyle U, ChevroletJC, et al: Lack of effectsof recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: A prospective, randomized, controlled study. CritCare Med 1996;24:403-413. 119. Takala J, Ruokonen E, Webster NR, et al: Increased mortality associated with growth hormone treatment in criticallyill adults. N Engl J Med 1999;341:785-792. 120. Osterzie1 KJ, Dietz R, Ranke MB: Increased mortality associated withgrowthhormone treatment in critically illadults. NEngl J Med 2000;342:134-135. 121. Van den Berghe GH: Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 2000; 342:135-136. 122. Van den Berghe GH, de Zegher F, Bowers CY, et al: Pituitary responsiveness to Gl-l-releasing hormone, GH-releasing peptide-Z and thyrotrophin-releasing hormone in critical illness. Clin Endocrinol (Oxf) 1996;45:341-351. 123. Van den BergheGH, de Zegher F, Bouillon R: The somatotrophic axis in critical illness: Effects of growth hormone secretagogues. Growth Horm 1GF Res 1998;8(suppl B):153-155. 124. Van den BG, de Zegher F, Baxter RC, et al: Neuroendocrinology of prolonged critical illness: Effects of exogenous thyrotropinreleasing hormone and its combination with growth hormone secretagogues, J Clin Endocrinol Metab 1998;83:309-319.
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Fluid and Electrolytes Todd W. Canada, PharmD, BCNSP Joseph I. Boullata, PharmD, BCNSP
CHAPTER OUTLINE Introduction Fluid and Electrolyte Homeostasis Fluid Disorders What Constitutes a Serious Electrolyte Abnormality? Sodium Disorders Potassium Disorders Magnesium Disorders Phosphate Disorders Calcium Disorders Conclusion
INTRODUCTION Clinicians caring for patients receiving nutritional support need to understand the primary physiologic principles of fluid and electrolyte regulation as well as the diagnosis and therapy of common clinical disorders of fluid and electrolyte regulation, which are often complex. A thorough appreciation of the body's homeostatic mechanisms for fluid and electrolytes may help prevent patient morbidity and, as a result, improve overall care. Patients requiring nutritional support often have alterations in their gastrointestinal and renal physiologic functions, thus predisposing them to clinically significant fluid and electrolyte disorders. In this chapter the focus will be on diagnostic and treatment strategies for common fluid and electrolyte disorders seen in the adult population receiving nutritional support.
FLUID AND ELECTROLYTE HOMEOSTASIS Water is freely permeable to all body compartments and will be distributed throughout to constitute total body water.1,2 Totalbody water isdivided among three main compartments: intracellular, transcellular, and extracellular
fluid compartments (Fig. 10-1). The amount of total body water, which is normally 50% to 60% of body weight in adults, depends on the lean body mass-to-fat ratio because the water content of fat is approximately 10% compared with 75% for muscle. Given the larger muscle mass of men, women tend to have slightly lower total body water content (generally 50%) owing to their increased total body fat content and lower lean body mass. Age also affects total body water content; in elderly men it tends to decrease to approximately 50% and in elderlywomen to 45%owing to their lower lean body mass." Physiologic fluid in each of the compartments is a solution made up of particles in water. This mass of particles, or solute, includes those that dissociate as ions (the electrolytes). Besides having electrochemical properties, the electrolytes are also osmotically active. The concentrations of electrolytes in physiologic fluid can be measured in milligrams per deciliter (mg/dL) but are more often measured in millimoles per liter (mmoIlL) or in milliequivalents per liter (mEq/L), which better describes the number of particles and their chemical ability to combine with each other. The number of particles per mEq will depend on the valence of the electrolyte, whereas the number of particles per mmol is always the same for all substances. Both mmol and mEq will be referred to in this chapter, recognizing that laboratory and clinical practices do vary by setting; briefly, for monovalent electrolytes 1 mmol = 1 mEq, and for divalent electrolytes 1 mmol =2 mEq. Although water moves freely across membranes between compartments, this is not true for electrolytes. As a result, electrolyte composition differs among compartments (Table 10-1). At the same time, the net electrical charge between cations and anions (including some proteins) is neutral within a compartment, and the fluid osmolality is the same across compartments. The intracellular fluid compartment is considered to be the largest compartment and comprises approximately two thirds of total body water content. Regulation of this compartment is required for normal cellular function and is achieved primarily by regulation of water balance. Dehydration, most commonly referred to as a total body water deficit, affects the intracellular compartment predominantly and is one form of hypovolemia (Fig. 10-2).3 Dehydration refers to losses of intracellular
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Total Body Water (TBW) 50%-60% of body weight
1
Extracellular Fluid (ECF) 1/3 of TBW or 20% of body weight
Intracellular Fluid (ICF) 2/3 of TBW or 40% of body weight Transcellular Fluid Volume (Salivary glands, pancreas, CSF, GI tract, aqueous humor) 2.5%ofTBW
Intravascular Space 1/ 4 of ECF or 5% of body weight
Interstitial Space 3/4 of ECF or 15% of body weight
FIGURE 10-1. Distribution of body water. CSF, cerebrospinal fluid; GI, gastrointestinal.
water that ultimately cause cellular desiccation with resulting hypematremia and elevated serum osmolality. Patients with pure dehydration may lack circulatory instability; however, most patients with dehydration also have concurrent volume depletion." The transcellular fluid compartment is the smallest of the three compartments and comprises only about 3% of the total body water. This compartment is rarely taken into consideration in assessment and management of fluid and electrolyte disorders. It is more often assumed to be part of the extracellular fluid space. The extracellular fluid compartment makes up about one third of total body water and is the most clinically important, because it contains the intravascular and interstitial spaces. The membrane between the intravascular space and the interstitial space is permeable to most electrolytes. However, the membrane separating the extracellular and intracellular fluid compartments does not allow passive distribution of electrolytes. The intravascular space is primarily affected by extracellular fluid loss, also known as volume depletion (another form of hypovolemia), that may be accompanied by
IlDIII!II
hyponatremia, hypematremia, or normal serum sodium (see Fig. 10-2).3 Volume depletion describes the loss of sodium with water from the extracellular fluid compartment (intravascular and interstitial space) that commonly occurs after gastrointestinal hemorrhage, vomiting, diarrhea, and diuresis. Patients with volume depletion exhibit circulatory instability.' The movement of water is generally governed by osmotic balance to maintain osmolality across fluid compartments. Potassium is the primary intracellular osmole and acts to hold water within the cells. Sodium is the dominant extracellular osmole and determines extracellular fluid volume as well as serum osmolality. The sodium-potassium adenosine triphosphatase (NatK+-ATPase) pump allows for maintenance of these differences in compartment composition. Although many particles exert some osmotic pressure, the sodium concentration in the extracellular fluid compartment is the primary determinant of serum osmolality unless the patient is severely azotemic or hyperglycemic. Whereas serum osmolality (milliosmoles per kilogram [mOsm/kg] of water) is rarely measured in clinical practice, the
Electrolyte Composition of Fluid Compartments Extracellular fluid
Electrolyte Sodium In rnmol/l, (mEq/L) Potassium In mrnol/L (mEq/L) Chloride in mmol/L (mEq/L) CO2 content in mmol/L (mEq/L) Magnesium in rnmol/L" (mg/dL) Phosphate in mmol/L (mg/dL) Calcium in mmol/l, (mg/dL) !
C'
*Magnesium mEq/L =mmol/L x 2.
'-'uv' r
Intracellular fluid
Plasma
Interstitial
10 (10) 150 (150) Minimal 10 (10) 15 (36) 80 (250) Minimal
140 (140) 4 (4) 105 (105) 25 (25) 1 (2.4) 1 (3) 2.5 (10)
145 (145) 4 (4) 115 (115) 30 (30) 1 (2.4) 1 (3) 1.5 (6)
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SECTION III • Nutrient Metabolism
Volume depletion
FIGURE 10-2. Types of hypovolemia.
97
Hyponatremic volume depletion Isotonic volume depletion Hypernatremic volume depletion
Hypovolemia
Dehydration 1----+1 Hypernatremia
proxy estimate is serum osmolarity (milliosmoles per liter [mOsmol/L] of fluid), which can easily be calculated (Table 10-2). There is no osmotic driving force if exogenously (intravenously) administered fluids are isotonic with body fluids; therefore, the electrolytes remain within the extracellular fluid, as does the administered water. In fact, approximately 93% of plasma is composed of water>; therefore, the true sodium concentration of plasma water (assuming a plasma sodium concentration of 143mmol/L) is 154 mmol/L or the equivalent of sodium contained in 0.9% NaCI intravenous fluid. The osmolarity of this intravenous fluid is 308 mOsm/L, approximating normal serum osmolarity. This explains why 0.9% NaCI is an ideal isotonic intravenous crystalloid solution for volume expansion in specific conditions. The reasons why 0.9% NaCI is used forvolume resuscitation, but electrolytefree water (e.g., 5% dextrose in water [DsW]) is not, can be explained by how the fluid is distributed and how much will remain in the intravascular space of the extracellular fluid compartment. If 1 L of DsW is infused, the dextrose is metabolized and the water distributes proportionally to all fluid compartments. That is, two thirds (667 mL) of it will distribute into the intracellular fluid compartment and one third (333 mL) into the extracellular fluid compartment. Of the one third (333 mL) distributed into the extracellular fluid compartment, only one quarter (85 mL) of it will remain in the intravascular space. This amount is obviously not clinically sufficient to replace a large volume deficit because it would take more than II L of DsW to replace approximately 1000mL
of intravascular space. On the other hand, I L of infused 0.9% NaCI distributes solely to the extracellular fluid compartment where one quarter (250 mL) of it remains in the intravascular space. Effective fluid resuscitation of the intravascular space with isotonic crystalloids (e.g., 0.9% NaCI or lactated Ringer's solution) potentially requires the administration of an amount equal to 4 times the intravascular deficit (because 25% of the fluid administered into the extracellular fluid distributes there). This amount will also depend on the degree of ongoing physiologic regulation. Extracellular fluid volume is normally regulated by varying the renal excretion of sodium. This occurs through various mechanisms (e.g., vascular receptors and renin-angiotensin-aldosterone) that influence function at each segment of the renal nephron. The renal handling of other electrolytes is regulated by these and other mechanisms (e.g., insulin for potassium and parathyroid hormone [PTH] for calcium, magnesium, and phosphorus). Varying water intake and excretion occurs through the thirst mechanism and arginine-vasopressin release from the pituitary. The result is production of urine that is either very dilute or concentrated as a means of regulating the osmolality of extracellular fluid. As the load of solute (e.g., nitrogen and electrolytes) that reaches the kidneys increases, as with nutritional support regimens containing inadequate free water, the ability of the kidneys to maximally concentrate the urine diminishes. All electrolytes are closely regulated by normally functioning kidneys because the reabsorptive capacity operates near its maximum (approximately 95% to 99%) for most
_ _ Conventional Formulas for Addressing Fluid Electrolyte Status Estimating serum osmolarity (2)(Serum sodium in mEq/L) + (serum glucose in mg/dL)/18 + (BUN In mg/dL)/2.8 (2)(Serum sodium) + (serum glucose) + (BUN) (If all are In rnmol/L) Estimating fluid correction Water excess = (TBW in L) - (TBW) (serum sodium In mmol/L + 140) Water deficit = (TBW in L) - (TBW) (140 + serum sodium In mmol/l.) Volume deficit = ( -10) + [(sodium content of desired Infusate - serum sodium In rnmol/L) + (TBW + 1)1 Estimating changes in serum electrolyte concentration Expected change in serum sodium after 1 L of Infusate (Sodium content of infusate - serum sodium in mmol/L) + (TBW + 1) Expected change in serum potassium after intravenous potassium administration (Potassium content of infusate in mmol/L + 80) + (serum potassium In rnmol/L) Serum electrolyte concentration adjustment Adjusted serum sodium for hyperglycemia (Serum sodium in mrnol/L) + (serum glucose In mg/dl, + 100) (2.4) Adjusted total serum magnesium for hypoalbuminemia (Total serum magnesium in rnmol/L) + [(40 - serum albumin in giL) + 200] Adjusted total serum calcium for hypoalbuminemia (Total serum calcium in rng/dl.) + [(40 - serum albumin in giL) + 12.5] BUN, blood urea nitrogen; TBW, total body water.
98
10 • Fluid and Electrolytes
_ _ Composition of Gastrointestinal Secretions
Saliva Gastric Pancreatic Hepatobiliary Small bowel Colon
Volume (mL/day)
Sodium (mmol/L)
Pota8lllum (mmol/L)
Chloride (mmol/L)
Bicarbonate (mmol/L)
1500 2000 600 900 1800
10 60 140 145 140 60
20 10 10 5 5-15 30
10 130 45 100 100 40
20 0 110 30 <5-30
patients. This implies that as normal serum concentrations of electrolytes are exceeded (such as with maintenance or replacement infusions), they are lost in the urine because the kidney is unable to retain more than its reabsorptive capacity, especially in the presence of a high solute load. Whereas the kidney is the predominant site of water and electrolyte regulation, the gastrointestinal tract plays a lesser role in secretion and reclamation of fluid and electrolytes. The gastrointestinal tract can be the source of multiple electrolyte disorders when any of the following exist: gastric suctioning, enterocutaneous and enteroenteric fistulae, jejunostomy, ileostomy, colostomy, diarrhea, or malabsorption. The composition of the fluid lost will vary with the fluid source (Table 10-3). For example, 1 L of lost gastric fluid generally contains 20 to 80 mmol of sodium, 10 to 20 mmol of potassium, 100 to 150 mmol of chloride, and virtually no bicarbonate, whereas lost fluid from the small bowel may contain higher concentrations of sodium and bicarbonate, which themselves can vary with the intestinal segment. It is estimated that in adults about 4 L of endogenous secretions pass the duodenojejunal flexure daily in addition to the volume of the diet.6,7 These fluids, which include saliva, gastric juice, and pancreatic and biliary secretions, each contain electrolytes. The specific composition of the secretion differs by anatomic site and with food intake (Table 10-3). Despite ongoing absorption, additional fluid may be secreted in the upper jejunum to 100 em from the duodenojejunal flexure. A patient with a proximal jejunostomy would therefore be likely to have a net loss of fluid after eating or drinking. The net absorption of fluid begins by the midjejunum, resulting in only about 1 L of fluid entering the colon, where most of it is absorbed. Given the low sodium content of most meals and enteral formulas relative to intestinal secretions, the resultant fluid passing the duodenojejunal flexure can be about 90 mmol/L, increasing to 140 mmol/L by the terminal ileum," The jejunum is much more permeable to water, sodium, and chloride than is the ileum. At lower luminal sodium concentrations of 90 mmol/L or greater, sodium absorption, coupled with water and glucose, can occur at the jejunum," At lower luminal concentrations jejunal sodium secretion is more likely to occur. This explains why maintenance of oral sodium intake while hypotonic fluid intake is limited is recommended for patients with a jejunostomy. At the ileum, however, sodium can be absorbed against a concentration gradient, where it is not coupled with glucose, and is responsive to aldosterone.s"
This allows the ileum to conserve sodium and water during periods of depletion. Active absorption of chloride in exchange for bicarbonate can also occur at the ileum. Intestinal secretions normally contain only modest amounts of potassium and very little magnesium. Intestinal secretion of fluid and electrolytes may be increased during fasting and malnutrition, further increasing the risk of fluid and electrolyte 10SS.1O The colon has the capacity to reclaim sodium and water. Chloride absorption, in exchange for bicarbonate, and potassium secretion can also take place in the colon. On average, fluid gains (in) should be in balance with fluid losses (out) over a period of several days. In health, this balance is maintained in the average adult with a fluid intake of about 30 to 40 mUkg/daily (Table 10-4). Water absorption across the gastrointestinal tract and distribution may normally take 15 to 30 minutes and is aided by SGLTl, the so-called water pump, which couples glucose, sodium, and water absorption together. When the kidneys or gastrointestinal tract is functioning abnormally, serum electrolyte abnormalities are common. A basic understanding of the physiology of most electrolytes is useful. The average adult body contains about 40 mmol (1 mmol = 1 mEq = 23 rng) of sodium per kilogram of body weight and typically takes in 50 to 200 mmol of sodium daily. The Dietary Reference Intake for this electrolyte was established as an adequate intake level of 50-65 mrnol/day.'! Most of the sodium in the body is found in the extracellular fluid; in fact sodium and its chloride and bicarbonate salts make up almost 90% of the solute in that compartment. Renal elimination varies greatly from less than 1 to more than 100 mmol/day; the capacity depends on renal function and the balance of factors that affect renal handling of this electrolyte. Urinary sodium concentration can be used as a marker for sodium balance and for renal function. The serum sodium value _ _ Fluid Balance in Health Source Intake Oral fluid Solid food Water of oxidation Output Urine Stool Insensible (lung) Insensible (skin)
Volume (mL/day)
1000-2000 700 250 1000-2000 250 300 400
SECTION III • Nutrient Metabolism
represents a ratio of sodium to water rather than an indication of sodium balance. The potassium content of the body is approximately 50 mmollkg (l mmol = 1 mEq = 39 mg), whereas intake can be 50 to 150 mmol daily. The Dietary Reference Intake for this electrolyte was established as an adequate intake level of 120 mmol/day." This electrolyte is involved extensively in metabolism and cardiac and neuromuscular function. Renal mechanisms act to maintain serum potassium. An acute load of potassium often results in renal excretion of a significant proportion within a few hours. This occurs mainly because of stimulation of aldosterone release that allows for increased potassium secretion at the distal renal tubule. Renal excretion is determined by several factors including serum potassium concentration, arterial pH, glomerular filtration rate, tubular flow rate, and the presence of nonreabsorbable anions, as well as aldosterone status. Additionally, a high serum potassium value can stimulate insulin release which then increases Na+-K+-ATPase to help drive potassium intracellularly. The distribution of potassium between the extracellular and intracellular fluid compartments depends on adrenergic activity, acid-base status, and osmolarity, as well as the activity of insulin. Renal elimination of potassium can vary, but there appears to be an obligatory loss of about 5 to 10 mmollday even with reduced intake. This means that in the absence of potassium administration, patients with normal renal function will develop a potassium deficitwhether or not it is reflected by the serum potassium concentration. Serum potassium represents only about 2% of total body potassium but does influence cell membrane polarization. This allows serum potassium, along with urinary potassium and clinical symptoms, to be used in the assessment of potassium disorders. Magnesium is found predominantly in the intracellular fluid compartment. Total body magnesium content is approximately 800 to 1200 mmol (l mmol = 2 mEq = 24 mg), with close to half found in bone; some of this is exchangeable from the surface-limited pool and is a source for endogenous supply. The remainder is located in skeletal muscle and soft tissues (liver, brain, heart, and kidney), with no more than 2% in the extracellular fluid including the serum.l>" Serum magnesium is about 33% protein bound, mostly to albumin.P'" About 61% of serum magnesium is in the ionized (free) form and 5% is complexed to phosphate, citrate, and other compounds. 15,17,18 This ultrafilterable (nonprotein bound) fraction is the physiologically active and homeostatically regulated fraction'? and may provide a more accurate assessment of magnesium deficiency (if the test is clinically available [normal 0.4 to 0.7 mmollL]) than does total serum magnesium, especially in hypoalbuminemic patients.P'" Daily magnesium intake averages 10-15 mmol/day, with 30 to 50%of it absorbed. 12.15,21 The Recommended Dietary Allowance was set at 12.9-17.5 mmol (310-420 mg) per day, depending on age and gender. 22 Magnesium absorption takes place primarily in the alkaline environment of the duodenum and jejunum by both passive and active transport. Renal elimination normally accounts for the loss of at least 1 to 3 mmol of
99
magnesium per day or approximately one third of absorbed magnesium intake. This can increase up to about 200 mmol in a day if needed. The unbound magnesium is freely filtered at the glomerulus and undergoes reabsorption in the renal tubules predominantly at the loop of Henle, with less at the proximal tubule and minor amounts at the distal tubule where some secretion may also take place." In fact, only about 3% to 5% of filtered magnesium remains unabsorbed. Given the near maximal reabsorption of magnesium under normal circumstances, it is easy to see how, in the absence of renal dysfunction, even small increases in serum magnesium can result in increased excretion of this electrolyte. 12,21.24,25 Only about 1% to 2% of endogenous magnesium is eliminated in the feces normally." Serum magnesium concentration represents only about 2%of body content and correlates poorly with body stores. Urinary magnesium concentrations may be used along with serum levels to determine disorders of magnesium balance. The circadian rhythm of magnesium renal excretion, occurring maximally at night, means that a 24-hour urine collection is more accurate than spot urinary magnesium measurements." Magnesium serves a number of functions important in nutritional support practice. 12-15,17,21,23,27-32 It is a cofactor in oxidative phosphorylation reactions in the mitochondria, it catalyzes enzymatic processes and activates phosphatases involved with transfer, storage, and utilization of adenosine triphosphate (ATP). Magnesium is also involved in second messenger generation with adenyl cyclase, and in DNA, protein, and fat synthesis, as well as glucose utilization. Magnesium is required for maintenance of the Na+-K+-ATPase pump and hence cell membrane action potential. It is also a structural component of bone and a factor in PTH secretion and possibly synthesis, neuromuscular transmission, cardiovascular excitability, vasomotor tone, and muscle contraction. Total body content of calcium and phosphorus averages about 1to 1.5 kg and 0.5 to 0.8 kg, respectively. More than 99% of the calcium and 85% of the phosphorus content of the body are found in the bone. This is used as a source to maintain tissue and the extracellular fluid concentrations. The latter represents only 0.1% of the total body content of each and includes the ionized (electrolyte) portion. Usual dietary calcium intake is approximately 20-30 mmollday (l mmol = 2 mEq = 40 rng), while phosphorus intake is approximately 25-50 mmollday (1 mmol = 31 mg). The Adequate Intake level for calcium was set at 25-30 mmol (1000-1200 mg) per day.22 The Recommended Dietary Allowance for phosphorus is 22.6 mmol (700 mg) daily.22 Phosphorus absorption can be reduced by pharmacologic doses of calcium- and aluminum-eontaining medications. At higher therapeutic doses, the absorption of phosphorus is limited by intestinal intolerance. Only a modest amount of endogenous calcium enters into intestinal secretions, with much of it being reabsorbed, but even less endogenous phosphate is secreted into the intestinal tract. Phosphorus is found biologically in combination with oxygen as phosphate. Aside from the amount found in bone, the remaining phosphorus is found mostly in an
100
10 • Fluid and Electrolytes
organic form as phospholipid bound to protein, with a minor portion (<0.1 % total body content) as inorganic phosphate. The tissues depend on this inorganic phosphate pool because it serves as the source of phosphorus for phosphorylation reactions, ATP production, and acid-base regulation. The concentration of inorganic phosphate in the intravascular fluid is normally about 1 mmol/L (0.8 to 1.3 mmol/L). This inorganic phosphate exists as sodium, magnesium, or calcium salts or in its dissociated forms. Although about 80% of inorganic phosphate is filtered renally, most phosphate can be reabsorbed at the proximal tubule, which has a limited capacity to reclaim phosphate. This is under the regulation of the PTH concentration. PTH allows rising phosphate levels when a deficit is being corrected, but little furtherincrease in concentration with administration once corrected. Administration of a large phosphate load is followed by increased urinary phosphate excretion, even without changes in serum values, as the result of this PTH activity. This reaction occurs only for patients with adequate renal function. The urinary excretion is also responsive to extracellular fluid volume statusincreasing with acute volume expansion and decreasing with volume depletion. Glucose phosphorylation reduces serum phosphorus after intravenous administration of dextrose-containing fluid. Of the normal total serum calcium concentration of 2.1 to 2.6 mmol/L (8.5 to 10.5 mg/dL), 40% is protein bound-most to albumin, but some to globulin. The unbound calcium is predominantly ionized calcium (normally 1 to 1.2mmol/L [4 to 5 mg/dL]), and the physiologically active portion, although a small portion of unbound calcium, is found complexed to bicarbonate, phosphate, and acetate. The amount of this complexed or chelated calcium may increase in uremia. Various equations attempt to correct for increases in unbound calcium in the presence of hypoproteinemia (see Table 10-2), but these do not replace the usefulness of the measured ionized calcium concentration. Hypematremia and acidosis can also each decrease the protein-bound calcium. The calcium ion has essential roles including neuromuscular activity, regulation of endocrine and exocrine secretion, blood coagulation, and maintenance of cellular integrity. Extracellular calcium is so critical to function that vitamin D, PTH, calcitonin, and the calcium-sensing receptor are all closely involved to regulate its levels. PTHhelps to maintain serum calcium in the presence of total body deficits by decreasing renal loss, improving gastrointestinal absorption, and increasing bone resorption. Most of the unbound calcium filtered at the glomerulus is reabsorbed (ionized more than the complexed calcium) at the proximal tubule. The usual urinary calcium excretion is about 100 flg/kg daily. Phosphate depletion can increase urinary loss of calcium, apparently without regard to PTH status.
FLUID DISORDERS Disorders of fluid balance can be classified as disturbances of volume, of concentration, or of composition.
These disturbances often occur simultaneously in clinical practice. Gain or loss of fluid (i.e., water and solute together) will alter extracellular fluid volume as determined by physical findings including cardiovascular parameters. Such a disturbance is referred to as volume overload or hypervolemia (gain) or conversely as volume depletion or hypovolemia (loss). The gain or loss of water alone is referred to as overhydration or dehydration, respectively, and is recognized by a change in serum sodium concentration and serum osmolarity. A disturbance of composition refers to gain or loss of potassium, magnesium, phosphate, calcium, chloride, bicarbonate, or hydrogen ion. The management of fluid and electrolyte disorders is focused not only on the intravascular space for correction of the serum values, but also to all physiologic compartments to address total body electrolyte status as for any other nutrient. Hypovolemia is often diagnosed clinically with postural vital signs, as patients often manifest physiologic events within 1 to 2 minutes after standing from the supine position. This occurs because approximately 7 to 8 mUkg of blood shifts to the lower body, thereby reducing the thoracic blood volume, stroke volume, and cardiac output and a compensatory increase in circulating norepinephrine occurs with an increased systemic vascular resistance.' The most prominent observations with postural vital signs are an increased heart rate and decreased systolic blood pressure. Clinical monitoring may help to identify when a volume deficit or excess is present and acts as a guide for fluid therapy. The clinical parameters routinely assessed to evaluate circulating blood volume include the following: presence of skin mottling; presence of pulmonary congestion and/or edema based upon detection of pulmonary rales and crackles; presence of congestive heart failure; presence of peripheral edema; detection of an enlarged third space including ascites and pleural effusions; presence or absence of fluid losses including chest and abdominal drainage or aspiration of gastric contents; fluid balance in the last 24 hours (generally considered positive balance if >400 mUday); and central venous pressure of 2 mm Hg or greater." When clinical signs and symptoms are present for hypovolemia, the homeostatic mechanisms responsible for correcting the primary etiology of either dehydration or volume depletion gain control physiologically (Fig. 10-3). Clinically, the improvements in heart rate, blood pressure, and urine output are the most important measures of physiologic correction when hypovolemia resolves. The therapeutic approach to fluid and electrolyte disorders requires the clinician to identify and address the etiology. For minor fluid disorders, volume replacement does not need to be identical in composition to the fluid loss. At the same time, any replacement should not place an undue burden on the patient's renal handling mechanisms. For more significant disorders, the patient's clinical presentation, previous and ongoing losses, and maintenance requirements need to be considered when volume replacement is calculated. Oral repletion typically requires a carbohydrate-based solution that also contains sodium, potassium, chloride, and citrate as a source
SECTION III • Nutrient Metabolism
Volume depletion
i
101
Dehydration Serum Osmolality
or J, Circulating Blood Volume Hypotension, tachycardia with renal hypoperfusion and oliguria
I r Thirst I
I t ADH Release I
I t Water ingestion I
I J, Water excretion I
iR enin release
I Angiotensinogen
Angiotensin I
I
1
Angiotensin converting enzyme : Angiotensin II :
1I
: Water retention
I r Aldosterone secretion I t
r
Renal sodium reabsorption and potassium secretion
-
Systemic blood pressure
1
I J, Renin release
r
I
I J, Serum osmolality and T circulating blood volume
I ECF Volume expansion and r circulating blood volume I
and
J, ADH Release with J, thirst
FIGURE 10-3. Physiologic mechanisms to correct hypovolemia. ADH, antidiuretic hormone; ECF, extracellular fluid.
of bicarbonate. Parenteral repletion will require selection of a dextrose-containing and/or a sodium-eontaining (crystalloid) solution. Equations exist to help estimate water and volume deficits (see Table 10-2).
WHAT CONSTITUTES A SERIOUS ELECTROLYTE ABNORMALITY? Before a discussion of the most common electrolyte disorders, a standard approach to electrolyte disorders is required to adequately provide safe and effective treatment. Definitions of the clinically relevant electrolyte
disorders are presented in Table 10-5. More important than understanding normal physiology and recognizing an electrolyte disorder by its serum value is being able to identify the etiology of the imbalance. The development of an electrolyte abnormality in an acute (<48 hours) versus a chronic (>48 hours) time period is also a key distinction. Generally, the development of an acute electrolyte abnormality is associated with symptoms that often require immediate treatment (e.g., altered mental status with a low serum sodium level). Conversely, the development of a chronic electrolyte disorder is often asymptomatic unless corrected too rapidly by an overzealous clinician (e.g., 3% NaCI for chronic hyponatremia with a
_ _ Definitions of Electrolyte Abnormalities~ Senam Electrolyte
Reduced
Elevated
Sodium Potassium CO2 content Magnesium! Phosphate Ionized calcium Total calcium
<130 mmol/L or mEq/L <3.5 rnrnol/L or mEQ/L <15 mrnol/L or mEq/L <0.8 mrnol/L or 1.9 mg/dl, <0.6 mmol/L or 1.9 mgjdL
>150 rnmol/L or mEq/L >5.5 mrnol/L or mEq/L >35 mmol/L or mEq/L >2 mrnol/L or 4.8 mg/dl, > 1.6 mrnol/l, or 5 mg/dl, > 1.5 rnmol/L or 6 mg/dl, >3 mmol/L or 12mg/dl,
*Normal concentrations will vary slightly with the method of laboratory assay, and are listed primarily for adults. 'Magnesium mEq/L =mmol/L x 2.
102
10 • Fluid and Electrolytes
rise in serum sodium >10 mmol/Uday). The chronologie trends in electrolyte values are generally more important, when available, than the absolute value on any given day, especially in the absence of symptoms. It is valuable to assess all measurable electrolytes, because rarely is only one electrolyte abnormality noted in most patients. Of the commonly measured intracellular electrolytes (potassium, magnesium, phosphate, and calcium), no more than about 1% are present in the extracellular fluid, which is used for determining disorder severity and dosage. Unfortunately, there is no precise method to determine the exact replacement for most electrolytes; therefore, monitoring the serum concentrations and symptoms are the only methods of ensuring patient safety. Once the etiology and timeliness of the electrolyte disorder has been determined, the next step in a standard approach to electrolyte abnormalities is choosing how to replace or remove the electrolyte(s). Obviously, an evaluation of the patient's renal function is essential. Renal function should be characterized as normal, increased, or decreased compared to the patient's baseline value (if known). Particular attention should be focused on the patient's current urine output (normally 0.5 to 2 mUkg/hr) because acute renal failure may manifest as nonoliguric (>400 mUday), oliguric «400 mUday), or anuric. For patients with normal renal function, the determination of an electrolyte maintenance or replacement dose may be characterized as low or high (Table 10-6). Patients must be evaluated individually for the most suitable maintenance or replacement dose based on their clinical presentation. Actual body weight should be used for electrolyte doses unless the body mass index is 30 kg/m'' or higher in which case an estimated lean or adjusted body weight may be used. Determining the appropriate route of administration is next in the standard approach; it may be selected based on the etiology of the electrolyte disorder. If the gastrointestinal tract is the cause for the electrolyte loss then intravenous administration may be a more appropriate route for retention of the electrolyte. The various routes available may include any of the following: oral, oro- or nasogastric tube, nasoduodenal tube, jejunostomy tube, and central or peripheral intravenous access, depending on the electrolyte involved. The rectal route is not a primary delivery route; however, it can be significant when phosphate-based enemas (approximately 470 mmol/dose) are instilled in patients with marginal renal function. The oral or enteral route is generally the safest unless the _ _ Common Electrolyte Do.age Range. Electrolyte Replacement
Low Dese"
High Dolle
Sodium mrnol/kg/day Potassium mrnol/kg/day
<0.5 <0.5 <0.5 <0.13 <0.1 <2.5
>3 >2 >3 >0.5 >0.5 >7.5
Bicarbonate" mrnol/kg/day Magnesium rnmol/kg/day Phosphate mrnol/kg/day Calcium mmol/day
* Although considered a low dose, this may be appropriate, depending on the degree of renal impairment.
electrolyte replacement solution has known irritant effects on the gastrointestinal tract (e.g., potassium chloride).34 If the oral or enteral route is selected, the rate of administration must be safely determined based upon patient tolerance, the degree (mild, moderate, or severe) of electrolyte abnormality, and the therapeutic index of the electrolyte. Potassium has the narrowest therapeutic index compared with those of sodium, magnesium, phosphate, and calcium. Therefore, conservative dosages may be required if other impending factors known to influence the electrolyte being replaced/administered are present, such as a moderate to severe metabolic acidosis in the case of potassium. Drug-nutrient interactions should also be a consideration when electrolytes are replaced because some drugs may result in greater electrolyte retention (e.g., spironolactone increases potassium) or loss (e.g., furosemide decreases potassium). Given the potential dangers associated with the intravenous infusion of electrolytes (namely potassium), the oral or enteral route is always the preferred method of replacement when feasible. Intravenous electrolytes should be used for supplementation only when the oral or enteral route of delivery is inaccessible or for potentially life-threatening situations. If the intravenous route is selected, determining how to dilute the electrolyte may be just as important as the dose administered. For example, dextrose-containing fluids may actually worsen serum potassium and phosphate values by influencing insulin secretion and redistribution of these electrolytes. Generally, most electrolytes are infused over short periods «4 hours) and a substantial portion (often >50%) may be lost in the urine as a result of exceeding the renal reabsorption threshold of the electrolyte. Another consideration with the intravenous route is the compatibility of the electrolyte replacement regimen with the patient's current medication regimen including maintenance intravenous fluids, parenteral nutrition, patient-eontrolled analgesia (e.g., morphine), and other medications. Unfortunately, a lack of compatibility information exists about the following electrolyte combinations in conventional intravenous fluids (excluding parenteral nutrition): calcium and phosphate, phosphate and magnesium, and potassium and magnesium. Another consideration about intravenous replacement is the potential harm to the patient if extravasation of the electrolyte being replaced occurs (especially with potassium and calcium). Catheter type, age (hours to days), and location should be carefully evaluated especially when the peripheral intravenous route is selected for potassium or calcium replacement. A final consideration in the approach is that a period of 3 to 7 days is needed for correction of most electrolyte disorders to normalize body stores,"
SODIUM DISORDERS Changes in serum sodium values reflect altered water balance, whereas true changes in sodium balance affect extracellular fluid volume. Clinically the disorders of sodium and volume are considered together. Aside from
SECTION III • Nutrient Metabolism
103
Hypernatremia Serum sodium> 150 mmol/L
1 Presence of symptoms: Altered mental status, lethargy, irritability, intense thirst I
ISodium and water losses I Low total body sodium
I
1
I Sodium Excess I
1 Elevated total body sodium
Renal Losses Osmotic diuresis (glucose, mannitol, urea)
Extrarenal Losses Excess sweating, diarrhea
1
1
Primary hyperaldosteronism Cushing's syndrome sodium bicarbonate
1
Urine Na
Urine Na
<20 mmol/L
>20 mmol/L
1
If hypovolemic, use 0.9% NaCI then 0.45% NaCI, D5W, or oral water/fluid
Renal Losses
Extrarenal Losses
Nephrogenic or central 01 Hypodipsia
Respiratory and insensible skin losses
~
Urine Na
Treatment
Normal total body sodium
1
>20 mmol/L
1
I
I
Water Losses
I
1
1
I
Urine Na variable
1
Urine Na variable
1
Treatment Discontinue offending agent Diuretics with Water replacement
Treatment 0.45% NaCI, D5W or oral water
FIGURE 10-4. Diagnosis and treatment of hypernatremia. 01, diabetes insipidus.
the serum sodium value, which by itself is not valuable in determining the nature of a disturbance, the serum osmolarity and volume status of the patient help in assessing the disorder. Hypernatremia is always a hypertonic state as reflected in central nervous system manifestations (e.g., restlessness, irritability, and seizure). It may be further classified based on extracellular fluid volume (Fig. 10-4). The therapeutic approach to managing hypernatremia includes addressing the underlying etiology and normalizing the osmolarity at a rate not to exceed a 10 mmol reduction of sodium per L per day. Hypervolemic hypernatremia results from accumulation of sodium in excess of an accumulation of water. This is often iatrogenic or due to mineralocorticoid excess. It is best managed by diuresis to eliminate the excess sodium. Because this also removes more water than desired, some replacement may be needed. Hypovolemic hypernatremia occurs after sodium and water loss where volume loss exceeds loss of sodium (i.e., a hypotonic loss). Renal (e.g., glycosuria
and diuretics) and nonrenal (e.g., severe diarrhea and profuse perspiration) losses are to blame. The patient with renal losses can be identified by urinary sodium concentrations in excess of 20 mmollL. The disorder may worsen in the patient who continues to receive isotonic crystalloid replacement. Management includes volume expansion with a relatively hypotonic saline solution based on an estimate of losses (see Table 10-2). Isovolemic hypernatremia describes loss of water without any change in the sodium content and hence little clinically significant change in markers of extracellular volume status. This disorder occurs after extensive insensible water loss or renal loss of water that occurs with diabetes insipidus. Water loss in patients with isovolemic hypernatremia is managed in part by replacement of electrolyte-free water based on an estimate of losses (see Table 10-2). Hyponatremia is common in hospitalized patients. Clinical manifestations are more likely when the serum sodium concentration drops quickly and when it falls
104
10 • Fluid and Electrolytes
below 120 mmol/L. Symptoms may reflect the altered osmolarity or altered volume status. The serum osmolarity will help differentiate etiologies of the hyponatremia. Patients with elevated osmolarity may be hyperglycemic, receiving hypertonic infusions, or accumulating an unidentified osmotically active substance (e.g., alcohols). The change in serum sodium value is the result of the diluting effect of water, and in the case of hyperglycemia can be adjusted for (see Table 10-2).35 Addressing the underlying cause will correct this hyponatremia in most patients.Rarely the hyponatremic patient may have a normal serum osmolarity indicative of the effect of another substance (e.g., hyperlipidemia) occupying plasma space while the concentration of sodium in the plasma water remains normal. The most attention is given to those patients whose serum osmolarity is
below normal (i.e., hypotonic hyponatremia). This hypotonic state can be further differentiated by volume status (Fig. 10-5). The therapeutic approach to managing patients with hyponatremia will again include addressing the underlying etiology and slowly correcting the osmolarity at a rate not to exceed a 5 to 10mmol/Llday increase in serum sodium. Hypervolemic hyponatremia is the result of accumulation of volume greater than the accumulation of sodium with the patient exhibiting edema. Although this can occur with renal failure and is identified by an elevated urinary sodium concentration, it can also occur with heart failure and cirrhosis. The restriction of both sodium and water is used to manage hypervolemic hyponatremia, whereas excess fluid may be mobilized as tolerated. Hypovolemic hyponatremia occurs when sodium losses exceed volume losses in a
Hyponatremia
Serum sodium < 130 mmol/L
Exclude Pseudohyponatremla:
1- Hyperglycemia, hyperproteinemia, hypertriglyceridemia, mannitol
Presense of symptoms: Lethargy, apathy, disorientation, muscle cramps, anorexia, nausea
~
~
!
Deficit of TBW and larger deficit of total body sodium
Excess TBW
Excess total body sodium and larger excess of TBW
ECF Volume depletion
I
Renal Losses
Extrarenal Losses
Diuretic excess Mineralocorticoid deficiency Salt-losing nephropathy Renal tubular acidosis
Vomiting Diarrhea 3rd Spacing: Acute pancreatitis trauma, burns
Urine Na >20 mmol/L
Urine Na <20 mmol/L
1
Modest ECF volume excess (no edema)
I ECF Volume excess (edema) I
Glucocorticoid deficiency Hypothyroidism SIADH Pain Drugs including: Cyclophosphamide, Carbamazepine, Vincristine, Vinblastine, Chlorpropamide
Congestive heart failure Cirrhosis Nephrotic syndrome
Acute renal failure Chronic renal failure
Urine Na >20 mmol/L
Urine Na <20 mmol/L
Urine Na >20 mmol/L
1
1
1
Treatment
Treatment
Treatment
NaCI-containing volume expansion
Water restriction
Water and Na restriction
FIGURE 10-5. Diagnosis and treatment of hyponatremia. SIADH. Syndrome of inappropriate antidiuretic hormone.
SECTION III • Nutrient Metabolism
patient (i.e., a hypertonic loss). These patients exhibit manifestations of volume depletion (e.g., orthostasis). Renal losses of sodium and water could occur with diuresis, mineralocorticoid deficiency, or salt-wasting nephropathy, among other causes. Volume losses through the gastrointestinal tract or skin are common causes. Volume expansion is necessary in the management of these patients with hypovolemic hyponatremia, again based on a reasonable estimate of losses (see Table 10-2). Isovolemic hyponatremia describes the retention of electrolyte-free water in the setting of normal sodium content as a result of impaired water regulation. This water "intoxication" may be seen in patients with inappropriate secretion or an exaggerated effect of argininevasopressin (often referred to as the syndrome of inappropriate antidiuretic hormone). In this situation management includes restriction of water. Patients with an ileostomy obviously lack the colonic function of fluid and sodium conservation. As a result they are at risk for volume depletion ifadequate amounts of water and sodium are not provided. Amounts of sodium from all sources, including enteral nutrition formulations, should provide as much as 6 to 10 mmol/kg daily for these patients." Inadequate sodium intake may limit glucose absorption, otherwise coupled to sodium absorption, leading to further fluid losses as a result of osmotic diarrhea. Additionally, intestinal losses of sodium severe enough to increase aldosterone secretion help to explain the hypokalemia and hypomagnesemia that often results despite the relatively low amounts of potassium and magnesium in intestinal secretions.
POTASSIUM DISORDERS Potassium is closely regulated by the body; however, hypokalemia (serum potassium <3.5 mmol/L) and hyperkalemia (serum potassium >5.5 mmol/L) occur often in clinical practice. A rational approach to disorders of potassium balance involves evaluating potassium intake (i.e., gastrointestinal and intravenous), output (i.e., gastrointestinal and rena!), and redistribution between cells. Hypokalemia is seen in about 20% of all hospitalized patients and is even more common in the critically ill.34 Although moderate hypokalemia (3 to 3.5 mmol/L) may be well tolerated by an otherwise healthy individual, patients with any disruption of cardiovascular homeostasis or anyone with more severe hypokalemia can experience significant morbidity and mortality. Hypokalemia can occur from insufficient intake, excessive losses, or redistribution into the intracellular fluid compartment. Malnourished patients and those receiving nothing by mouth without sufficient potassium to replace obligatory losses can become hypokalemic. More commonly potassium is lost through the gastrointestinal tract (e.g., vomiting, gastric suction, fistula, surgical drains, and diarrhea, each compounded by volume depletion) or through the kidneys (e.g., mineralocorticoid excess, renal tubular acidosis, ketoacidosis. hypomagnesemia, and induced by drugs). An intracellular shift of potassium can occur with hypothermia, alkalosis, 132 agonists,
105
and insulin whether administered exogenously or as a response to refeeding in the malnourished patient. Hypokalemia can affect neuromuscular, cardiovascular, gastrointestinal, renal, and metabolic function. Of particular concern to the patient receiving nutritional support, hypokalemia can cause respiratory muscle weakness and paralysis, dysrhythmias, reduced intestinal motility, polyuria, reduced secretion of insulin and growth hormone, and negative nitrogen balance. The therapeutic approach to hypokalemia obviously requires identification of the etiology with correction if possible (e.g., if the patient is hypomagnesemic) and returning the serum potassium concentration to a goal of about 4 to 4.5 mmol/L. True potassium deficits may be as high as 100 to 200 mmol for each 1 mmol/L drop in serum potassium concentration. The patient with chronic or asymptomatic hypokalemia may receive potassium supplementation through the gastrointestinal tract at a daily dose of about 40 to 120 mmol divided throughout the day, keeping in mind the adverse local effects if the dose is not properly diluted. For the symptomatic patient, potassium will need to be administered intravenously. Depending on the degree of hypokalemia, parenteral potassium may be administered either slowly by adding it to maintenance fluids or over a shorter period via intermittent infusion doses; in either case an infusion pump is needed for administration. Potassium should never be given by intravenous push, nor should more than a 40 mmol dose be administered or a rate exceeding 10 mmol/hr be used through a peripheral venous access. Cardiac rhythm should be monitored during repletion by intermittent infusion. In anephric or hemodialysisdependent patients, it is rarely necessary to provide supplemental potassium for levels of 3 mmol/L or greater. The serum potassium concentration needs to be obtained 2 hours after supplementation, especially if the supplement is given for correction of severe hypokalemia or in patients with multiple medical problems. Hyperkalemia is more often the result of an increase in extracellular potassium content rather than an increase in total body potassium content. Concern is greatest in patients with poor renal function or when levels increase to greater than 6.5 to 8 mmol/L. Hyperkalemia occurs as a result of excessive intake, decreased excretion, or redistribution from the intracellular compartment. Excessive intake causes hyperkalemia in the presence of poor renal function, and renal excretion of potassium can also be reduced in the presence of limited mineralocorticoid activity or other disorders or medications that decrease potassium secretion. An extracellular shift of potassium is seen after tissue trauma, rhabdomyolysis, and some types of metabolic acidosis. Hyperkalemia can also have an impact on neuromuscular, cardiovascular, and gastrointestinal function. Treatment is based on severity. Limiting all sources of exogenous potassium when possible may be all that is needed for asymptomatic patients with improving renal function. Symptomatic hyperkalemia, however, requires a strategy of antagonizing the cell membrane effects (intravenous calcium), redistributing the potassium intracellularly (insulin), and increasing its elimination
106
10· Fluid and Electrolytes
from the body (polystyrene sulfonate or hemodialysis) as needed.
MAGNESIUM DISORDERS Disorders of magnesium balance, particularly hypomagnesemia, are common in hospitalized patients. An approach to these disorders, parallel to alterations in potassium balance, involves evaluating magnesium intake (i.e., gastrointestinal and intravenous), output (i.e., gastrointestinal and rena!), and redistribution between cells. Hypomagnesemia has been reported in 6.9% to 47%of hospitalized patients27,37-43 and in as many as 68% of patients in intensive care units (ICUS).19,39.41,4448 These patients have higher mortality rates than normomagnesemic patients.Pr" About 38% to 61% of hypokalemic patients are also hypomagnesemic, and 22% to 28% of those with hypocalcemia are concurrently hypomagnesemic. 40,43,45,49 Serum magnesium is not routinely obtained, and only 10% of hypomagnesemic patients may be identified by physician-initiated requests." In fairness, laboratory diagnosis of a deficit is often difficult.13,30 Whereas the serum magnesium concentration may fall to less than 0.8 mmol/L, it may actually remain normal in patients with magnesium deficits." Furthermore, the cellular effects of hypomagnesemia are difficult to predict based on the serum concentration alone." When cellular magnesium concentrations were compared with serum magnesium concentrations in studies of critically ill patients, only 7.7% to 9% of patients were hypomagnesemic despite 47% to 53% of them having reduced cell magnesium content. 46.50 The serum magnesium concentration better reflects acute serial changes than total body stores. Measurement of the ultrafilterable magnesium level is useful in hypoalbuminemic patients or critically ill patients with an acid-base disorder and is indicative of hypomagnesemia at concentrations less than 0.4 rnmol/L." An equation to adjust the total serum magnesium concentration for these patients may be of value if an unbound magnesium concentration is unavailable (see Table 10-2). A 24-hour urinary magnesium concentration less than 0.5 to 1 mmol indicates a magnesium deficient state, which may actually develop before the serum magnesium decrease is apparent. Urinary magnesium concentration may be useful in evaluation of a patient suspected of having a magnesium deficit based on clinical presentation (Fig. 10-6). After an intravenous magnesium load, the patient with a deficiency will excrete less than 50% of the load in the next 24 hours (normal >70%). This retention test may be a useful method of assessment but assumes normal renal function, no use of diuretics, and an accurate urine collection." Hypomagnesemia can occur with insufficient intake or absorption, excessive losses, or redistribution into the intracellular fluid compartment. 13,14.21,27,52,53 Reduced intake or absorption is seen with protein-ealorie malnutrition, prolonged administration of magnesium-free intravenous fluid or parenteral nutrition, alcoholism, malabsorption syndromes, intestinal bypass operations,
and short bowel syndrome. Magnesium losses can occur through the gastrointestinal tract (e.g., gastric, biliary, pancreatic, fistula, or diarrheal losses) or the kidneys. Renal losses may be caused by renal tubular acidosis, nephrotic syndrome, acute tubular necrosis, hyperaldosteronism, Bartter syndrome, renal transplant, or hypercalcemia or may be drug-induced. Intracellular redistribution may occur with refeeding, diabetic ketoacidosis, hyperthyroidism, and myocardial infarction. Patients with hypomagnesemia can exhibit central nervous system, neuromuscular, cardiovascular, and metabolic (e.g., insulin resistance) symptoms associated with hypokalemia and hypocalcemia." Management must deal with the underlying etiology of the hypomagnesemia. The magnesium deficit, which can be as much as 1 mmol/kg in patients with a serum magnesium concentration less than 0.4 mmol/L, will need to be corrected, keeping in mind the fact that significant portions of the dose will still be lost renally." The dose may be administered intravenously if the patient is symptomatic (e.g., torsade de pointes, refractory ventricular fibrillation, or generalized tonic-elonic seizures) or has severe deficits and is administered at a rate not to exceed 8 mmol/hr after an initial 8 mmol bolus dose (e.g., 1 g of magnesium sulfate contains 4 mmol or 8 mEq of magnesium). In mild to moderate hypomagnesemia (0.4 to 0.8 mmol/L), the dose for the first 24 hours of treatment can be up to 0.5 mmol/kg. All doses should be reduced in patients with renal insufficiency to prevent hypermagnesemia. Correction will often require 3 to 5 days of dosing (0.25 mmol/kg/day) because magnesium repletion of tissues is slow. Less severe deficits or asymptomatic patients may receive about 40 to 80 mmol daily through the gastrointestinal tract (e.g., 400 mg of magnesium oxide contains 10 mmol of magnesium) if not cathartic. Vital signs, urine output, electrocardiogram, and deep tendon reflexes can be monitored regularly during repletion. Asa result of the close renal regulation of magnesium, renal failure is the most common cause of hypermagnesemia along with excessive intake. Although it occurs in about 5% to 10% of hospitalized patients, it is rarely symptomatic but may affect neurologic, neuromuscular, or cardiovascular function at mag nesium levels greater than 2 mmol/L.37,43 Provision of doses appropriate for renal function is the best strategy to avoid hypermagnesemia. Management of hypermagnesemia includes antagonizing the neuromuscular and cardiovascular effects (intravenous calcium), forced diuresis (saline and a loop diuretic), or hemodialysis in patients with renal impairment.
PHOSPHATE DISORDERS Altered serum phosphate concentrations can be commonly found in acutely ill patients. Hypophosphatemia is defined as a serum phosphate concentration less than 0.6 mmol/L and can occur with reduced intake or absorption, increased losses, or intracellular shifts. Manifestations may be neurologic (ataxia, confusion, or paresthesias),
SECTION III • Nutrient Metabolism
107
Suspected Mg Deficiency Unexplained hypocalcemia or hypokalemia Cardiac arrhythmias
Measure
Serum Mg
I
~
~
Low
Normal
Serum Mg < 0.8 mmol/L
Serum Mg 0.8-1 mmol/L
1
I 24-hr Urinary Mg collection I I
~ GI Mg Losses Diarrhea Malabsorption Fistula> 500 mUday Jejunostomy Ileostomy Colostomy Short bowel syndrome
Low +-Urine Mg < 1 mmol/day
1
Mg Deficient I
1 Treatment 0.25-0.5 mmol/kg IVPB at ~ 4 mmol MgSO,Jhr
1 Recheck serum Mg in 12-24 hrs, if still < 0.8 mmol/L, repeat above or increase dosage
1 Begin maintenance Mg therapy (diet, oral or enteral supplements)
~ Normal or High Urine Mg > 1-2 mmol/day
-l Renal Mg Wasting I
1
I
IMg Replete Intrinsic Etiology Renal tubular acidosis Post-obstructive diuresis Diuretic phase of ATN Hereditary Mg wasting Renal transplantation Amphotericin B Aminoglycosides Cisplatin/carboplatin Ifosfamide Cyclosporine Tacrolimus
Extrinsic Etiology f--
Alcohol Diuretics Hyperaldosteronism
Monitor for diarrhea with oral or enteral supplements, serum Mg > 1.5 mmol/L
FIGURE 10-6. Diagnosis and treatment of hypomagnesemia. ATN, acute tubular necrosis.
neuromuscular (weakness, myalgia, or rhabdomyolysis), cardiopulmonary (cardiac and ventilatory failure), or hematologic (reduced 2,3-diphosphoglycerate concentration or hemolysis). Suggested replacement doses for mild to moderate hypophosphatemia in patients without renal impairment are 0.16 to 0.32 mrnol/kg.f More severe deficits may require 0.64 mmol/kg. The calculated dose should be administered over 4 to 6 hours for mild or moderate hypophosphatemia and over 8 to 12 hours for severe hypophosphatemia. Phosphate boluses should always be ordered as millimoles of phosphate rather than in terms of sodium or potassium content. The potas-
sium salt is preferred unless the serum potassium concentration is 4 mmol/L or greater or renal impairment exists. Hyperphosphatemia with phosphate values greater than 1.5 mmol/L is rare except in patients with poor renal function, but can be due to increased intake, decreased excretion, or an extracellular shift. Manifestations may be related to calcium-phosphate precipitation or disturbance of calcium balance. Precipitation may be more likely in vivo as phosphate levels increase to 2 mmol/L and greater in a patient with baseline calcium concentrations in the normal range. Providing doses of phosphate
108
10 • Fluid and Electrolytes
appropriate for renal function is the best method to avoid hyperphosphatemia. If hypocalcemic tetany occurs, intravenous calcium administration will be required.
CALCIUM DISORDERS The identification of calcium disorders may be based on total or ionized calcium concentrations. Hypocalcemia, defined as a total calcium concentration less than 2 mmol/L, may occur due to poor intake or absorption, increased losses, or altered regulation. Hypoparathyroidism, vitamin D deficiency, hypomagnesemia, the hungry bone syndrome, tissue trauma, massive blood transfusion, or certain drugs can result in hypocalcemia. Patients exhibit tetany, paresthesias, muscle weakness, muscle and abdominal cramps, and electrocardiographic changes. It is common in the critically ill patient and is also associated with sepsis, rhabdomyolysis, acute pancreatitis, and blood transfusions." Many patients with hypocalcemia based on total serum values may in fact be hypoalbuminemic resulting in less bound calcium but may have normal levels of unbound physiologically active calcium. Although a number of convenient equations exist to adjust the serum calcium level based on the low albumin concentration (see Table 10-2), they are not always valuable, particularly in critically ill patients. Decreased total serum calcium concentrations occur in 70% to 90% of patients in ICUs, but decreased ionized calcium concentrations occur in 15% to 50% of patients in ICUs.56 For these patients ionized calcium levels should be obtained to determine true hypocalcemialess than 1 mmol/L (4 mg/dL). Incidentally, recovery from hypocalcemia is reported within 5 days after recovery of acute illness. Manifestations may be cardiovascular (e.g., hypotension, decreased myocardial contractility, or prolonged QT interval due to prolonged ST interval) or neuromuscular (e.g., distal extremity paresthesias, Chvostek sign, Trousseau sign, muscle cramps, tetany, or selzures)." Consideration should be given to administering diluted intravenous calcium through a central vein to treat the patient with hemodynamic instability or tetany, often requiring 2.25 to 4.5 mmol of calcium (l to 2 g of calcium gluconate contains 90 to 180 rng of elemental calcium = 2.25 to 4.5 mmo\). This dose should be administered at a rate not to exceed 0.25 to 0.5 mmol/min initially. Calcium levels should be rechecked in 2 to 4 hours after administration. If an additional dose is required, administration at a rate of no more than 0.75 to 1 mmol/hr should be considered. Correction of hypomagnesemia must also occur if it is present. An evaluation of PTH status may also be needed. High doses of sodium may increase renal calcium excretion with estimates that 20 mmol of sodium in the urine takes about 0.25 mmol of calcium with it.57 Asymptomatic patients can receive calcium orally to meet the adequate intake level. Hypercalcemia, defined either as a total serum calcium concentration greater than 3 mmol/L or an ionized calcium concentration greater than 1.5 mmol/L, is most commonly observed in hyperparathyroidism and cancer
with bone metastases. It can also occur with toxic levels of vitamin A or vitamin D.Patients complain of fatigue, weakness, nausea, and vomiting and can exhibit polyuria, mental status depression, psychosis, and coma. Management includes aggressive expansion of the extracellular fluid volume with 0.9% NaCI solution.
CONCLUSION In summary, adequate management of fluid and electrolyte status always requires consideration of intake, output, distribution, and concurrent clinical processes. Particular consideration must be given to the type and route of fluid and electrolyte repletion for successful patient care outcomes. REFERENCES 1. Feig PU, McCurdy DK: The hypertonic state. N Engl J Med 1977;297: 1444-1454. 2. Defronzo RA, Thier SO: Pathophysiologic approach to hyponatremia. Arch Intern Med 1980;140:897-902. 3. Sarhill N, Walsh D, Nelson K, et al: Evaluation and treatment of cancer-related fluid deficits: Volume depletion and dehydration. Support Care Cancer 2001;9:408-419. 4. McGee S, Abernethy WB, Simel DL: Is this patient hypovolemic? JAMA 1999;281:1022-1029. 5. Narins RG,Jones ER,Stom MC, et al: Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am J Med 1982;72:496-520. 6. Borgstrom B, Dahlqvist A, Lundh G, Sjovall J: Studies of intestinal digestion and absorption in the human. J Clin Invest 1957;36: 1521-1536. 7. Fordtran JS, Locklear TW: Ionic constituents and osmolality of gastric and small intestinal fluids after eating. Am J Dig Dis 1966;11: 503-521. 8. Fordtran JS, Rector FC, Carter NW: The mechanisms of sodium absorption in the human small intestine. J Clin Invest 1968;47: 884-900. 9. Levitan R, Goulston K: Water and electrolyte content of human fluid after d-aldosterone administration. Gastroenterology 1967;52: 510-512. 10. Ferraris RP, Carey HV: Intestinal transport during fasting and malnutrition. Annu Rev Nutr 2000;20:195-219. 11. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes: Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC; National Academy Press, 2004. 12. Rude RK: Physiology of magnesium metabolism and the important role of magnesium in potassium deficiency. Am J Cardiol 1989; 63:31G-34G. 13. Berkelhammer C, Bear RA: A clinical approach to common electrolyte problems: 4. Hypomagnesemia. Can Med Assoc J 1985;132: 360-368. 14. Gums JG: Clinical significance of magnesium: A review. Drug lntell Clin Pharrn 1987;21:240-246. 15. Elin RJ: Assessment of magnesium status. Clin Chem 1987;33: 1965-1970. 16. Kroll MH, Elin RJ: Relationships between magnesium and protein concentrations in serum. Clin Chem 1985;31:244-246. 17. Zaloga GP:Interpretation of the serum magnesium level [editorial). Chest 1989;95:257-258. 18. Speich M, Bousquet B, Nicolas G: Reference values for ionized, complexed, and protein-bound plasma magnesium in men and women. Clin Chem 1981;27:246-248. 19. Zaloga GP, Wilkens R, Tourville J, et al: A simple method for determining physiologically active calcium and magnesium concentrations in critically ill patients. Crit Care Med 1987;15:813-816.
SECTION III • Nutrient Metabolism
20. D'Costa M, Cheng P: Ultrafilterable calcium and magnesium in ultrafiltrates of serum prepared with the AmiconMPS.1 system. Clin Chem 1983;29:519--522. 21. Cronin RE, Knochel lP: Magnesium deficiency. Adv Intern Med 1983;28:509--533. 22. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D,and Fluoride. Washington, DC, National AcademyPress, 1997. 23. Ryan MP: Diuretics and potassium/magnesium depletion:Directions for treatment.Am1 Med 1987;82(suppl 3A):38-47. 24. Rude RK, Bethune lE, Singer FR: Renal tubular maximum for magnesium in normal, hyperparathyroid, and hypoparathyroid man. 1 Clin EndocrinolMetab 1980;51:1425-1431. 25. Rude RK, Ryzen E: TmMg and renal Mg threshold in normal man and in certain pathophysiologic conditions. Magnesium 1986;5: 273-281. 26. Nicoll GW, StruthersAD, FraserCG: Biological variation of urinary magnesium. ClinChem 1991;37:1794-1795. 27. Whang R: Magnesium deficiency: pathogenesis, prevalence, and clinical implications. Am1 Med 1987;82(suppl 3A):24-29. 28. Whang R, Flink EB, Dyckner T, et al: Magnesium depletion as a cause of refractory potassium repletion. Arch Intern Med 1985;145:1686-1689. 29. Seelig M: Cardiovascular consequences of magnesium deficiency and loss: Pathogenesis, prevalenceand manifestations-Magnesium and chloride loss in refractory potassium repletion. Am 1 Cardiol 1989;63:4G-21G. 30. Flink EB: Nutritional aspects of magnesium metabolism. West 1 Med 1980;133:304-312. 31. AnastCS, Mohs 1M, Kaplan SL, BumsTW: Evidencefor parathyroid failure in magnesium deficiency. Science 1972;177:606-608. 32. Anast CS, Winnacker Jl, Forte LR, Bums TW: Impaired release of parathyroid hormone in magnesium deficiency. 1 Clin Endocrinol Metab 1976;42:707-717. 33. Stephan F, Flahault A, Dieudonne N, et al: Clinical evaluation of circulatingblood volume in critically ill patients-Contribution of a clinicalscoringsystem. Br1 Anaesth 2001;86:754-762. 34. Gennari Fl: Hypokalemia. NEngl 1 Med 1998;339:451-458. 35. Hillier TA, Abbott RD, Barrett EJ: Hyponatremia: Evaluating the correction factor for hyperglycemia. Am 1 Med 1999;106: 399-403. 36. Sacher P, Hirsig 1,Gresser 1,SpitzL: The importance of oral sodium replacement in ileostomy patients. Prog Pediatr Surg 1989;24: 226-231. 37. Wong ET, Rude RK, SingerFR, ShawST: Ahigh prevalence of hypomagnesemia and hypermagnesemia in hospitalized patients.Am1 Clin Pathoi 1983;79:348--352. 38. Whang R, Aikawa lK, Oei TO, Hamiter T: The need for routine serum magnesiumdetermination. ClinRes 1977;25:154A. 39. Rubeiz GJ, Thill-Baharozian M, Hardie D,Carlson RW: Association of hypomagnesemia and mortality in acutely ill medical patients. Crit Care Med 1993;21:203-209.
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40. Whang R, Oei TO, Aikawa lK, et al: Predictors of clinical hypomagnesemia: Hypokalemia, hypophosphatemia, hyponatremia, and hypocalcemia. Arch Intern Med 1984;144:1794-1796. 41. England MR, Gordon G, Salem M, Chernow B: Magnesium administrationand dysrhythmias after cardiac surgery: A placebocontrolled, double-blind, randomized trial. lAMA 1992;268: 2395-2402. 42. Salem M, Kasinski N, Andrei AM, et al: Hypomagnesemia is a frequent finding in the emergency department in patients with chest pain. Arch Intern Med 1991;151:2185-2190. 43. Whang R, Ryder KW: Frequency of hypomagnesemia and hypermagnesemia:Requested vs. routine. lAMA 1990;263:3063-3064. 44. Chernow B, Bamberger S, Stoiko M, et al: Hypomagnesemia in patients in postoperativeintensivecare. Chest 1989;95:391-397. 45. DesaiTK, Carlson RW, Geheb MA: Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting.Am1 Med 1988;84:209--214. 46. Fiaccadori E,DelCanale S, Coffrini E,et al: Muscle and serum magnesium in pulmonary intensive care unit patients. Crit Care Med 1988;16:751-760. 47. Reinhart RA, Desbiens NA: Hypomagnesemia in patients entering the lCU. CritCare Med 1985;13:506-507. 48. Ryzen E,WagersPW, SingerFR, Rude RK: Magnesium deficiencyin a medicallCU population. CritCare Med 1985;13:19-21. 49. Boyd lC, Bruns DE, Wills MR: Frequency of hypomagnesemia in hypokalemicstates. ClinChem 1983;29:178-179. 50. Ryzen E, Elkayam U, Rude RK: Low blood mononuclear cell magnesium in intensive cardiac care unit patients. Am Heart 1 1986;111:475-480. 51. GullestadL, DolvaLO, Waage A,et al: Magnesium deficiencydiagnosed by an intravenous loading test. Scand 1 Clin Lab Invest 1992;52:245-253. 52. Chernow B,Smith1,RaineyTG, FintonC:Hypomagnesemia: implications for the critical care specialist. Crit Care Med 1982;10:193-196. 53. Reinhart RA: Magnesium metabolism: A review with special reference to the relationship between intracellular and serum levels. Arch Intern Med 1988;148:2415-2420. 54. Dickerson RN: Guidelines for the intravenous management of hypophosphatemia,hypomagnesemia,hypokalemia,and hypocalcemia. Hosp Pharm 2001;36:1201-1208. 55. Zivin lR, GooleyT,ZagerRA, RyanMl: Hypocalcemia: A pervasive metabolic abnormalityin the criticallyill. Am 1 Kidney Dis2001;37: 689-698. 56. Zaloga GP: Hypocalcemia in critically ill patients. Crit Care Med 1992;20:251-262. 57. Nordin BEC, PolleyKJ: Metabolic consequences of the menopause: a cross-sectional, longitudinal, and intervention study on 557 normal, postmenopausal women. CalcifTissue Int 1987;41:S1-S59.
III Macronutrients Dipin Gupta, MD Rolando Rolandelli, MD
CHAPTER OUTLINE Introduction Lipids Body Lipids Lipid Biochemistry: Classification of Fatty Acids Essential Fatty Acids Dietary Fat Fatty Acids as a Fuel Source Structured Lipids Immune Modulation by Fatty Acids Carbohydrates Definitions and Classification Dietary Carbohydrates Digestion Absorption Brush Border Enzyme Renewal Food Processing Metabolism and Energy Storage Metabolism Proteins Definitions and Classification Dietary Protein Digestion and Absorption Adaptation of Brush Border Peptidase Activity Hepatic Metabolism Amino Acid Metabolism Conclusion
INTRODUCTION In the normal physiologic state, the gastrointestinal tract is a finely integrated system with the ability to process a variety of foodstuffs, derive energy from ingested substrates in a relatively efficient manner, and excrete excess substances. To better understand the effects of enteral nutrition on the gastrointestinal system as well as on the body as a whole, it is important to have a basic understanding of these digestive and absorptive processes.
110
LIPIDS Lipids provide most of the energy in oral diets and in defined formula diets because of their high caloric density. With the realization that the body depends on the exogenous supply of linoleic and linolenic acids, oil sources with high concentrations of these essential fatty acids, such as com oil or soybean oil, have become the standard fat source in enteral diets. In recent years, however, several questions have been raised about the wisdom of using long-ehain triglycerides as a calorie source. Conversely, other fat sources have been noted to be beneficial in certain clinical conditions. Within the context of these controversies, in this chapter we will review the biochemistry and physiology of lipids as well as the role of fat in enteral nutrition.
Body Lipids Fat accounts for approximately 15% of body weight. About one half of the total body fat is in the subcutaneous tissue, and the remaining one half is distributed in other body tissues. Subcutaneous fat was thought to serve only as a mechanical cushion and an insulating layer. In the 19505, however, investigators demonstrated that the adipose tissue is also a reservoir of energy that can be mobilized in the form of nonesterified fatty acids to other tissues.P Lipids circulate in the bloodstream in the form of lipoproteins. Lipoproteins are classified as very lowdensity lipoproteins (VLDL), low-density lipoproteins (LDLs), high-density lipoproteins (HDLs), and chylomicrons depending on their centrifugation characteristics. Chylomicrons are the largest and the lightest of the lipoproteins. They are made of triglyceride (approximately 90% weight), cholesterol (4%), phospholipid (4%), and protein (2%). Chylomicrons transport dietary fat from the intestinal mucosa via the thoracic duct to most tissues and are ultimately cleared by the liver. VLDLs consist of triglyceride derived from the liver (60%), cholesterol (15%), phospholipid (15%), and protein (10%). LDLs originate, in part, from VLDL degradation and are composed of
SECTION III • Nutrient Metabolism
III
FIGURE 11-1. Mosaic model of cell membranes with lipid bilayer and proteins scattered throughout (black). The polar head of phospholipids (A) is exposed to both surfacesextracellular and intracellular. The nonpolar fatty acid tails (8) are hidden between the two layers. Proteins can be transmembrane proteins (e) or surface proteins (D).
10% triglyceride, 45% cholesterol, 20% phospholipid, and 25% protein. Hlll.s originate in the liver, independently of VLDts, and are composed of roughly 20% cholesterol, 30% phospholipid, and 50% protein. Lipids are also constituents of cell membranes. Singer and Nicholson" described the biomembranes as fluid-like phospholipid bilayers. Various proteins are scattered throughout the lipidic bilayer in the form of a mosaic (Fig. 11-1). The proportion of lipids and proteins varies from membrane to membrane within a cell and between different cells. The outer mitochondrial membrane, for example, consists of approximately 50% protein and 45% lipid, whereas the inner mitochondrial membrane consists of roughly 75% protein and 25% lipid. Most cell membranes, however, consist of 50% protein and 50% lipid. The composition of myelin is unique, with more than 75% of its content being lipid, including glycosyl ceramides and sphingolipids. The phospholipids present in membranes are 1,2-diacylphosphoglycerides, of which phosphatidylcholine predominates in humans. The acyl chains of phosphatidylcholine are occupied with evennumbered fatty-acids. Whereas the n-l position is occupied by saturated fatty acids, the n-2 position includes unsaturated fatty acids such as 18:1, 18:2, 18:3, and 20:4. The type of fatty acid incorporated into membrane phospholipids varies depending on the type of dietary fat. Increasing amounts of polyunsaturated fatty acids in the diet change the membrane fluidity, which in turn may affect cellular function.t-'
Lipid Biochemistry: Classification of Fatty Acids Lipids are classified according to their chain length and the position and number of double bonds. Several nomenclature systems are used to refer to fatty acids, one of which uses the chain length followed by the number of double bonds in the same word, preceded by the type and position of double bonds. According to this system linoleic acid, for example, is expressed as 9, 12-octadecadienoic acid. An alternate, simpler system uses the number of carbons separated from the number
of double bonds by a colon and then followed by a subscript with the position of the double bonds. In this system, linoleic acid is expressed as 18:2Ll9.12. Many fatty acids have been given a name, such as arachidonic acid or linoleic acid, usually related to their metabolic characteristics or abundance in nature. Naturally occurring fatty acid double bonds are in the cis position. Unsaturation in the trans position occurs during hydrogenation or processing by intestinal bacteria. In the aforementioned examples the carbon chain is numbered from the carboxyl group; 9 and 12 refer to the 9th and 12th carbons, counting from the carboxyl end of linoleic acid. Biochemists have introduced another classification system for fatty acids in which the numbering is begun from the methyl group end. According to this system, fatty acids are divided in series (00 or n) depending on the location of the first double bond: 3-<0 or n-3 series. The 3, 6, 7, and 9 series are common in humans (Fig. 11-2). Finally, another classification system divides fatty acids into three groups according to the length of the carbon chain: short-, medium-, or long-chain fatty acids. The short-chain fatty acids of interest in human physiology are acetate (two-carbon chain), propionate (threecarbon chain), and butyrate (four-earbon chain). These fatty acids are produced by bacteria, usually from a carbohydrate source, and their metabolism more closely resembles that of carbohydrates than of lipids. For instance, the respiratory quotient of short-ehain fatty acid oxidation is approximately 0.8 to 0.9 instead of the typical 0.7 of fat oxidation. The medium-chain fatty acids (MCFAs) are those with chains between 6 and 12 carbons. MCFAs are degraded by IWxidation, yielding a low respiratory quotient. These molecules enter the mitochondrion for oxidation independent of transporters. Long-ehain fatty acids (LCFAs) are those with chains between 14 and 24 carbons. Because of their diverse effects on the body and their essential nature, LCFAs have been extensively studied. Contrary to MCFAs, LCFAs require a transporter (l-earnitine, the acyl transferase system) to enter the mitochondrion for oxidation (Fig. 11-3). Fatty acids with more than two double bonds are called polyunsaturated fatty acids (PUFAs). These
112
11 • Macronutrients
FIGURE 11-2. Schematic representation of fatty acids. Some of the key fatty acids are stacked together to demonstrate the basis for the different nomenclature systems used to classify fatty acids. The arrow on the left side of the graph indicates the direction of the chemical numbering of carbons from the carboxyl group to the methyl group. The biologic classification numbers the carbons beginning in the methyl group (arrow on the right side of the graph). The vertical double lines within the rectangles indicate the position of double bonds. Fatty acids are grouped in series (omega) according to the position of the first double bond. Oleic acid belongs to the 9-00 series. Linoleic, y-linolenic (GLA), and arachidonic (AA) acids are part of the 6-00 series whereas a-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexanoic acid (DHA) are part of the 3-00 series.
molecules are precursors for the synthesis of eicosanoids (prostaglandins, leukotrienes, and thromboxanes). Eicosanoids act on target cells at very low concentrations and for a brief period of time, indicating that they behave as autocrine or paracrine mediators rather than as systemic hormones.
Essential Fatty Acids The essential fatty acids are linoleic and a-linolenic acids. Since the advent of parenteral nutrition, it has become evident that deprivation of linoleic and 0.linolenic acid from the diet or from parenteral nutrition formulas leads to a deficiency syndrome characterized by scaly dermatitis, hair loss, thrombocytopenia, and poor wound healing," The body can synthesize fatty acids from glucose. For instance, palmitic (16:0) and stearic (18:0) acids can be synthesized from glucose via lipogenesis. These fatty acids are desaturated to produce, respectively, palmitoleic (16:1n-7) and oleic (18:1n-9) acids by tJ.9 desaturase. In turn, these fatty acids can be further elongated and desaturated, but the products will always remain with the 7 and 9 series (the first double bond in either the seventh or the ninth carbon), as shown in Figure 11-4. There are two families of essential fatty acids, one with the n-6 series and the other with the n-3 series. The precursor of the n-6 series is linoleic acid (18:2n-6) and the precursor of the n-3 series is a-linolenic acid (18:3n-3). These fatty acids are desaturated by tJ.6 desaturase to be converted into a-linolenic (18:3n-3) and stearidonic (18:4n-3) acid, respectively. o-Linolenicacid is then elongated to dihomo-o-linolenic acid (DHLA, 20:3n-6) and desaturated to arachidonic acid (20:4n-6). Stearidonic acid is elongated (20:4n-3) and then desaturated to produce eicosapentaenoic acid (20:5n-3).
If essential fatty acids are absent, the body tries to compensate for this deficit by overproducing metabolites of palmitic and stearic acid. The end products of metabolism of these nonessential fatty acids are icosatrienoic acid (20:3n-9) and docosatrienoic acid (22:3n-9). Therefore, the diagnosis of essential fatty acid deficiency (EFAD) is made by calculating the ratio of trienoic fatty acids to tetraenoic fatty acids in plasma. When this ratio is less than 0.4, a diagnosis of EFAD is established." Clinical signs of EFAD are usually seen after 3 weeks of consumption of a diet devoid of long-chain triglycerides (LCTs). The need for essential fatty acids is met by providing 1% to 2% of total calories as linoleic acid. In the average-weight adult, this is equivalent to 2.5 to 5 g/day. Despite providing sufficient quantities of linoleic acid with formulas containing soybean oil, patients have developed EFAD.8.9 This deficiency of a-linolenic acid results in scaly and hemorrhagic dermatitis, hemorrhagic folliculitis of the scalp, growth retardation, and delayed wound healing. 10 a-Linolenic acid is a 3-<0 fatty acid precursor of eicosapentaenoic acid (EPA). The requirement for 0.linolenic acid is even less than that for linoleic acid. This need is met by providing 0.5% to 0.6% of total calories as linolenic acid. In the average-weight adult, this is equivalent to 2 to 3 g/day.
Dietary Fat Vegetable oils are rich in saturated fatty acids and derivatives of linoleic acid, the 6-ro series. The only fatty acid of the 3-<0 series present in vegetables is a-linolenic acid. Fatty acids with longer carbon chains in the 3-<0 series, such as EPA or docosahexaenoic acid, are present in cold-water fish, shellfish, and fish oils. Beef and dairy products also contain linoleic acid. Medium-chain
SECTION III • Nutrient Metabolism Long chain fatty acid + ATP + CoASH
113
Cytoplasm
Thiokinase
I
AMP + Pi
Outer mitochondrial membrane
Acyltransferase I
FIGURE 11-3. Carnitine-mediated transport of longchain fatty acids into mitochondria. AMP, adenosine monophosphate; Pi, inorganic phosphorous. (From Tao RC, Yoshimura NN: Carnitine metabolism and its application in parenteral nutrition. JPEN J Parenter Enter Nutr 1980;4:469-486.)
Intermembrane space
Acyltransferase II
Innermitochondrial membrane
Mitochondrial matrix
triglycerides (MCTs) are present in oils with high concentrations of saturated fat such as those obtained from the coconut and the palm kernel. The liquid diets marketed by the pharmaceutical industry contain variable amounts of fatty acids. The early elemental diets provided sufficient amounts of LCTs to prevent EFAD and used carbohydrates as a source of calories. This made elemental diets hyperosmolar, which resulted in tube feeding intolerance. As ready-to-use liquid diets were developed, the side effects of overfeeding carbohydrate calories became known. These side effects included respiratory insufficiency from the excess carbon dioxide produced from carbohydrate oxidation and deposition of fat in the liver. To reduce the osmolality and also the side effects of carbohydrate overfeeding, more and more fat was added to enteral diets. Diets with as much as 50 gIL of linoleic acid were developed and marketed as being therapeutic for pulmonary diseases. As knowledge of lipid metabolism has evolved, two significant changes have been
introduced in enteral diets. Many diets now include a proportion of MCfs and 3-<0 fatty acids. As mentioned, PUFAs such as linoleic and a-linolenic acids are the precursors for the synthesis of eicosanoids such as prostaglandins, leukotrienes, and thrornboxanes. The two major pathways of eicosanoid synthesis are the cyclooxygenase and Iipooxygenase pathways. The cyclooxygenase pathway results in prostanoids, prostaglandins, and thromboxanes, and the metabolites of the Iipooxygenase pathway are leukotrienes, hydroxyeicosatrienoic acid, and Iipoxins (Fig. 11-5). The substrates for eicosanoid synthesis are arachidonic acid and EPA, and the main source of the acids is the membrane phospholipids. Arachidonic acid is released from phosphatidylcholine by the action of phospholipase A 2. 11 Eicosanoids derived from arachidonic acid are mainly the dienoic prostanoids and the tetraenoic leukotrienes; the metabolism of EPA, however, yields trienoic prostanoids and pentanoic leukotrienes.l-P In addition to being a substrate for
114
11 • Macronutrients
~4
~5
~9
,--....
,
....
-....
,
....
,..--...
-....
,-- ...
, 16:2\ r--~" 18:2\ ,...--~' 18-3\ r--~' 20:3\ r--~r 20:4 \ , ---------~ L...-_ _-"
'- n-?,' _-
,
'- n-?,' _-
....
....
'-'-n-?,'
'- ....n-?,' _-
'- n-?,' _....
,
Palmitoleic A.:
,---------------. I
"
, ~ -, 18:1 \,
'- n-?,' '-~
Stearic A.
Oleic A. '---------+1
'-----'
20:1 n-9
-, I
Linoleic A: I
Gamma
DHLA
,, ,, ,
Essential fatty acids families
, n-s. '-~
I
:-
AA
iI--------------~'~2~3\I
: LinolenicA
-- - - ---
-..
, .... _....
, __ ....
... __ ....
'20:2\- - - - - - - - - - - -~,'22:2\,... \' ...n-6 ', ...n-6 _.... "" _.... ' ,
-
- - - - - - - - -~,'24:2\ \' ...n-6 _...... "
,'2""2~5\~2:6 -, EPA
6.EFA Deficiency symptom D Parent Fa
:
<>
Icosanoid precursor
I
n-3
....
,""_ ...
,
'22'4'
.
'--~'
I I
,, ,,
'- n-3 _-, ,
I I I
DHA \
'- n-3 _,' " ....
,--....
, - - ...
" 20:3\ '22:3\ --------------~ I------------~' '- n-3 '- ....n-3 _-' , __ ,
,
....
...
FIGURE 11-4. Biosynthesis of fatty acids. (From Halperin MJ [ed.]: lipid Metabolism and Its Pathology. Amsterdam, Elsevier Science, 1986, 213-223.)
different eicosanoid production, 3-<0 fatty acids directly suppress the activity of cyclooxygenase." Eicosanoids influence cellular activity by altering the intracellular levels of the cyclic nucleotides adenosine 3':5'-phosphate and guanosine 3':5'-monophosphate. The ratio between these two nucleotides determines cell function rather than the absolute concentrations. For instance, prostaglandin (Pfl) E2, a product of cyclooxygenase metabolism, suppresses blastogenesis by lymphocytes through an increase in this ratio. I I Thromboxane A2 and leukotriene 8 4, both products of arachidonic acid via linoleic metabolism, are potent
vasoconstrictors and induce platelet aggregation whereas thromboxane A3 is only a mild vasoconstrictor and inhibits platelet aggregation. Other PUFAs can be synthesized by conversion of linoleic and a-linolenic acids. One of the limiting steps in the conversion of linoleic and a-linolenic acids to their derivatives is the enzyme d 6-desaturase. This enzyme is regulated by many factors. Whereas dietary protein and insulin levels activate il6-desaturase, starvation, carbohydrates, and counter-regulatory hormones inhibit it.IS A peculiar mode of regulation is by the presence of linoleic acid. Contrary to other chemical
SECTION III • Nutrient Metabolism
115
Ar~chidonic ~PA acid / I:
FIGURE 11-5. Eicosanoid synthesis. The two rows on the bottom illustrate the influence of dietary lipids on the synthesis of eicosanoids. Diets rich in 6-(0 fatty acids result in the production of eicosanoids of the 2 or 4 series whereas diets enriched with 3-(0 fatty acids result in the production of eicosanoids of the 3 and 5 series.
Leukotrienes (LT)
Prostaglandins (PG) Thromboxanes (TX)
6-0mega
PGE2
3-0mega
PGE2
reactions in which substrate stimulates an enzyme, the activity of d 6-desaturase is inhibited by an excess of linoleic acid. This phenomenon was elegantly demonstrated in rats receiving parenteral nutrition for 1 week with either no lipids or with a soybean emulsion. Analysis of the liver phosphatidylcholine of these animals revealed a decrease in all the upper derivatives of both linoleic and a-linolenic acids whereas high levels of linoleic acid were being supplied.F Similarly, in children receiving a short course of parenteral nutrition with a soybean emulsion, the liver phosphatidylcholine was deficient in upper derivatives of the 3-<0 and 6-ro families." An interesting study of the effects of various fat sources was published by Diboune and colleagues." This group studied critically ill patients receiving three different types of enteral diets. Group A received an enteral diet with only LCFAs provided as soybean oil. Group B received the same enteral diet, but 50% of the fat was provided by LCFAs and 50% by MCFAs. Group C also received an enteral diet with 50% LCFAs, but 42.5% was given as LCFAs, and 7.5% was given as black current seed oil. This type of oil is composed of 14% a-linoleic acid and 4%stearidonic acid, which are products of the 3-<0 series beyond the step of the d 6-desaturase. To assess the metabolism of fatty acids, the group studied the lipid composition of circulating erythrocytes. They demonstrated that patients in group A had an inhibition of the d 6-desaturase as demonstrated by an increase in linoleic acid without a corresponding increase in DHLA. Replacing 50% of fat calories with MCFAs reduced this inhibition, and adding black current seed oil increased both DHLA and EPA. Further studies are needed to delineate the exact needs for fatty acids under different pathologic conditions. In the typical Western diet, fat is present in the form of LCTs. When ingested fat reaches the duodenum, it
Hydroxyeicosatetranoic acid Lipoxins
TXA2
LT84 LT85
stimulates the release of cholecystokinin, which delays stomach emptying and produces contraction of the gallbladder and pancreatic secretion. LCTs are then hydrolyzed by pancreatic lipase in the alkaline environment provided by pancreatic juice. Colipase is another substance present in pancreatic juice that produces adherence of lipase to the oil droplets. Fat hydrolysis is usually incomplete and results in glycerol, fatty acids, and monoglycerides. Monoglycerides and fatty acids are then incorporated into micelles, which are aggregates of bile salts with a hydrophilic and water-soluble external surface and a hydrophobic internal core. These micelles allow the transport of fatty acids across the unstirred layer of water that overlies the villi. Once in proximity to the epithelial cells, the micelles break up and the fatty acids are transported into the jejunal epithelium whereas bile salts return to the lumen to be absorbed later in the ileum. Within the epithelial cells of the jejunum LCTs are resynthesized and then combine with phospholipids, cholesterol, and proteins to form chylomicrons. Chylomicrons are transported through lacteals and then through the thoracic duct into the systemic circulation. Fat not absorbed in the small intestine creates water secretion in the colon and steatorrhea. Steatorrhea is associated with large, greasy, foul-smelling stools. Causes for steatorrhea include bile salt deficiency, pancreatic enzyme deficiency, or defects in lymphatic transport. A deficiency of bile salts in the intestinal lumen may be due to lack of excretion (e.g., in biliary obstruction) or excessive loss (e.g., with ileal resection). Disorders of the lymphatic transport are more rare and include chylous fistula due to injury of the thoracic duct in addition to congenital lymphangiectasia and Whipple disease.
116
11 • Macronutrients
Fatty Acids as a Fuel Source The smaller molecular size of MCTs compared with that of LCTs facilitates the action of pancreatic lipase. MCTs are hydrolyzed faster and more completely than LCTs. Studies in humans have demonstrated that MCTs do not stimulate pancreatic secretion whereas LCTs significantly increase pancreatic secretion." Because their intraluminal hydrolysis is complete, MCTs are rapidly absorbed as free fattyacids. MCFAs are absorbed via the portal venous system. When MCFAs reach the liver, they undergo extensive metabolism with only a very small amount passing out of the liver. Another major difference between MCFAs and LCFAs is their intracellular metabolism. MCFAs cross the double mitochondrial membrane rapidly and, once inside the mitochondria, are activated to acyl-eoenzyme A (CoA). LCFAs entering the cell are first activated by thiokinases with extramitochondrial CoA-SH at the expense of adenosine triphosphate. Activated LCFAs, in the form of acylCoA, are impermeable to the mitochondrial membrane. To traverse the mitochondrial membrane, acyl-CoA is converted to acyl carnitine by acyltransferase I. Another enzyme, translocase, transports the acyl carnitine through the intermembrane space. At the inner mitochondrial membrane acyltransferase II removes the carnitine and replaces the CoA to form acyl-CoA ready to enter jHlxidation. 19 Carnitine is ~hydroxy-"'ttrimethylaminobutyric acid. The carbon chain of carnitine derives from lysine, which is methylated by S-adenosyl-methionine to produce etrimethyl-lysine. e-Trimethyl-lysine first undergoes hydroxylation and later dehydrogenation, requiring ascorbic acid, iron, and pyridoxal phosphate. Although all these reactions normally maintain an adequate supply of carnitine, conditions such as uremia, cirrhosis, and sepsis can result in a relative deficiency of carnitine. Under these circumstances LCFAs cannot be oxidized and accumulate in muscle, resulting in lipid storage myopathy and cardiomyopathy.-" Under normal conditions the carnitine palmityl transferase is rather inactive. Therefore, LCFAsare preferentially redirected to lipogenesis instead of oxidation. MCFAs, however, are preferentially oxidized to acetyl-CoA. A fraction of the acetyl-CoA produced from MCFA oxidation enters the Krebs cycle for complete oxidation. Another fraction of acetyl-CoA is redirected toward the synthesis of ketone bodies, which explains the ketogenic capacity of MCTs.21 A single oral dose of MCTs results in slight hypoglycemia." This is caused by a decrease in hepatic output of glucose rather than an increase in peripheral utilization of glucose. Paradoxically, insulin levels increase at the same time, presumably due to stimulation of the islets of Langerhans by ketone bodies or by MCFAs. However, MCTs tend to improve carbohydrate tolerance.P Other side effects reported with the use of MCTs are increased thermogenesis and a derangement in lipoproteins leading to a proatherogenic lipid profile. In summary, the physicochemical properties of MCFAs make them a readily available source of calories. MCFAs
are not stored in adipose tissue and do not produce hyperlipidemia; however, they are rapidly oxidized and are ketogenic. In addition, by replacing LCT calories with MCT calories the immunosuppressive effects of linoleic acid and its 6-ro derivatives can be minimized.
Structured Lipids It has now become apparent that neither LCTs nor MCTs alone can meet the body's needs for fat and fuel for oxidation or prevent the development of EFAD. Therefore, many commercial diets include various proportions of LCT and MCT oil (fable 11-1). A novel approach is the combination of MeI's and LeI's within the same molecule to create a structured triglyceride or structured lipid." These particles are made by hydrolysis and reesterification of LCTs and MCTs after random mixing in a process called transesterification. The final products are either two LCFAs with one MCFA or one LCFA with two MCFAs. The proportions of structured triglycerides resulting from a mixture can be predicted, depending on the starting proportions of the base oils. The combination of LCFAs and MCFAs provides both esterified fatty acids and a readily available fuel source, and in addition, seems to potentiate the effects of each. In a rat model of bum wound, administration of structured triglycerides through a gastrostomy tube resulted in an increase in the protein fractional synthetic rate of the liver and improved nitrogen balance." These structured triglycerides were made from 35% MCTs, 50% butter, and 15% safflower oil. Similar results were obtained in the rat model of burn wound using structured triglycerides made from palm kernel oil and sunflower oil26 or from MCTs and fish oil.27
Immune Modulation by Fatty Acids Long-chain unsaturated fatty acids are incorporated into the membranes of all mammalian cells where they influence fluidity and function. This is of particular importance in cell-to-eell interactions, particularly in antigenpresenting cells, in the response of the cells to injury, and in cytolysis. For example, large amounts of arachidonic acid in the membrane phospholipids yield higher amounts of PGE2 and prostacyclin. PGE2 is a potent immunosuppressive agent. One of the mechanisms for its immunosuppressive effect is the stimulation of suppressor T-cell activity." Other mechanisms for the immunosuppressive effects of 6-ro fatty acids are stimulation of macrophages to release superoxide.P decreased synthesis of fractions of complernent.P and depression of delayed hypersensitivity responses.l-" The immunosuppressive effect of 6-ro fatty acids has been exploited for therapeutic purposes. In rats, supplementation with linoleic acid prolongs the life of skin allografts'": supplementation with linoleic acid in conjunction with a donor-specific transfusion prolongs survival of heart allografts.P Linoleic acid can also act synergistically with cyclosporine and transfusion to
--
SECTION III • Nutrient Metabolism
117
Composition of Commercial Diets
Fonnula
Total
Alterna Amln-Aid Attain Compleat Reg Compleat Mod Comply Criticare HN Deliver 2.0 Ensure Ensure Plus Ensure with Fiber Entera Entera Iso Entera OPD Flbersource Flbersource HN Glucerna Hepatic-Aid II Immun-Aid Impact Isocal Isocal HN Isosource Isosource HN Isotein HN Jevlty Lipisorb Magnacal Newtrition HN Newtrltlon Isofiber Newtrition Iso Newtrltion 1 & % Nutren 1.0 Nutren 1.0 with Fiber Nutren 1.5 Osmollte Osmolite HN Pediasure Peptamen Pulrnocare Reabilan Reabilan HN Replena Replete Resource Liquid Resource Plus Stresstein Sustacal Sustacal HC Sustacal with Fiber Toterex Traum-Aid HBC TraumaCal Ultracal Vital HN Vltaneed VivonexTEN
15.6 46.2 35.0 42.8 36.8 60.0 5.3 102.0 37.1 53.2 37.1 34.0 34.0 26.0 51.6 51.6 55.7 36.2 22.0 28.0 44.0 45.0 41.6 41.6 34.0 36.8 48.0 80.0 40.0 40.0 36.0 50.0 38.0 38.0 67.5 38.5 36.8 50.0 39.0 92.0 39.0 51.9 95.0 33.0 37.0 53.1 27.3 23.0 58.0 35.0 1.45 12.4 68.0 45.0 10.7 40.0 2.8
% Cal 38.1 21.2 30.0 36.0 31.0 36.0 4.5 45.0 31.5 32.0 30.5 30.0 30.0 22.0 30.0 30.0 50.0 27.7 20.0 25.0 37.0 37.0 30.0 30.0 25.0 30.0 48.0 36.0 30.0 29.0 31.0 30.0 33.0 33.0 39.0 31.4 30.0 44.5 33.0 55.2 35.0 35.0 43.0 30.0 32.0 32.0 20.0 21.0 34.0 30.0 1.3 11.2 40.0 37.0 9.4 36.0 2.5
Unolelc Acids 0.5 10.2 7.2 17.5 14.4 26.2 3.3 38.0 20.0 28.6 20.0 19.1 19.1 19.1 5.2 5.2 11.0 8.0 2.1 2.2 19.4 14.4 4.1 4.1 3.7 12.3 3.9 29.6 8.16 10.88 9.79 8.16 14.7 14.7 17.4 12.9 12.3 11.4 4.8 52.0 12.5 15.4 19.9 17.0 21.8 31.3 4.09 8.7 35.0 19.2 1.16 1.6 27.0 13.1 4.1 22.1 2.17
MeT 0 0 17.3 0 0 0 0 29.0 0 0 0 4.0 13.0 14.3 25.8 25.8 0 0 11.0 7.0 8.9 17.8 20.5 20.5 8.5 18.5 41.0 0 15.0 20.0 18.0 25.0 9.0 9.0 32.7 19.25 18.25 9.9 27.0 0 15.4 19.95 0 0 0 0 16.9 0 0 0 0 5.0 20.0 18.2 4.8 0 0
30m Fatty Acids 0.1 0.92 0.2 0.43 0.37 0.72 0.13 5.6 0.46 0.7 0.46 0 2.3 0 2.06 2.06 0.75 0.75 1.2 1.7 2.7 2.3 1.7 1.7 0.34 0.33 <0.1 4.8 0.56 0.56 0.5 0.7 0.38 0.38 0.56 0.34 0.33 1.1 0.21 1.2 0.56 1.0 0.85 0.42 0.37 0.53 0.55 0.4 0.3 0.4 0 0.15 4.3 2.2 0 0 0
011Source Soy Soy, lecithin, glycerides Corn, MCT Beef, corn Beef, corn Corn Safflower Soy, MCT Corn Corn Corn Sunflower, MCT Soy, MCT Sunflower, MCT Canola, MCT Canola, MCT Safflower, soy, oleic Soy, lecithin, glycerides Canola, MCT Menhaden, MCT, kernel/sunflower Soy, MCT Soy, MCT Canola, MCT Canola, MCT Soy, MCT Corn, soy, MCT Corn, MCT Soy Corn, MCT Com, MCT Corn, MCT Corn, MCT Corn, MCT Corn, MCT Corn, MCT Corn, soy, MCT Corn, soy, MCT Safflower, soy, MCT Sunflower, MCT, lecithin Corn Primrose, soy, MCT linoleic, MCT Safflower (high oleic), soy Corn Corn Corn Soy, MCT Soy Corn Corn Safflower Soy, MCT Soy, MCT Soy, MCT Safflower, MCT Corn, beef Safflower
HN, high nitrogen; ISO, isotonic; MeT,medium-ehain triglycerides. Modified from Gottschlich MM: Selection of optimal lipid sources in enteral and parenteral nutrition. Nutr Clin Pract1992:7:155-156.
produce a permanent allograft survival." Another demonstration of the role of fatty acids on the immune response is that the effects of donor-specific transfusion on allograft survival can be blocked by cyclooxygenase inhibition and enhanced by lipooxygenase inhibition." In other studies 6-0> fatty acids have been shown to alter the response to endotoxin. In rats with EFAD, the
mortality after endotoxin challenge was 24%. However, when the EFAD was reversed by administration of arachidonic acid 2 days before the endotoxin challenge, the mortality was 100%.36 The response to the endotoxin was lessened in guinea pigs receiving a diet with 3-ro fatty acids compared with that in animals receiving safflower oiJ.37
118
11 • Macronutrients
Similarly, guinea pigs recovering from a major burn wound had improved immune function when they received the same amount of fat in the diet (10% of calories) but in the form of 3-<.0 fatty acids compared with animals that received 6-co fattyacids or 100% linoleic acid. Animals fed 3-<.0 fattyacids had better cell-mediated immune responses, better opsonic indexes, higher splenic weights, and lower C3 levels." One concern with the dietary supplementation of 3-<.0 fatty acids is the development of glucose intolerance. Glucose intolerance has been described as a side effect in patients with non-insulin-dependent diabetes when they received a supplement of 3-<.0 fatty acids. However, to our knowledge this has not been a problem in hospitalized patients receiving tube feedings.
mammals. It is composed of a molecule of glucose and a molecule of galactose. Maltose is a compound arising from the breakdown of starch and is composed of two molecules of glucose. The two main polysaccharides consumed in the human diet are starch and cellulose. Starch (seeds or roots) is a polymer of glucose. Some starches are readily digested in their native form, and others become digestible only after heating. Along with sucrose, starch is the largest component of ingested carbohydrates." Cellulose, present in many cereals, fruits, and vegetables, is not digestible in humans" and thus plays a minor metabolic role. Sorbitol, the alcohol form of glucose, is used as a replacement carbohydrate in diabetic patients. It is converted to fructose during hepatic metabolism.
CARBOHYDRATES
Digestion
The extraction process of sugar was first described in India in approximately 3000 Be. Sugar cane was brought to Europe from India and then brought to the New World by Columbus in 1493. Carbohydrates are often thought of solely for their role in energy storage, but in fact, more recently they have been implicated in many human pathologic states such as dental disease, cardiovascular disease, diabetes, and obesity. Indeed, they playa role not only in contributing to the taste and texture of food, but also in determining viscosity, in preserving food, and, most importantly, in sweetening foods. Today, carbohydrates account for 50% of the daily caloric intake of adults consuming a Western-type diet 39 and close to 80% of daily caloric intake of adults in poorer countries.
Monosaccharides are linked together to form larger molecules in a manner in which the first carbon (CI) of one monosaccharide is bound to the fourth carbon (C4) of the next. The structure of this 1A-glucosidic bond has important implications in starch digestion. Cellulose, for example, has a ~ I A-glucosidic bond, and human enterocytes do not contain the enzyme necessary for hydrolysis of compounds in this orientation. Starch, on the other hand, is made of polymers of glucose joined by either a-I,4-glucosidic or a-I,6-glucosidic bonds, which are easily hydrolyzed by enterocyte enzymes. Starch is composed of amylose (20%) and amylopectin (80%). Amylose is a straight-ehain polymer of glucose linked by a-lA-glucosidic bonds, whereas amylopectin is a branched-ehain polymer of glucose linked by a-lA-glucosidic bonds and o-l.Sglucosidlc bonds. The enzyme responsible for breakdown of the aIA-glucosidic bond is a-amylase, which is present in saliva, pancreatic juice, and in the brush border of enterocytes.f Free salivary amylase is inactivated by the acidic gastric environment (irreversibly denatured at pH <3.0), and pancreatic amylase is, therefore, the only active carbohydrase present in the small intestine lumen. Starch is broken down to maltose, maltotriose, and a-limit dextrins (Fig. 11-6). Most dextrins are composed of 5 to 10 glucose molecules that are not released by a-amylase. The enzyme responsible for breakdown of the a1,6-glucosidic is isomaltase," which is present in the brush border of the small intestine enterocyte. The brush border also contains the enzymes sucrase and glucoamylase to further hydrolyze the products of luminal digestion. Lactase activity is lower" than that of the other disaccharidases, and it is the only one of those enzymes for which hydrolysis is the rate-limiting step in assimilation." Glucose, in particular, has the ability to limit lactase activity. Oligosaccharidases are located predominantly in the upper and middle jejunum, allowing for more distal jejunal and ileal absorption if monosaccharides are not completely absorbed more proximally. Nevertheless, well over one half of the world's adults have a deficiency of the enterocyte enzyme lactase and develop diarrhea after ingestion of more than 5 g of lactose.
Definitions and Classification The strict definition of carbohydrates is "substances composed of multiples of the empiric formula Cn(H20)n'" Humans, however, are able to digest and/or absorb only the so-called "available" carbohydrates. This group includes monosaccharides (glucose, fructose, and galactose), disaccharides (maltose, sucrose, and lactose), polysaccharides (starch), and sugar alcohols (sorbitol, mannitol, galactitol, lactitol, and maltitol). "Unavailable" carbohydrates include indigestible oligosaccharides (raffinose and stachyose) and polysaccharides (cellulose).
Dietary Carbohydrates Glucose (grape sugar or dextrose) is the main carbohydrate present in the body, although it is largely consumed in the form of the starch. Fructose (fruit sugar or levulose) has the same chemical structure as glucose, but its atoms are in a different spatial arrangement. Galactose is, like glucose, rarely consumed in its natural form. The most common disaccharide in the human diet is sucrose (cane sugar or beet sugar), which is composed of a molecule of glucose and a molecule of fructose. Lactose is found in milk, and as such is only found in
119
SECTION III • Nutrient Metabolism
FIGURE 11-6. Digestion by pancreatic a-amylase of linear (amylase) and branched (amylopectin) forms of starch. 0 = reducing agent; o = glucose limits; horizontal links denote a-I,4 linkages, and vertical links indicate a-I,6 linkages. (From Johnson LR red]: Physiology of the Gastrointestinal Tract. New York, Raven, 1994, pp 1723-1749.)
Amylopectin
Some vegetables contain the oligosaccharides raffinose, stachyose, and verbascose. These compounds all contain a-galactose links, which cannot be digested by enzymes present in human enterocytes. Thus, if consumed in large quantities, these compounds will cause abdominal discomfort and flatulence. All carbohydrates must be hydrolyzed into their constituent monosaccharides to cross the intestinal wall and be absorbed. Some absorbed monosaccharides are used by the enterocyte for its own metabolism, but most are carried to the liver via the portal circulation.
Absorption Mechanisms present for transport of monosaccharides from the enterocytes to splanchnic capillaries include passive diffusion, facilitated diffusion, and active transport. Passive diffusion is used for transport of sugar alcohols, and the L-isomers of glucose and galactose. These compounds promote water withdrawal from cells, which prevents steep concentration gradients. Thus, the amount that an adult can consume before developing symptoms of abdominal comfort is approximately 50 grams at a time. Facilitated diffusion is used for the 0isomer of fructose. Thus, fructose cannot be absorbed against a concentration gradient. The blood levels are kept very low, allowing for efficient passive absorption of this sugar. One hundred grams of this compound can be ingested in an average adult before osmotic diarrhea occurs. Active transport is used for o-isomers of glucose and galactose. As shown in Figure 11-7, the element Na' is critical to this process, and the carrier functions in a cotransport system. 46,47 Conversely, Na" absorption is also somewhat dependent on glucose, as shown by the fact that patients with cholera are given water containing glucose as well as other electrolytes. Despite the fact that low Nat levels are seen when bulk luminal contents are analyzed, it is likely that the Na' used in this cotransport system is derived from an unstirred water layer immediately adjacent to the intestinal brush border. Because of this active transport mechanism, luminal contents may contain negligible glucose levels whereas serum levels remain in the range of 80 mg/dL. The binding of both Na" and glucose to the carrier present on the brush border membrane causes a transformational change such that the Na" and glucose are
a-Limit dextrins
then exposed to the interior of the cell. Because the Na" concentration of the cell interior is much lower than that of the lumen, the Na' tends to dissociate from the carrier. The loss of Nat reduces the affinity of the carrier for glucose, which also enters the cell interior. The loss of Na' and glucose causes the carrier to return to its original configuration in which the binding sites for Na" and glucose are once again exposed to luminal contents. The intracellular Na" concentration of the enterocyte is maintained at lower levels than the extracellular concentration as a result of the sodium-potassium adenosine triphosphatase pump on the basal surface of the cell. The driving force for uphill glucose transport is thus partially provided by concurrent transport of the Na" ion down its concentration gradient. In addition, the luminal surface of the epithelial cell is positively charged relative to the intracellular compartment. Thus, during
Brush border membrane
Glucose----{
Glucose
ATP ADP Glucose F==~ Na+-K+-ATPase ' - - - - - - - - -...... active carrier FIGURE 11-7. Model of active transport of glucose across intestinal epithelial cells. Glucose enters the cell by an Na+dependent carrier molecule in the brush border and leaves via a separate Na+-independent carrier in the basolateral membrane. The energy needed to operate the brush border carrier is derived from the gradient of Na+ across the cell membrane which is maintained by Na+-K+-dependent ATPase. ADP, adenosine triphosphate; ATP, adenosine triphosphate; ATPase, adenosine triphosphase. (From Bouchier lAD, Allan RN, Hodgson HJF, Keighley MRB reds]: Gastroenterology. Philadelphia, WB Saunders, 1993, pp 386-408.)
120
11 • Macronutrients
Na-glucose absorption, Na' also flows down its electrical gradient. The absorptive capacity of the small intestine for glucose and galactose is much larger than any quantity likely to be ingested. However, the absorption of fructose is delayed compared with that of glucose or galactose, and malabsorption is noted after ingestion of as little as 37.5 g. This is roughly the amount of fructose that would be ingested with a few glasses of concentrated fruit juice. Lactose is characterized by its small size and its osmotic activity. If not absorbed or hydrolyzed, a large fluid flux into the small intestine lumen results as water and sodium move down their concentration gradients. Malabsorption of 50 g of lactose results, through this mechanism, in more than 1 L of extraluminal fluid, with resultant flatulence and diarrhea. Colonic bacteria are able to metabolize significant amounts of carbohydrate to fatty acid, which can then be absorbed. This provides a mechanism for energy gain from some substrates which pass through the small intestine.
whereas storage as fatty acids has a 28% energy COSt. 56 Glycogen stores are relatively small-ISO g may be stored in muscle and 90 g may be stored in the liver. With aggressive training, the amount of storage possible in muscle may be increased to 70 g. By dietary manipulation, endurance athletes can increase the amount of energy stored in muscle in anticipation of a sporting event."
Metabolism Glucose may be used for energy production immediately or may be stored for possible later use as glycogen or fat. Glucose is the most common form of energy available to cells by breakdown to carbon dioxide and water. During this process, the glucose is phosphorylated and converted to trioses before entry into the tricarboxylic cycle. Fructose and galactose can be metabolized in a similar fashion. Conversion to glycogen or fat occurs in the liver or may also occur in peripheral tissues's; the glycogen or fat is then recycled to the liver.
Brush Border Enzyme Renewal PROTEINS Enterocyte brush border oligosaccharidases have variable rates of turnover with some as little as 4 hours (sucrase)." Mechanisms proposed include removal by contact with luminal pancreatic enzymes," particularly elastase. Aging has also been suggested as a stimulus for changes in enzyme activity in various parts of the intestinal epithellum." Dietary manipulations have been seen to have a trophic effect on epithelial enzyme acivity." Diffusemembrane shedding.P vesiculation of rnlcrovilli.P and cleavage by luminal bacterial enzymes are alternative proposed mechanisms.
Food Processing Starches are hydrolyzed to near completion by the processes described above, but in vivo digestion may not be fully efficient because of incomplete access of the substrate to the enzyme. Food starches usually are associated with hydrophobic proteins, which protect the carbohydrates from aqueous solutions. Heating can change the starch to a gel-like structure, which when re-cooled forms a crystalline starch structure that is much more resistant to hydrolysis with o-amylase." Additionally, physical cracking or milling of grains has a dramatic effect on the efficiency of starch processing.f
Metabolism and Energy Storage In the absence of dietary carbohydrate, approximately 130 g/day of glucose may be produced through gluconeogenesis. However, approximately 180g/day of glucose are needed for fat oxidation. Thus, 50 g/day of glucose are needed from dietary sources to maintain homeostasis. Excess glucose may be stored as glycogen or fatty acid. Storage as glycogen has an energy cost of approximately 5% compared with the direct oxidation of glucose,
Definitions and Classification Amino acids may be categorized as essential or nonessential. The essential amino acids have carbon skeletons that cannot be synthesized within humans and include histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and arginine. All of these amino acids occur in most proteins (Fig. 11-8). Nonessential amino acids can be synthesized from simple precursors and include alanine, aspartic acid, asparagine, glutamic acid, glutamine, glycine, proline, and serine. Each of these amino acids (with the exception of glycine) has an asymmetric carbon atom and thus has two distinct optically active isomers. Regardless of their reaction to polarized light, the amino acids used for protein synthesis are designated the t-isomer, and the amino acids not found in proteins are designated the o-isomer.
Dietary Protein Adult males in Western countries consume, on average, approximately 100 g/day of protein. An additional 70 g enters the gastrointestinal tract from turnover of desquamated intestinal cells (30 g), luminal secretions (30 g), and bile (10 g). 59 Of this load of 170 g, approximately 10 g is excreted and 160 g is absorbed as amino acids or small peptides. Experiments using labeled amino acids show that 250 to 300 g of protein are synthesized daily in adults, suggesting that a large amount of amino acids are reutilized.
Digestion and Absorption Gastric secretions contain pepsin, which initiates the breakdown of dietary amino acids. 60,61 Pepsin is most
SECTION III • Nutrient Metabolism
General formula
/ NH2 R-CH "-COOH
Aliphatic Amino Acids
Aromatic and Heterocyclic Amino Acids
R= *
Glycine
H-
Alanine
CH3CH3<,
* Valine
*
FIGURE 11-8. Formulas of common amino acids found in proteins. Essential amino acids are marked with an asterisk (*).
Leucine
* Isoleucine
CH-
CH3/ CH3 <, CH-CH2 CH3/ CH3-CH2 "-CHCH3/
Serine
HO- CH2HO,,-
*
Threonine
CH-
CH3/ Cysteine
Phenylalanine Tyrosine
* Tryptophan
t~-CH2-
* Histidine
* Lysine
N H NH2- CH2- CH2- CH2- CH2-
Arginine NH2- NH- CH2- CH2-CH2-
"-C/
HS-CH2-
I
NH
S- CH2-
Cystine
I
Acidic Amino Acids and their Amides
S- CH2* Methionine
CH3-S-CH2-CH2-
O~
"::C-CH HO/ 2
Aspartic acid
o
Asparagine Proline
Q-COOH
121
Glutamicacid
H
Glutamine
~C-CH -
NH2/
2
O~ HO/C-CH2-CH2O~ C-CH2-CH2-
NH2/
active on peptide bonds involving leucine and the aromatic amino acids phenylalanine and tyrosine. This phase of proteolysis requires an acidic pH. Therefore, these gastric enzymes, upon entering the duodenum, where the pH is above 5, no longer have any proteolytic activity. The pancreas secretes several zymogen (precursor) enzymes that are sequentially activated after the conversion of trypsinogen to trypsin by intestinal enterokinase (an endopeptidase localized to the villous tip).62 These include chymotrypsin, elastase, and carboxypeptidase.63 Secretion of the pancreatic proteolytic enzymes is subject to a negative feedback 100p64 in which, for example, free trypsin (present only after saturation of luminal substrate) would cause pancreatic acinar cells to terminate synthesis of trypsinogen. These proteolytic enzymes act to digest bonds between particular amino acids. Pepsin, for example, hydrolyzes bonds adjacent to leucine or to aromatic amino acids. Likewise, pancreatic peptidases have specificity for bonds adjacent to lysine or arginine (trypsin), to aromatic amino
acids (chymotrypsin), or to neutral aliphatic amino acids (elastase). Other peptidases specifically hydrolyze either the free carboxyl terminus or the amino terminus of proteins. After the action of the gastric and pancreatic enzymes, a mixture of amino acids and oligopeptides is present in the intestinal lumen. Approximately 40% of the dietary protein is completely hydrolyzed to free amino acids before absorption. The remaining 60% of dietary protein is absorbed in the form of di- and tripeptides. The amino acids are then taken up by amino acid carriers, dipeptides and tripeptides are taken up by the peptide carrier system, and oligopeptides with greater than three amino acid residues are hydrolyzed to absorbable products by the peptide hydrolase enzymes. Separate amino acid carrier systems (Fig. 11-9) are responsible for transport of neutral (leucine and methionine) and basic amino acids (lysine and arginine). Transport actions of these carrier systems are energy mediated, occurs against a higher concentration gradient, and probably involves cotransport with sodium
122
11 • Macronutrients
ICarbohydrate I
Blood
Lumen DisaCCharides) Glucose polymers G2-G9 a-Limit dextrins Monosaccharides
I
Peptides
Peptide.
I
c,.c,)
Amino acids, peptides Tripeptides -""",""f-++--""'OO'""-""'OO'""---i+ -25%
Dipeptides
FIGURE 11-9. Hydrolysis and absorption of oligomeric products of pancreatic enzyme hydrolysis. All low-molecular-weight polymers of carbohydrate and protein are derived from actions of pancreatic enzymes except for the dietary disaccharides. The thickness of the arrows across the cell corresponds to the proportion of product absorbed.The quantitative recovery of secreted proteins has not been determined. The circles on the microvilli represent carrier transporters. Not depicted is the intracellular pool of amino acid and the processes that affect it, i.e., protein degradation, amino acid synthesis increasing the pool, and amino acid metabolism decreasing it, in addition to the synthesis of proteins shown here. (FromJohnson LR led]: Physiology of the Gastrointestinal Tract. New York, Raven, 1994, pp 1723-1749.)
..
-~~~-:::""--1----+
-70% Amino acids
..
_~--+~t---:~-~_--+-
Structural proteins
?
ion. 65 Absorption rates are variable among different amino acids and predictable. For example, methionine and branched-chain amino acids (leucine, isoleucine, and valine) display the highest rates of absorption, whereas glutamic acid and aspartic acid display the lowest,66 Variable rates of amino acid absorption are due to differences in structure (longer side chains lead to faster absorption), differences in charge (neutral amino acids have faster absorption), and differences in affinity for the absorption sites. Peptide carrier systems have been noted to be more efficient than amino acid carrier systems (solutions containing glycyl leucine are absorbed faster than separate solutions of equal amounts of glycine and leucine). Peptide hydrolases in the brush border include endopeptidases, aminopeptidases, and carboxypeptidases. Finally, a population of hydrolases exist in the cytoplasm of intestinal epithelial cells." These enzymes are very specialized for the hydrolysis of absorbed peptides. Thus, only a small fraction of ingested peptides reach the portal circulation in intact form.
Adaptation of Brush Border Peptidase Activity Peptidases present on the mucosal surfaces of enterocytes are subject to many of the same regulatory factors as oligosaccharidases. Hydrophobic amino acids,68 for example, have an inhibitory effect on brush border peptidases. High-protein diets increase aminopeptidase
activity, as does feeding of specific substrates. Starvation reduces the activity of these enzymes.
Hepatic Metabolism Absorbed amino acids are transported to the liver via the portal vein (Fig. 11-10). The liver is the major site of catabolism for the majority of the essential amino acids. The exception to this rule are the branched chain amino acids, which are degraded mainly in muscle. After a protein-containing meal is consumed, the quantity of amino acids present in the portal vein increases dramatically, but decreases to a much lesser degree in plasma. In this way, the liver monitors the absorbed amino acids and adjusts the rate of their metabolism according to bodily needs. An interaction of amino acid uptake and carbohydrate intake is mediated through insulin. After a carbohydraterich meal is consumed, the concentration of most plasma amino acids decreases due to deposition in muscle through insulin-mediated transport. This effect is especially dramatic for branched-chain amino acids, whose plasma levels may fall by as much as 40% after a dose of glucose.
Amino Acid Metabolism A portion of the free amino acid pool is incorporated into tissue proteins. Because of protein breakdown, these amino acids return to the free pool after a variable
SECTION III • Nutrient Metabolism
123
Diet Protein (100 g)
1
Pancreas
t Free Peptides ~ trypsin
i-===:+' Endogenous protein ---+-(70 g) Mucosa
Amino acids
1 Fecal protein (10 g)
Amino acids
.
Amino acids Transamination (glu, asp) Mucosa
FIGURE 11-10. Fate of dietary protein, secretion of endogenous protein, feedback control of pancreatic enzyme secretion, and absorption through the mucosa. (From Shils ME, Olson JA, Shike M reds): Modern Nutrition in Health and Disease; Malvern, PA, Lea & Febiger, 1994, p 11.)
length of time and thus become available for reutilization in protein synthesis or other reactions. Another portion of free amino acids undergoes catabolic reactions. This process leads to loss of the carbon skeleton as CO2 or to its deposition as glycogen or fat. Nitrogen is eliminated as urea. Finally,a portion of the free amino acid pool is used forsynthesis of new nitrogen-containing compounds, such as purine bases, creatine, and epinephrine. Additionally, this portion of amino acids may be used for synthesis of the nonessential amino acids. Amino nitrogen can return to new amino acids via transamination or urea recycling. Urea has been regarded as the end product of protein metabolism. However, this belief has been challenged by very elegant studies. If 100 mg of labeled urea (radioisotope or heavy isotope) is administered intravenously to a human or a mammal, only 90 g are excreted in urine. In experimental animals the remaining 10% can be traced to proteins in tissue and plasma. This process is known as urea recycling. Because mammals do not produce urease, they depend on gastrointestinal bacteria for urea breakdown. Most of the urease activity in humans takes place in the colon, although it is now well known that the Helicobacter pylori bacterium produces urease to breakdown urea in the stomach. The ammonia released from ureolysis is absorbed and transported to the liver for either ureagenesis or amination of carbon chains.
CONCLUSION Lipids, carbohydrates, and proteins undergo specialized reactions for their breakdown and conversion to energy. Assimilation of these macronutrients is a relatively
efficient process, and critical to physiologic homeostasis. In patients requiring supplemental enteral nutrition, the relative quantities of these factors may be adjusted specifically for the disease process. In Chapter 17 the way in which macronutrients are added to enteral formulations for use in various pathophysiologic states is presented. REFERENCES 1. Gordon RS: Unesterified fatty acid in human plasma. II. The transport function of unesterified fatty acid. J Clin Invest 1957;36: 810-815. 2. Dole VP: A relation between non-esterified fatty acids in plasma and the metabolism of glucose. J Clin Invest 1956;35:150-154. 3. Singer SJ, Nicholson GL: The fluid mosaic model of the structure of cell membranes. Science 1972;175:720-731. 4. Berlin E, Bhathena SJ, Judd IT: Dietary fat and hormonal effects on erythrocyte membrane fluidity and lipid composition in adult women. Metabolism 1989;38:790-796. 5. Leger CL,Daveloose 0, Christon R, et al: Evidence for a structurally specific role of essential polyunsaturated fatty acids depending on their peculiar double-bond distribution in biomembranes. Biochemistry 1990;29:7269-7275. 6. Caldwell MD, Jonsson HT, Othersen HB, et al: Essential fatty acid deficiency in an infant receiving prolonged parenteral alimentation. J Pediatr 1972;81:894-898. 7. McCarthy MC, Cottam GL, Turner WW, et al: Essential fatty acid deficiency in critically ill surgical patients. Am J Surg 1981;142: 747-751. 8. Holman RT,Johnson SB, Hatch SF: A case of human linolenic acid deficiency involving neurological abnormalities. Am J Clin Nutr 1982;35:617-623. 9. Bjerve KS, Mostad IL, Thoresen L: Alpha-linolenic acid deficiency in patients on long-term gastric tube feeding. Estimation of linolenic acid and long chain unsaturated n-3 fatty acid requirement in man. Am J Clin Nutr 1987;45:66-77. 10. Bjerve KS: n-3 fatty acid deficiency in man. J Intern Med Suppl 1989;225: 171-175.
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11 • Macronutrients
11. Janninger CK, Racis SP: The arachidonic acid cascade: An immunologically based review. J Med 1987;18:69-80. 12. Needleman P, Raz A, Minkes MS, et al: Triene prostaglandins: Prostacyclin and thromboxane biosynthesis and unique biological properties. Proc Natl Acad Sci USA 1979;76:944-948. 13. Granstrom E: The arachidonic acid cascade: The prostaglandins, thromboxanes, and leukotriene. Inflammation 1984;8:S15-524. 14. Lokesh BR, Kinsella JE: Modulation of prostaglandin synthesis in mouse peritoneal macro phages by enrichment of lipids with either eicosapentaenoic or docosahexaenoic acids in vitro. lmmunobiology 1987;175:406-419. 15. Spielmann D, Bracco U, Traitler H, et al: Altemative lipids to usual ro-6 PUFAs: 'tlinolenic acid, a-linolenic acid, stearidonic acid, EPA, etc. JPEN J Parenter Enter Nutr 1988;12:111s-123s. 16. Martinez M, Ballabriga A: Effects of parenteral nutrition with high doses of linoleate on the developing human liver and brain. Lipids 1987;22:133-138. 17. Diboune M, Ferard G, Ingenbleek Y, et al: Composition of phospholipids fatty acids in red blood cell membranes of patients in intensive care units: Effects of different intakes of soybean oil, medium-ehain triglycerides, and black currant seed oil. JPEN J Parenter Enter Nutr 1992;16:136-141. 18. Mott CB, Sarles H, Tiscomia 0: Action difference des triglycerides a chain courtes, moyennes ou longues, sur la secretion pancreatique exocrine de l'homme. Bioi Gastroenterol 1972;5:79-84. 19. Brosnan IT, Fritz 1B: The permeability of mitochondria to camitine and acyl camitine. Biochem J 1971;125:94p-95p. 20. Tao RC, Yoshimura NN: Camitine metabolism and its application in parenteral nutrition. JPEN J Parenter Enter Nutr 1980;4:469-486. 21. Bach A, Schirardin H, Werhya A, et al: Ketogenic response to medium-ehain triglyceride load in the rat. J Nutr 1977;107: 1863-1870. 22. Bach A, Weryha A, Schirardin H, et al: Influence of oral MCT orLCT load on glycemia in Wistar and Zucker rats and guinea pigs. Ann Bioi Anim Biochem Biophys 1979;19:625-635. 23. Tantibhedhyangkul P, Hashim SA, Van Itallie TB: Effects of ingestion oflong-ehain and medium-ehain triglycerides on glucose tolerance in man. Diabetes 1967;16:766-769. 24. Babayan VK: Medium-ehain triglycerides and structured lipids. Lipids 1987;22:417-420. 25. DeMichele 51, Karlstad MD, Babayan K, et al: Enhanced skeletal muscle and liver protein synthesis with structured lipid in enterally fed bumed rats. Metabolism 1988;37:787-795. 26. DeMichele 51, Karlstad MD, Bistrian BR,et al: Effect of total enteral nutrition with structured lipid on protein metabolism in thermally injured rats. Fed Proc 1987;46:1086. 27. Teo TC, DeMichele 51, Selleck KM, et a1: Administration of structured lipid composed of MCT and fish oil reduces net protein catabolism in enterally fed bumed rats. Ann Surg 1989;210:100-107. 28. Friend N, Lock SO, Gurr MI, et al: Effect of different dietary lipids on the immune responses of Hartley strain guinea pigs. Int Arch Allergy Immunol 1980;62:292-301. 29. Bromberg Y, Pick E: Unsaturated fatty acids as second messengers of superoxide generation by macrophages. Cell Immunol 1983;79: 240-252. 30. Strunk RC. Kunke K, Nagle RB. et al: Inhibition of in vitro synthesis on the second (C2) and fourth (C4) components of complement in guinea pig peritoneal macrophages by a soybean oil emulsion. Pediatr Res 1979;13:188-193. 31. WagnerWH, Silberman H: Lipid-based parenteral nutrition and the immunosuppression of protein malnutrition. Arch Surg 1984:19: 809-810. 32. Ring J, Seifert J, Mertin J, et al: Prolongation of skin allografts by treatment with linoleic acid (letter). Lancet 1974;2: 1331. 33. Perez RV, Munda R, Alexander JW: Dietary immunoregulation of transfusion-induced immunosuppression. Transplantation 1988;45: 614-617. 34. Perez RV, Munda R,Alexander JW: Augmentation of donor-specific transfusion and cyclosporine effects with dietary linoleic acid. Transplantation 1989;47:937-940. 35. Perez RV, Babcock GF, Alexander JW: Immunoregulation of transfusion-induced immunosuppression with inhibitors of the arachidonic acid metabolism. Transplantation 1989;48:81h
36. Cook JA, Wise WC, Knapp DR, et al: Essential fatty acid deficient rats: A new model for evaluating arachidonate metabolism in shock. Adv Shock Res 1981;6:93-105. 37. Mascioli EA, Iwasa Y, Trimbo S, et al: Endotoxin challenge after menhaden oil diet: Effects on survival of guinea pigs. Am J Clin Nutr 1989;49:277-282. 38. Alexander JW, Saito H, Trocki 0, et al: The importance of lipid type in the diet after bum injury. Ann Surg 1986;204:1-8. 39. Caspary WF: Physiology and pathophysiology of intestinal absorption. Am J Clin Nutr 1992;55:S299-5308. 40. Reiser S: In Berdanier CD (ed): Carbohydrate Metabolism. New York, John Wiley & Sons, 1976, pp 45-78. 41. Whelan WJ: Biochem Soc Symp 1953;11:17-26. 42. Jesuitova NN, DeLacey P, Ugolev AM, et al: Digestion of starch in vivo and in vitro in a rat intestine. Biochim Biophys Acta 1964;86:205-210. 43. Dahlqvist A, Auricchio A, Semenza G, et al: Human intestinal disaccharidases and hereditary disaccharide intolerance. The hydrolysis of sucrose, isomaltose, palatinose (isomaltulose), and a 1,6-alpha-oligosaccharide (isomalto-oligosaccharide) preparation. J Clin Invest 1963;42:556-562. 44. Gray GM,Santiago NA: Disaccharide absorption in normal and diseased human intestine. Gastroenterology 1966;51:489-498. 45. Alpers DH, Cote MN: Inhibition of lactose hydrolysis of dietary sugars. Am J Physiol 1971;221:861h
SECTION III • Nutrient Metabolism
65. Rosenburg IH, ColemanAL, Rosenburg LE: The role of sodium ion in the transport of amino acids by the intestine. Biochim Biophys Acta 1965;102:161-171. 66. Adibi SA, GraySJ, Menden E: The kinetics of amino acid absorption and alterationof plasma composition of freeamino acids after intestinal perfusion of amino acid mixtures. Am J Clin Nutr 1967;20:24-33.
125
67. Adibi SA, Kim YS: Peptide absorption and hydrolysis. In Johnson LE, ed. Physiology of the Gastrointestinal Tract. New York, Raven Press 1981:1073-1095. 68. Kim YS, Brophy EJ: Effect of amino acids on purified rat intestinal brush border membrane amino oligopeptidases.Gastroenterology 1979;76:82-87.
II Vitamins Charlene Compher, PhD, RD
CHAPTER OUTLINE Introduction Dietary Reference Intakes Indices Water-Soluble Vitamins B Vitamins Vitamin C Fat-Soluble Vitamins Vitamin A and Carotenoids Vitamin D Vitamin E Vitamin K Conclusion
INTRODUCTION For many years humans have recognized the physiologic symptoms of vitamin deficiency and appreciated the rapid return of wellness with optimal intake. The most common role of vitamins is as coenzymes in metabolic reactions, which affect diverse body systems. Recent advances in the understanding of vitamin receptors at the molecular level and gene regulation have opened new vistas for potential vitamin functions and previously unrecognized interactions between vitamins. New assay techniques have enabled more precise determination of actual vitamin content of foods and biologic samples and of functional biomarkers of vitamin status. The role of normal to pharmacologic intake of particular vitamins on disease prevention has been examined in epidemiologic and intervention trials. In this chapter, updates on these key concepts and current understanding of optimal vitamin intake are addressed. Vitamins are complex organic compounds that are either water-soluble (thiamin, riboflavin, niacin, biotin, pantothenic acid, vitamin B6, vitamin B!2' folate, and vitamin C) or fat-soluble (vitamins A, 0, E, and K). The watersoluble vitamins are easily absorbed in the upper small intestine, once cleaved from their food delivery systems. Fat-soluble vitamins require dietary fat for stimulation of 126
of bile release into the duodenum, emulsification of the vitamins, and then chylomicron formation for vitamin transport into the plasma, often by a carrier protein.
DIETARY REFERENCE INTAKES For approximately 60 years, the U.S. Food and Nutrition Board has recommended intakes of vitamins that are adequate to avoid deficiency in most individuals. For the latest revisions, the desirable intake levels of vitamins were expanded beyond prevention of deficiency to include support of optimal physical function and prevention of chronic disease, when there was adequate research evidence to support such findings. These newer Dietary Reference Intakes (ORis), guidelines for both the United States and Canada, are expressed by four measures. The Estimated Average Requirement (EAR) defines the amount of a nutrient that will maintain a specific body function in one half the population. The Recommended Dietary Allowance (RDA) is a recommendation that would meet the needs of 98% of the population. When adequate scientific evidence to establish an EAR or RDA is not available, an Adequate Intake (AI) level is defined as the average intake of a specific nutrient in healthy people. Excessive intake of many vitamins also causes symptoms of toxicity; thus, a tolerable Upper Intake Level (UL) is also specified.' Table 12-1 lists the most recent DRls.I-3 Guidelines for pregnant and lactating women and for pediatric and geriatric patients are addressed in Chapters 6, 7 and 8.
INDICES Adequacy of vitamin status in humans has most often been described by static measurement of the concentration of a vitamin structure in a bodily fluid, usually blood. However, the concentration in the bloodstream may not approximate active tissue or cellular stores. Functional biomarkers, which better approximate the actual activity of a vitamin in a particular role, include enzyme activity, production of a metabolite, or the measurement of a vitamin-related physiologic function. A more complete understanding of the full array of
6 8 12 16 16 16 16 12 14 14 14 14
0.5 0.6
0.9 1.3 1.3 1.3 1.3
0.9 1 1.1 1.1 1.1
0.5 0.6
0.9 1.2 1.2 1.2 1.2
0.9 1
1.1
1.1 1.1
2 4
(mg)*
Niacin
0.3 0.4
(mg)*
Riboflavin
0.2 0.3
Thiamin (mg)*
20 25 30 30 30
20 25 30 30 30
8 12
5 6
(j..lg)t
Biotin
4 5 5 5 5
4 5 5 5 5
2 3
1.7 1.8
Pantothenic Acid (mg)t
1 1.2 1.3 1.5 1.5
1 1.3 1.3 1.7 1.7
0.5 0.6
0.1 0.3
(mg)*
Vitamin
~
400
300 400 400 400
300 400 400 400 400
150 200
65 80
ij.Lg)*
Folate
425 425 425
400
375
375 550 550 550 550
200 250
125 150
(mg)t
Choline
1.8 2.4 2.4 2.4 2.4
1.8 2.4 2.4 2.4 2.4
0.9 1.2
0.4 0.5
ij.Lg)*
Vitamin B 12
45 65 75 75 75
45 75 90 90 90
15 25
40 50
(mg)*
Vitamin C
600 700 700 700 700
900
900 900
600 900
300 400
400 500
ij.Lg)*
Vitamin A
5 5 5 10 15
5 5 5 10 15
5 5
5 5
ij.Lg)t
Vitamin D
15 15 15 15
11
15 15 15 15
11
6 7
4 5
(mg)*
Vitamin E
60 75 90 90 90
60 75 120 120 120
30 55
2 2.5
ij.Lg)t
Vitamin K
1AI, Adequate
*RDA, Recommended Dietary Allowance. Intake. Reproduced from Committee on Dietary Reference Intakes, Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin Bt;, Folate, Vitamin 8 12 , Pantothenic Acid, and Choline. Washington, DC, National Academy Press, 1998;Committee on Dietary Reference Intakes, Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids. Washington, DC, National Academy Press, 2000; and Committee on Dietary Reference Intakes, Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC, National Academy Press, 2000.
Infant 0-0.5 0.5-1.0 Child 1-3 4-8 Male 9-13 14-18 19-50 51-70 >70 Female 9-13 14-18 19-50 51-70 >70
Years
_ _ Dietary Reference Intakes
m
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128
12 • Vitamins
vitamin functions will enable the selection of more powerful biomarkers for the future.
be incomplete and delayed. A dose of 100 mg/day is often given when deficiency is suspected.
Toxicity
WATER·SOLUBLE VITAMINS
B Vitamins The B vitamins act primarily as coenzymes in the same energy metabolic pathways and are found naturally in common food sources. Clinical signs of B vitamin deficiency often include cheilosis, glossitis, fatigue, and dermatitis. Overlap in clinical symptoms between B vitamins complicates the determination of deficiency status for a specific vitamin. Because most B vitamins have limited toxicity, it may be helpful to use multivitamin rather than individual vitamin supplements, particularly because the amount of vitamin B6 is limited to the RDA in multivitamin supplements.
Thiamin Function Thiamin functions primarily in energy metabolism as thiamine pyrophosphate, the coenzyme for pyruvate dehydrogenase and transketolase in carbohydrate metabolism, a-ketoglutarate dehydrogenase in the citric acid cycle, and branched-ehain keto acid dehydrogenase in metabolism of branched-ehain amino acids." Thiamine triphosphate activates a chloride ion channel in nerves.'
Sources The strongest food sources of thiamine include whole or fortified grain products and pork. Because the vitamin is easily destroyed by heat and leaches into cooking water, cooking methods such as steaming or microwave cooking preserve thiamin activity in foods.' Little is known about the bioavailability of thiamin. The RDA is 1.1 to 1.2 mg/day in adults, and median intake is 2 mg/day in men and 1.2 mg/day in women.'
Deficiency Thiamin deficiency occurs in the context of a calorieand nutrient-poor diet in developing countries, whereas in developed cultures thiamin deficiency is more often associated with alcoholism. When alcohol is metabolized, thiamin absorption is limited and excretion is enhanced, and alcoholics often ingest diets with limited thiamin intake," Thiamin deficiency called beriberi, with symptoms of muscle wasting, edema, cardiomegaly, weakness. apathy, confusion, anorexia, and weight loss. WernickeKorsakoff syndrome, an encephalopathy characterized by nystagmus, abducens and conjugate gaze palsies, gait ataxia, and confusion," was previously described with alcoholism and severe thiamin deficiency. However, the variation in the international prevalence of the syndrome is not accounted for by variations in alcohol consumption and cases in individuals with no history of alcohol abuse were described.? suggesting that genetic susceptibility may be an important factor.' With thiamin repletion, the recovery from derangements in mental function may
Toxicity symptoms have not been reported, and no UL has been established. Immunoglobulin E-mediated anaphylaxis from intravenous thiamin supplements is rarely reported.s"
Indices Functional measures of thiamin status are currently limited. Transketolase activation by thiamin in vitro may be indicative of subjects with greater thiamin need.' Thus, the serum thiamin concentration is used to describe status.
Riboflavin Function Riboflavin is a coenzyme in oxidation-reduction reactions for energy metabolism, where, in the form of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), the vitamin picks up hydrogen ions (W) and electrons from the tricarboxylic acid cycle and carries them into the electron transport chain for maximum energy transfer into adenosine triphosphate. Recent studies have described an interaction between riboflavin and folate metabolism. Both the cystathionine synthase (B6 cofactor) and methylation (B!2 and folate cofactors) pathways of homocysteine (Hey) metabolism require riboflavin. The former uses FMN to activate pyridoxal phosphate and the latter uses FAD as a prosthetic group for production of Srnethyltetrahydrofolate.'? In 52 healthy elderly Irish subjects with biochemical evidence of riboflavin deficiency, riboflavin supplementation treated the deficiency but did not reduce the total Hey (tHcy) level.10 Data from the Framingham Offspringcohort (collected before folate supplementation in grains) suggested that riboflavin status affected tHcy metabolism in the segment of subjects with limited folate nutriture and the methylene tetrahydrofolate reductase (MTHFR) C677f homozygote (==12% of the population) genotype." This relationship remained even after folate supplementation corrected suboptimal folate status." Clearly, more examination of any interaction between riboflavin and folate is needed to ascertain which segments of the population are at risk.
Sources The strongest food sources include milk products, enriched or whole grains, and liver. Riboflavin is easily destroyed by ultraviolet light and irradiation." Riboflavin bioavailability is 95%. The RDA is 1.1 to 1.3 mg/day, and average intake from foods is 2 mg/day in men and 1.5 mg/day in women.'
Deficiency In developed countries, frank deficiency, termed ariboflavinosis, is rarely seen, except in approximately 50% of alcoholics with poor diets." Deficiency symptoms include sore throat, oral and pharyngeal edema, angular stomatitis, cheilosis, glossitis, seborrheic dermatitis, and
SECTION III • Nutrient Metabolism
a normochromic, normocytic anemia.' In Bhutanese refugee camps, angular stomatitis was noted in 26.8% of residents and biochemical riboflavin deficiency in 85.8% with a strong association between the two measures."
Toxicity Toxicity has not been reported, and no UL has been established. Anaphylaxis to oral riboflavin supplements has been described," raising the concern of risk associated with unmonitored vitamin supplementation.
Indices Riboflavin status is usually detected by the tissue FAD concentration." The stimulation of FAD-dependent erythrocyte glutathione reductase in vitro, expressed as an activation coefficient (EGRAC) has been suggested as a functional measure, even though the EGRAC does not really define a physiologic function."
129
Indices There is no available functional marker of niacin activity. The accepted measures of niacin status are the concentration of niacin or its metabolites in plasma, erythrocytes, or urine."
Biotin Function Biotin functions as a critical coenzyme in the production of oxaloacetate for the tricarboxylic acid cycle. Biotin is also a coenzyme in gluconeogenesis, fatty acid synthesis, and the catabolism of several amino acids and fatty acids. Biotin is a coenzyme for four carboxylases: pyruvate, acetyl-coenzyme A (CoA) , propionyl-CoA, and methylcrotonyl-CoA carboxylase. Biotin also binds covalently with histones and may be important in embryologic development.'
Niacin
Sources
Function
Biotin is widespread in the food supply, with egg yolks, organ meats, fish, soybeans, and whole grains being particularly strong sources. In 1998, an AI level was established at 30 ug/day for adults.
Forms of niacin are nicotinamide, the major form in circulation, and nicotinic acid. As nicotinamide adenine dinucleotide (NAD) and its phosphated form (NADP), niacin functions as a cofactor in the metabolism of glucose, fat, and alcohol and in the electron transport chain.
Deficiency
Niacin can be synthesized from the amino acid tryptophan, and niacin intake is described in niacin equivalents (NE). A food source that contains 60 mg of tryptophan provides 1 NE. Good food sources are milk, eggs, poultry, fish, meat, whole-grain or enriched breads and cereals, and nuts.' Bioavailability is only 30%.1 The RDA is 14 to 16 mg/day in adults, and median intake is 17 to 20 mg/day.'
Biotin deficiency is rare, seen only in patients receiving long-term total parenteral nutrition (TPN) (before the addition of biotin to vitamin preparations) or those eating large quantities of uncooked egg whites, in which the avidin protein binds biotin and prevents its absorption. Deficiency symptoms include a scaly dermatitis, predominantly in the periorbital, perinasal and peribuccal areas, with hair loss, similar to that with cutaneous candidiasis or zinc deficiency.' Depression, lethargy, and paresthesias in the extremities may also occur.
Deficiency
Toxicity
Niacin deficiency, called pellagra, produces symptoms often described as the four Os: diarrhea, dermatitis (in Iight-exposed skin), dementia, and death. Other symptoms include glossitis, depression, apathy, fatigue, and memory loss.' Populations from regions of the world where consumption of a low-protein diet is common, particularly with corn as the dietary staple, are at risk of deficiency, although it is rare in developed countries. Alcoholics can develop a niacin deficiency because they use NAD and NADH for ethanol metabolism but fail to replace the vitamin from dietary sources.f
Toxicity has not been reported, and no UL has been established."
Sources
Toxicity Niacin toxicity is not generally seen from food sources but occurs with nicotinic acid intake at three to four times the RDA, usually as treatment for hypercholesterolemia. The vitamin causes capillary vasodilation and tingling that improves with reduced dosage. Hepatotoxicity and impaired glucose tolerance can occur," as well as blurred vision, macular edema, toxic amblyopia, and cystic maculopathy.' The UL for niacin is set at 35 mg/day.
Indices Biotin functional status can be determined by the in vitro pyruvate carboxylase stimulation test in erythrocytes from vitamin-deficient patients.'
Pantothenic Acid Function Pantothenic acid is a component of CoA in energy metabolism and plays key roles in the synthesis of lipids, neurotransmitters, steroid hormones, and hemoglobin.'
Source Pantothenic acid is widespread in the food supply, with organ meats, avocado, broccoli, mushrooms, and whole grains being the strongest sources. Bioavailability is 40% to 60%.1 Food processing destroys vitamin activity." The AI for pantothenic acid in adults is 5 rug/day.'
130
12 • Vitamins
Deficiency
Toxicity
Deficiency is rare and was reported as burning foot syndrome (nutritional melalgia) in severely malnourished prisoners of war in the Far East during World War 11. 5 General symptoms of pantothenic acid deficiency include fatigue, nausea, vomiting, abdominal cramping, insomnia, depression, and hypoglycemia. The AIlevel for adults is 5 rug/day.'
Unlike other water-soluble vitamins, excess vitamin B6 is stored in muscle (80%), and toxicity can occur. Toxicity symptoms include depression, fatigue, headaches, and a peripheral sensory neuropathy, a constellation seen in women with premenstrual syndrome treated with 2 g of vitamin B6 daily. Thus, a ULfor adults is set at 100 mg/day.
Toxicity Because no toxicity has been reported, no UL has been established.
Indices There is no good way to assess optimal functional status, beyond symptoms of frank deficiency."
Pyridoxine Function Pyridoxine (vitamin B6) actually occurs in three chemical forms in foodstuffs, pyridoxal, pyridoxamine, and pyridoxine, all of which can be converted to the active coenzyme pyridoxal phosphate (PLP). PLP is carried by albumin in the bloodstream, and both PLP and pyridoxal are bound to hemoglobin in red blood cells (RBCs). PLP is a coenzyme in more than 100 reactions including deamination, transamination, the urea cycle, the formation of niacin or serotonin from tryptophan, and synthesis of heme, nucleic acids, and lecithin. Acetaldehyde, produced from the metabolism of ethanol, competes with PLP for its enzyme sites, which results in the rapid destruction of free PLP, with deterioration of vitamin status in 50% of alcoholics," Because PLP is bound and inactivated by isoniazid, the vitamin must be supplemented during isoniazid therapy for tuberculosis.
Sources The best food sources of vitamin B6 are meats, fish, poultry, legumes, potatoes, fortified cereals, noncitrus fruits, and soy products. The vitamin is rapidly destroyed by heat, and its bioavailability is lower in plant than in animal products, but averages 75%. I The RDA for adults is 1.3 mg/day, and the AI is 2 mg/day for men and 1.5 mg/day for women.'
Deficiency The neurologic symptoms seen with vitamin B6 deficiency may occur on the basis of limited neurotransmitter production and include depression and confusion (in adults) and seizures (in infants). Seborrheic dermatitis, microcytic anemia, stomatitis, cheilosis, and glossitis also occur. Carpal tunnel syndrome has been treated with vitamin B6 supplements, but evidence suggests that the effects are no different from those of a placebo. 15 Vitamin B6 deficiency is associated with impaired immune function, decreased interleukin-2 production, and lymphocyte proliferation.
Indices Laboratory assays to determine vitamin B6 functional status have not yet been fully developed. An index is currently being developed by stimulation of aspartate aminotransferase or alanine aminotransferase (ALT) by added PLP in erythrocyte hemolysate,?
Folate Function Folate functions as a coenzyme for pathways of methyl transfer in the metabolism of amino acids and nucleic acids. Folate is essential for DNAsynthesis (biosynthesis of purines and thymidylates) and repair, as tetrahydrofolate and 5,IG-methylenetetrahydrofolate, and for amino acid synthesis and transamination reactions. The transsulfuration or methyl cycle pathway, with folate as coenzyme, provides S-adenosylmethionine for a wide range of substrates, including the production of myelin basic protein. 16 Some individuals may benefit from folic acid supplementation." See Chapter 6 for a discussion of folate supplementation and neural tube defects. Hyperhomocysteinemia is associated with a risk of myocardial infarction" and cerebrovascular and cardiovascular thromboses.lv'? When Hcy levels are reduced, typically by folate supplementation, coronary artery restenosis.P hypertension." and resistance vessel reactivity" are all reduced. Clinicians have opted to treat patients either with supplemental folate or with a combined supplement of folate, cobalamin (vitamin BI2) . and pyridoxine. The latter supplement is safer, because it reduces the likelihood of masking a deficiency of vitamin B12. Adequate folate intake lessens the risk of colorectal, breast, and pancreatic cancer, particularly in ethanol users. Of 20 published epidemiologic studies, most support a 40% reduction in risk of colorectal cancer in individuals in the top quartile of folate intake.P The Nurses Health Study showed a 75% reduction in colorectal cancer risk in women taking 499 ~g of folate for 15 years.P Higher folate intake or multivitamin use was associated with reduced risk of breast cancer among women who regularly consumed alcohol." This protection associated with folate intake in alcohol users has also been observed for colon cancer and coronary heart disease. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study of more than 29,000 Finnish male smokers documented a 55% reduction in risk of pancreatic cancer with higher dietary folate intake and serum folate concentrations; these findings were replicated by a smaller case-control study from Australia.P The optimal dose of folate needed for prevention of
SECTION III • Nutrient Metabolism
colorectal, breast, and pancreatic cancer is not yet clear, nor is the mechanism behind protection by folate.
Sources Food folates are a mixture of reduced folate polyglutamates, with the greatest concentrations in fortified grains, green leafy vegetables, legumes, seeds, and liver. Bioavailablity of folate in food sources is 25% to 50%, owing to limited intestinal conjugase activity, whereas bioavailability of folic acid in synthetic supplements is 100%.16 The chemical stability of folates in foods are also poor, and they are destroyed by heat and leached into cooking water.' The RDA for adults is 400 Jlg/day.
Deficiency Symptoms of folate deficiency include malabsorption, glossitis, confusion, fatigue, and weakness." Ingestion of ethanol increases urinary and fecal folate excretion, and 37.5% of alcoholics exhibit folate deficiency," Because of the interaction between vitamin BI2 and folate in the methylation cycle, in which each vitamin activates the other, repletion doses of folate may mask a deficiency of vitamin BI2 by correcting the macrocytic anemia that could result from either vitamin deficiency. When dietary folate intake is inadequate, both DNA production and the methylation cycle are limited, reducing the division of rapidly dividing cells such as erythrocytes (macrocytic anemia), leukocytes, and thrombocytes. With folate deficiency, DNA synthesis is ineffective. In fact, methotrexate and 5-fluorouracilantifolate chemotherapies depend on this disruption of effective DNA synthesis for their therapeutic effect. With interruption of the methylation cycle, the spinal cord and nerves are demyelinated (subacute combined degeneration), leading to neuropathy, ataxia, paralysis, and possibly death." Subacute combined degeneration is not usually seen unless the folate deficiency is severe and prolonged, perhaps because nerves concentrate folate to five times the level in plasma. A reduction in the methylation cycle also results in elevated levels of plasma homocysteine (Hcy), an independent risk factor for cardiovascular disease and stroke. 16
Indices Folate status is monitored in several ways. Serum folate concentrations are clinically available, but RBC folate is more reflective of chronic vitamin status. The tHcy concentration, although not specific for folate status alone (deficiencies of vitamin B12 or B6 can also increase total homocysteine [tHcy]), together with RBC folate concentration, gives an adequate picture of folate nutriture."
Choline Function Choline is a quaternary amine with primary roles in the structural integrity of cell membranes and methyl donation. Choline is a precursor for phosphatidylcholine, a component of cell membranes with roles in membrane structure and function, transmembrane signaling, and
131
the export of very low-density lipoprotein from the liver. As a precursor for acetylcholine, choline plays a role in cholinergic neurotransmission and memory. Choline is a precursor for betaine, which can spare vitamin BI2 and folate in the pathway for Hey metabolism to methionine. Although a metabolic pathway exists for de novo synthesis of choline from phosphatidylethanolamine using S-adenosylmethionine as the methyl donor, choline deficiency can occur with extended consumption of a low-eholine diet, such as with TPN. Thus, a dietary requirement for choline was not recognized until 1998.
Sources Obtaining the full description of choline absorption has been complicated by the rapid conversion of the vitamin to betaine or methylamines by gut bacteria. Food sources supply choline as free choline or as phosphocholine, glycerophosphocholine, sphingomyelin, phosphatidylcholine, or lecithin. Free choline enters the hepatic circulation, whereas other forms probably require lymphatic uptake. The strongest food sources are milk, liver, eggs, and peanuts. The AI level is 550 mg/day for men and 425 mg/day for women.
Deficiency Choline deficiency has been described in patients receiving long-term TPN.I In these patients, choline deficiency resulted in hepatic steatosis associated with elevated ALT levels. These abnormalities resolved with intravenous administration of choline and recurred when this supplementation was stopped. Consumption of a choline-deficient diet for more than 3 weeks in healthy male volunteers also resulted in hepatic damage and elevated ATP levels.
Toxicity Toxic effects of pharmacologic doses of choline include fishy body odor (due to excretion of a choline metabolite), diaphoresis, hypotension, and mild hepatotoxicity. A ULof 3.5 g/day was selected to prevent hypotension.
Indices Clinical biochemical measures of choline status are not available, but research laboratories measure plasma free choline by high-performance liquid chromatography.
Vitamin 8'2 Function Vitamin BI2 (cobalamin) has a porphyrin ring with four pyrroles and cobalt bound in the center. Bacteria in the intestinal tracts of animals produce cobalamin, which is incorporated into muscle and liver of animals or in milk. Cobalamin is the cofactor for two human enzymes, methionine synthase (methyl cycle), and methyl malonylCoA mutase, a pathway for the metabolism of branchedchain amino acids and odd-ehain fatty acids." The absorption of vitamin BI2 is complex, requiring gastric acidity for release of the vitamin from food sources in the stomach. Freed vitamin is bound to R proteins
132
12 • Vitamins
or haptocorrins, which protect the vitamin from chemical denaturation in the stomach. Intrinsic factor is also released by gastric parietal cells and picks up the cobalamin in the upper small bowel as the pH increases, causing release of R protein. The vitamin Bl2-intrinsic factor complex is then absorbed by phagocytosis at specific ileal receptors. In pernicious anemia, autoantibodies are produced against parietal cells, causing them to atrophy and lose the ability to produce intrinsic factor or secrete HCI, resulting in loss of vitamin BI2 enterohepatic circulation and negative vitamin balance. Pernicious anemia only affects 1%of the population, mostly those older than age 50.16 Far more common is achlorhydria, which prevents the release of vitamin BI2 from food but does not interfere with its absorption from supplements, and enterohepatic circulation is not lost. When the terminal or significant portions of ileum have been surgically resected, cobalamin injections are needed because of the lack of ileal vitamin absorption. Sources
The bioavailability of vitamin BI2 from food sources varies from IO% to 60%, and the strongest food sources are animal products and fortified cereals. Cobalamin is destroyed by microwave cooking.' The RDA is 2.4 ug/dey; the AI is 4 to 5 ug/day in men and 3 Jlg/day in women. Deficiency
Hepatic stores of vitamin BI2 last 3 to 5 years in individuals with optimal status, but deficiency symptoms can progress rapidly. As with folate deficiency, vitamin BI2 deficiency may present with macrocytic anemia, glossitis, and fatigue. A progressive paresthesia with stocking and glove distribution and decreased vibratory and position sense is typical of early subacute demyelination and may be irreversible if left untreated." Toxicity
No toxicity has been reported for vitamin B12, and no UL has been established. Indices
Excess methylmalonic acid is produced during vitamin BI2 deficiency and has been adopted as a measure of vitamin BI2 functional status." Because serum concentrations of the vitamin have limited sensitivity and specificity (due in part to complex interplay with folate metabolism), measurement of cobalamin concentration together with methylmalonic acid in serum or urine provides greater clarity about cobalamin status.'" The presence of holotranscobalamin, a carrier of cobalamin from the intestine into most cells, has been investigated as an early marker of changes in cobalamin homeostasis,26 although a test is not yet clinically available.
Vitamin C Function Ascorbic acid (AA) is the reduced form and dehydroascorbic acid is the oxidized form of vitamin C, both
with antioxidant and antiscorbutic properties. Vitamin C is an essential cofactor for many enzymes, particularly for oxidation-reduction in aqueous phases, in which AA donates electrons to neutralize free radicals, as well as to restore the antioxidant activity of vitamin E and glutathione." Tissues with particular oxidant challenges have high concentrations of vitamin C. For example, photolytically generated free radicals occur in the eye, reactive oxygen species (ROS) are produced by phagocytosis in neutrophils, and oxidative protection to DNA in sperm are all provided by AA.3 AA scavenges ROS in the aqueous phase to prevent lipid peroxidation of low-density lipoprotein and regenerates the fat-soluble antioxidant capacity of vitamin E. AA is a reducing agent for mixed-function oxidases in the microsomal drug-metabolizing system to inactivate endogenous hormones (corticosteroids, aldosterone, and cholesterol) or xenobiotics.' Vitamin C promotes collagen formation by its cofactor role with iron in the hydroxylation of proline and lysine and may modulate collagen gene synthesis.' AA is a cofactor in the hydroxylation of carnitine and for the production of neurotransmitters and thyroxin. The AA concentration modulates neurotransmitter receptors, neuron function, and synthesis of glial cells and myelin," AA is a cofactor for the amidation of peptide hormones and for tyrosine metabolism. The absorption, transport, and storage of iron are modulated by AA, and the vitamin may play a role in prostaglandin synthesis, with secondary bronchodilatory, vasodilatory, and anticlotting effects." Vitamin C has an impact on the immune system by neutralizing ROS produced by phagocytes during oxidative destruction of microbes and may modulate leukocyte phagocytosis, chemotaxis, adhesion, and immune globulin production." Intestinal absorption varies with intake, with 70% to 90% absorption at 3D- to 18D-mg intake levels but with more than 50% absorption at intake less than I g/day." The vitamin is transported into cells as dehydroascorbic acid, where it is reduced to L-ascorbic acid. Renal clearance of vitamin C increases with increasing vitamin intake because of saturable tubular reabsorption. The combined effects of saturable intestinal absorption and nonlinear renal clearance additively produce a ceiling in plasma concentrations.P Total body content is 300 mg (near scurvy) to a maximum of 2 g. AA can be catabolized to oxalic acid with potential adverse effects on renal stone formation. Although data in healthy subjects are not impressive." a risk is seen in those with renal insufficiency or a history of renal stones.v" Sources
The strongest food sources are citrus fruits, cruciferous vegetables, dark green vegetables, cantaloupe, strawberries, tomatoes, lettuce, potatoes, papayas, and mangoes. The vitamin is rapidly destroyed by heat and oxidation." The RDA for vitamin C was increased to 75 rug/day for women and 90 mg/day for men in view of its antioxidant roles, although only 10 mg/day are needed to avoid deficiency.' Cigarette smokers have greater AA turnover and lower serum concentrations, and their requirement is 35 mg/day greater than the RDA,27
SECTION III • Nutrient Metabolism
Deficiency
Deficiency of vitamin C results in scurvy, detected clinically ?y bleeding gums, follicular hyperkeratosis, ~etechla, ecchymoses, poor wound healing, joint effusions, arthralgias, depression, and sudden death." Data from the National Health and Nutrition Examination Survey (NHANES) II associated low serum AA concent~ations at baseline with increased risk of death (relative risk = 1.57, Cl = 1.21 to 2.03) and death from cancer (relative risk = 1.62, Cl = 1.01 to 2.5) in rnen." Alcoholics exhibit significantly reduced AA status," Pharmacologic doses of vitamin C have been studied for immune protection and chronic disease prevention. Clinical trials of vitamin C protection against the common cold have shown limited impact," and any modest benefit from ingestion of high doses needs further evaluation." Pharmacologic doses (1 to 2 g/day) of vitamin C have been associated with vasodilation in patients with vascular disease, hypertension, diabetes, and hyperchol~ster?lemia, an ~utc.ome attributed to the prevention by vitamin C of oxidative destruction of nitrous oxide." Intake of vitamin C up to 110 mg/day has been associated with prevention of oral, esophageal, lung, gastric, colorectal, and breast cancers, although higher intake doe~ not h~ve an added benefit. Data for vitamin C protection against cataracts are currently inconclusive, and protection against asthma and obstructive lung disease has been reported but data are limited at this point.' Toxicity
Toxicity of vitamin C is not seen with intake from food sources, but use of vitamin supplements can provide doses that will produce nausea, cramping, and diarrhea. Excess vitamin C intake interferes with urine glucose and fecal 07cult b.lood tests and anticoagulant drugs. In patients with a history of nephrolithiasis, excess vitamin C intake may increase the riskof recurrent stone formation. Vitamin C supplements are particularly contraindicated for patients with iron overload syndromes, because they can increase the absorption of iron and modify its oxidative state. A VL of 2000 mg/day was set to avoid gastrointestinal toxicity; however, patients with nephrolithiasis or iron overload syndromes should not take more than the RDA.3 Indices
Plasma or leukocyte AA levels are used to define deficiency, because no functional status markers have been established." A potential future functional marker may be the ratio of urine deoxypyridinoline to total collagen cross-links if sensitivity and specificity questions can be resolved."
FAT-SOLUBLE VITAMINS
Vitamin A and Carotenoids
133
esters that are rapidly converted to retinol in the intestinal lumen. Plant food sources provide carotenoids some with vitamin A activity. /3-Carotene, from carrots, i~ cleaved to form 2 molecules of retinol in the intestine or the liver, although the absorption and conversion to retinol is less efficient than retinoid interconversion. The limited absorption of carotenoids (only 30%) and ineffic~ent ~eta~.oli~~ (5?%.to 75%) contribute to their poor ~Ioava"ability. Retinoic acid participates in the regulation of genes that specify body axis patterns in embryonic development and genes that control growth hormone, ~h~sphoenolpyruvate carboxykinase, epithelial different~atlOn: spe.rmatogenesis, and bone growth. After absorption,.vttarrun A undergoes active homeostatic control by the liver, where the vitamin is coupled with retinol binding protein (RBP) and transthyretin in a 1:1:1 complex or stored, based on physiologic need. Plasma concentrations of retinoic acid are regulated by the rate of release of ~he ~omplex into circulation from the liver and by the oxidation of precursor retinol to retinal. 32 Vitamin A, supplied as [3-carotene,was hypothesized to provide antioxidant protection against cardiovascular disease, . and epidemiologic data looked promising. A randomized, placebo-controlled intervention trial in 11,036 healthy physicians for 12 years' duration showed no protection against cardiovascular disease.P /3-Carotene has been tested for antioxidant protection against cancer, usually in high-risk individuals. ~ Carotene supplements do not reduce cancer risk in smo~e!5 or asbestos-exposed individuals or in healthy physicians, nor do they reduce skin or colon cancer occurrence in high-risk individuals.P The Health Professionals Follow-up Study linked lycopene intake (primarily in tomatoes, tomato sauce, and pizza) to a risk reduction of 0.79 (Cl = 0.64 to 0.99) for prostate cancer, a finding not replicated by a large (58,279 men) Dutch trial.33 Further trials are needed to clarify this issue. The macula of the eye contains high concentrations of the carotenoids lutein and zeaxanthin, intake of which has been postulated to protect against macular degeneration by either antioxidant activity or absorption of highenergy blue light.33 The Eye Disease Case Control Study docum~nted a risk reduction to 0.43 (0.2 to 0.7) based on lutein and zeaxanthin intake by a semiquantitative food frequency questionnaire, findings that have not been validated.P
Sources Recommended intake levels for vitamin A (fable 12-2) are expressed in retinol equivalents (RE): 1 RE =Illg of retinol =3.33 IV of vitamin A =61lg of [3-carotene = 12 Ilg of other c~rotenoids..Plant foods that provide vitamin A are recogmZ~d by their dark green or yellow colors (spinach, brocCO~l, cantaloupe, carrots, and sweet potatoes), whereas animal food sources include liver, fish liver oils, dairy products, and eggs.' The RDA for adults is 700-900 Ilg.
Function Th~
three active forms of vitamin A in the body (retinol, retinal, and retinoic acid) are collectively termed retinoids. In general, animal food sources provide retinyl
Deficiency Vitamin A status depends on the amount of vitamin A stored in the liver, which varies with dietary intake and
... 134
12 • Vitamins
Vitamin Summary
Vitamin
Roles
Deficiency
Toxicity
Thiamin
Energy metabolism
NA
Riboflavin Niacin
Redox reactions Redox reactions
Beriberi; Wernicke encephalopathy Ariboflavinosis Pellagra
Biotin
Synthesis of oxaloacetate for TCAcycle; amino acid and fatty acid catabolism, gluconeogenesis Coenzyme A In energy metab; synthesis of lipids, neurotransmitters, steroid hormones, hemoglobin Amino acid reactions; synthesis of heme, nucleic acids, lecithin DNA synthesis; methyl donor; prevent neural tube defects; prevent cancer In alcoholics; improved cardiovascular risk
Pantothenate
Pyridoxine Folate
Choline
Methyl donor; precursor for acetylcholine, phospholipids, betaine
Bl~
BCAA metabolism; methyl cycle; odd-chain fatty acid metabolism; myelin synthesis Antioxidant; synthesis of collagen, carniline, peptide hormones, neurotransmitters, thyroxin, myelin Growth; vlslon; immunity
C
A
0
E
K
Bone growth, remodeling; immune response; cell growth, proliferation, apoptosis Antioxidant; .j, platelet aggregation; cardiovascular protection; T immunity; delay progress of Alzheimer disease Activate clotting; hydroxylate osteocalcin
Interactions
Indices
Serum thiamine Folate, B12, B6
Facial rash
NA Capillary vasodilation; hepatic Injury; visual change NA
Melalgia
NA
Deficiency symptoms
Anemia; depression; glossitis
Neuropathy
Pyridoxal phosphate
Macrocytic anemia; .j, DNA synthesis; .j, methyl donor; confusion; weakness; subacute combined degeneration; t tHcy Hepatic steatosis
Mask B12 deficiency
Activates B12
RBC folate; tHcy
Hypotension; cholinergic reaction; fishy body odor NA
Folate, BI2
NA
Activates folate
Serum B12; methylmalonic acid
Macrocytic anemia; paresthesias; .j, vibratory sense; .j, DNA synthesis Scurvy
Hyperkeratosis; night blindness; xerosis; xeropthalmla; blindness; .j, immunity Rickets, osteoporosis; muscle weakness Peripheral neuropathy, retinopathy Bleeding
EGRAC Serum niacin
Pyruvate carboxyiase activlty
Diarrhea
Serum or leukocyte ascorbic acid
Hyperkeratosis; bone pain; liver failure
D, K (bone)
Plasma retinol/retinol binding protein
Bone pain; hypercalcemia; muscle weakness Bleeding
A, K (bone)
25-(OH) D3; parathyroid hormone; DEXAscan a-Tocopherol; TBARS
Hemolysis
E
K, with K deficiency
Prothrombin; osteocalcin hydroxylation
25-(OH) D3, 25-hydroxyvitamin D3; EGRAC, erythrocyte glutathione reductase activation coefficient; NA, not available; RBC, red blood cell; TBARS, thiobarbituric acid-reactivesubstances; TCA, tricarboxylic acid; tHcy, total homocysteine.
SECTION III • Nutrient Metabolism
age, leaving infants and children in developing nations, particularly during times of famine or war, and children following a strict vegan diet particularly susceptible to deficiency. In contrast, most adults in Western cultures have 1 to 2 years of vitamin A stored at any time. Because vitamin A is carried by RBP, individuals with severely limited protein intake over an extended time may also have secondary vitamin A deficiency." Deficiency affects the immune system and visual function and causes skin changes. A synergism between vitamin A deficiency and infections is the major cause of mortality in children in the developing world." Thus, the World Health Organization (WHO) and UNICEF have initiated programs focused on vitamin A supplementation in high-riskareas. The earliest visual change with vitamin A deficiency is night blindness, in which the retina cannot regenerate visual pigments bleached by light because of inadequate retinal availability. With prolonged vitamin A deficiency this progresses to blindness or xerophthalmia. Initially, the cornea dries and hardens, a condition called xerosis, and then softens or melts, called keratomalacia, with irreversible blindness. Epithelial cells change shape and secrete keratin, producing the classic dry, rough, scaly skin, called hyperkeratosis. During experimental vitamin A deficiency, the number of goblet cells in the intestinal tract are also reduced, limiting mucus production and nutrient absorption, and an inflammatory response is seen." Similar changes in epithelial cells may enhance susceptibility to respiratory, urinary, vaginal, and inner ear infections. 34,35
Toxicity Toxicity of vitamin A occurs when more is ingested than can be carried by RBP, so that free vitamin A is in the circulation. Toxicity symptoms may include liver failure due to excess vitamin A storage, increased osteoclastic activity with joint pain, stunted growth, headache, and increased intracranial pressure.P Although excess intake is not usually obtainable from food sources, persons taking vitamin supplements can readily exceed the UL of 3000 ug/day for adults. In contrast, excess intake of f3carotene from food sources, such as carrots, may tum the skin yellow but is not harmful and is fully reversible with a reduction in intake.
Indices Although serum retinol concentrations vary widely, plasma levels are not influenced by dietary intake (although hormonal factors can have an impact on them). A plasma retinol concentration less than 0.7 umol/L is correlated with impaired epithelial cell structures and integrity in the eye and the gut. An increase in circulating serum retinol by 20% after a challenge dose indicates limited hepatic vitamin A stores. The ratio of plasma retinol to RBP is usually around 1 in healthy Western populations, but often is less than 1 in Third World environments.F The ratio of retinol to RBP falls during infection by 50%, a factor that may increase the risk of repeated Infection." Precise measurement of dark
135
adaptation has been suggested as a sensitive marker of vitamin A status.t' although the instrumentation required limits its use.
Vitamin D Function Vitamin D can be synthesized in response to sunlight by conversion in the skin of hepatically produced 7-dehydrocholesterol to vitamin D3, which can also be obtained directly from food sources. For most individuals, 10 to 15 minutes of sunlight exposure a few times weekly should maintain vitamin D status, although in regions above 40° N latitude sun exposure is very limited for up to 6 months of the year. Vitamin D3 is hydroxylated by the liver and activated to 1,24-dihydroxyvitamin D3 by the cytochrome P450/C25 and P450/C1 pathways." The activated hormone regulates more than 60 genes with actions in calcium homeostasis; immune response; and cell growth, differentiation, and apoptosis. Inactivation of the vitamin occurs by the P450/C24 pathway." Vitamin D receptors are found in greater concentrations in immature thymic cells and CD8 T lymphocytes." Vitamin D is selectively immunosuppressive in animal models of human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythema, type I diabetes, inflammatory bowel disease, and encephalomyelitis." The vitamin stimulates transforming growth factor ~-1 and interleukin-4 production, which may be the mechanism of suppression of T-cell activity. At physiologic concentrations, vitamin D protects cell membranes and proteins against peroxidation, induces apoptosis in cancer cells, prevents DNA strand breaks, and stabilizes chromosome structure." The vitamin also stimulates adult alveolar cell proliferation for lung development as well as replication, differentiation, and regulation of cancer cells. Clearly, human trials are needed to bring these exciting molecular findings into our clinical understanding. Vitamin D functions as a hormone in the control of bone growth and remodeling with tissue effects mediated by the vitamin D receptor.P In response to a low serum calcium concentration, parathyroid hormone is released from the parathyroid glands, causing calcium, phosphorus, and magnesium to be released from bone and absorbed from the intestine and calcium to be retained by the kidney. When the calcium level rises, calcitonin is released with effects counter to those of parathyroid hormone. Vitamin D effects on muscle continue to be examined, because muscle weakness is a symptom of deficiency that responds rapidly to vitamin D supplementation." Vitamin D and calcium supplementation have provided significant protection against steroid-induced osteoporosis, with a 0.7 (CI =0.34 to 0.85) reduction in risk of fractures." Because vitamin D receptors have been identified in many tissues, such as the central nervous system, pancreas, skin, muscle, reproductive organs, and cancer cells, many more functions of the vitamin may yet be discovered.
136
12 • Vitamins
Sources Food sources of vitamin D are primarily fortified milk products, butter, margarine, cereals, cocoa, beef, egg yolks, liver, veal, and fatty fish and their oils." For adults, the AI level is 5 ug/day until age 50, 10 ug/day between ages 51 and 70, and 15llg/day after age 70.
Deficiency Vitamin D deficiency is seen as inadequate mineralization or demineralization of bone. In children, the disease is called rickets, with characteristic features of widened ends of long bones, rachitic rosary, frontal bossing, and bowed legs.' In adults, the deficiency is more often seen as osteomalacia, with bowed legs and stooped shoulders, and porous bone from loss of calcium.' The elderly are particularly susceptible to vitamin D deficiency, because of limited sunlight exposure, limited dairy product intake if lactose intolerance develops, and gradual loss of the ability of aging organs to activate vitamin D. Patients with intestinal malabsorption syndromes can also have vitamin D deficiency.
Toxicity Vitamin D toxicity, hypervitaminosis D, can occur with excess intake of dietary supplements. Symptoms include weakness, joint pain, anorexia, headache, nausea, vomiting, hypercalcemia, hyperphosphatemia, hypercalciuria, and metastatic calcifications in soft tissues and blood vessels. The UL is 50 Ilg/day.
Indices Vitamin D status is best reflected by serum 25-hydroxyvitamin D3 concentrations, although guidelines regarding levels that define deficiency are not universally accepted." Evaluation of skeletal health by a dual energy X-ray absorptiometry (DEXA) scan of bone mineral density with concurrent serum 25-hydroxyvitamin D3 and parathyroid hormone concentrations is a standard measure.'
Vitamin E Function Vitamin E appears in eight chemical forms: 0.-, [3-, "t, and Stocopherols and 0.-, [3-, 't. and o-tocotrienols. The tocotrienols have unsaturated side chains, whereas the tocopherols contain phytyl tails with three chiral centers, naturally in the RRR configuration. Dietary sources provide more "t than a-tocopherol, but plasma "ttocopherol is only 10% of the a-tocopherol concentration. The 0.tocopherol transport protein sorts out a-tocopherol for incorporation into very low-density lipoprotein for transport, whereas other forms are less vigorously retained and readily excreted via bile or urine. The capacity to increase plasma a-tocopherol concentrations beyond normal is limited, regardless of intake, and vitamin E absorption is limited in individuals with fat malabsorption or biliary obstruction. Vitamin E is metabolized by
cytochrome P3A, and it is unclear whether vitamin E metabolism has an impact on drug metabolism. Degradation of the vitamin may be controlled by a-tocopherol transport protein capacity more than by plasma a-tocopherol concentrations." Vitamin E is the most effective chain-breaking lipidsoluble antioxidant in biologic membranes, where it promotes membrane stability and protects against free radical damage. In this antioxidant role, a-tocopherol inhibits low-density lipoprotein oxidation, which may be the mechanism of its protection against cardiovascular disease. Vitamin E limits protein kinase C activity, with modulation of cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes.' The vitamin down-regulates the expression of intercellular cell adhesion molecule (ICAM-l) and vascular cell adhesion molecule-l (VCAM-l), resulting in reduced cell adhesion," Vitamin E up-regulates the expression of cytosolic phospholipase A2 and cyclooxygenase-l, resulting in enhanced release of prostacyclin with vasodilation and inhibition of platelet aggregation." Platelet aggregation is inhibited with pharmacologic vitamin E supplements, but it is not yet clear what effects typical levels of dietary vitamin intake have on platelet function. In an 8-week prospective randomized clinical trial in healthy adults, tocopherol intake of a mixed tocopherol supplement at two times the RDA, was compared to intake of al/-rac-a-tocopherol. Equivalent serum 0.tocopherol concentrations were achieved with both supplements, but platelet aggregation was more potently inhibited by the mixed tocopherol supplement, with increased nitrous oxide release, constitutive nitrous oxide synthase activation and superoxide dismutase protein content in platelets." Vitamin E supplementation may decrease the risk of cardiovascular disease. Results of large epidemiologic studies have generally supported the existence of a protective effect of vitamin E intake against cardiovascular risk in healthy subjects.! In a series of four large intervention trials with higher-risk populations (those with prior myocardial infarction or cardiovascular accident and smokers), a range of vitamin E supplement doses (50 to 268 mg/day) were used; some results were promising, but others showed limited effects. It has been postulated that the findings may be variably affected by the extent of preexisting vascular lesions.! Thus, the extent of clinical benefit, which is plausible based on molecular effects, needs further study.P Immune function, documented by delayed hypersensitivity skin testing or antibody response to tetanus toxoid vaccine, is impaired during vitamin E deficiency and improved with supplementation. Evidence of improved immune function in elderly patients and in subjects with tropical sprue exists, but further data on other ages and healthy populations are needed to verify disease
prevention." Accumulating evidence suggests that nutritional deficiencies of the host can affect the virulence of a viral pathogen. Host vitamin E (or selenium) deficiency has resulted in the mutation of an avirulent Coxsackievirus B strain to a virulent one that produces cardiomyopathy even in normally nourished rats." An epidemic of optic
SECTION III • Nutrient Metabolism
and peripheral neuropathy in Cuba in the early 1990s affected more than 50,000 people and was associated with lower blood concentrations of riboflavin, vitamin E, selenium, a- and ~-carotenes, and lycopene. The symptoms responded to intravenous vitamin supplementation, and cerebrospinal fluid viral cultures yielded strains related to Coxsackievirus A9 and B4, providing evidence in humans that the nutritional status of the host can have profound influence on a virus." Oral multivitamin supplementation to unaffected individuals stemmed the epidemic, further suggesting that vitamin deficiencies were an important factor in the disease. The benefits of pharmacologic vitamin E supplementation on neurologic disorders have been examined. Although data suggested that vitamin E supplementation does not have an impact on Parkinson disease, there is evidence of improvement in Alzheimer disease and tardive dyskinesia symptoms with supplementation.? One limitation in these study designs is the lack of earlier biomarkers of disease presence that would delineate a patient group with a less progressive (and more modifiable) disease course."
Sources Vitamin E is widely distributed in the food supply, with the strongest sources being polyunsaturated vegetable oils, green, leafy vegetables, whole grains, liver, egg yolks, nuts, and seeds.' Vitamin E is destroyed by heat and oxidation, so freshly prepared and minimally processed foods are stronger sources. Vitamin E activity is expressed as milligrams of a-tocopherol equivalents (a-TE) with 1 mg of a-TE equal to the activity of 1 mg of RRR-a-tocopherol or 1.49mg of all-rae-atocopheryl acetate. The RDA for adults is 15 mg/day, and vitamin supplements typically provide 30 mg/day. Intakes of 40 to 400 mg/day are supplemental, whereas intake of more than 400 mg is considered pharmacologlc.t-"
Deficiency Full clinical expression of vitamin E deficiency is rare and is usually seen with significant malabsorption or genetic abnormalities of the carrier protein. Deficiency symptoms include peripheral neuropathy, due to degeneration of axons in the sensory neurons; spinocerebellar ataxia; skeletal myopathy; and pigmented retinopathy.- Data from NHANES III, however, indicated that 27% of adults had low serum a-tocopherol concentrations, with a greater prevalence of lower concentrations in African-American and Hispanic subjects, raising the question of greater occurrence of suboptimal vitamin status among socioeconomic groups."
137
supplementation with concurrent anticoagulant therapy should be discouraged, and monitoring of coagulation status in patients with questionable vitamin K status is advised. Toxicity symptoms may include nausea, cramping, blurred vision, and fatigue. The UL for vitamin E is 1000 mg/day, an intake that can only be achieved with supplement use. Intervention trials have used doses up to 3200 mg/day for several months with no reported ill effects'"; however, the impact of pharmacologic doses over a prolonged time is unknown.'
Indices More sensitive markers of marginal or limited vitamin E intake are needed. Excess vitamin E intake is stored primarily (90%) in adipocytes, with the adipocyte vitamin E concentration being strongly associated with dietary intake. The invasive nature of adipose tissue sampling, however, makes it impractical for clinical use. The vitamin E content of buccal mucosal cells may be a valuable measure of vitamin E status in the future. Serum concentrations of a-tocopherol may be meaningful when low but do not correlate with vitamin intake over usual intake ranges.! a-Tocopherol concentration are affected by age, sex, plasma lipids, lipid-lowering drugs, and smoking. Functional biomarkers of vitamin E status to date are not specific. In vitro stimulation of RBC hemolysis after exposure to dilute HzOz or 2,2-azo-bis(2-amidinopropane) dihydrochloride reflects impaired cell membrane integrity but is not specific for vitamin E status. Malondialdehyde production during exposure to HzOz measured by thiobarbituric acid-reactive substances is also modified by factors other than vitamin E status. Oxygen consumption by erythrocyte ghosts during exposure to 2,2'-azo-bis(2-amidinopropane)dihydrochloride, with greater consumption signifying worse vitamin E status, has been suggested, but data to date are limited. Breath pentane production is elevated during vitamin E deficiency and is reduced rapidly after vitamin E supplementation; this is a noninvasive functional status measure that is not widely used due to the difficulty of quantitative gas sample collection.
Vitamin K Function The primary function of vitamin K is the regulation of clotting proteins II, VII, IX, X, XII A , XI A , and XA but not of protein S for blood coagulation. Vitamin K plays a role in the hydroxylation of osteocalcin, a protein that binds calcium for incorporation into the bony matrix. Other roles for vitamin K in the kidney, cardiovascular system, and nervous system are under investigation.
Toxicity The toxicity of tocopherols is due to their oxidation product, tocopheryl quinone, which inhibits platelet aggregation. In patients with suboptimal vitamin K status, bleeding has been reported with intravenous vitamin E administration, an interaction that is rapidly reversed by vitamin K administration. Thus, pharmacologic vitamin E
Sources Vitamin K is readily available as phylloquinone from green, leafy vegetables, cruciferous vegetables, dairy products, eggs, cereals, and particular oils (soy, canola, cottonseed, and olive) and their products." Vitamin K can be synthesized by intestinal bacteria and absorbed
138
12 • Vitamins
by human hosts to supply approximately 50% of requirements, except during antibiotic therapy. The RDA for adults is 90-120 Ilg.
Deficiency Primary vitamin K deficiency is rare in adults, although deficiency is seen due to liver disease, drug therapy (warfarin and phenytoin), and vitamin K-free TPN with symptoms of easy bruisability and hemorrhage. See Chapter 6 for a discussion of vitamin K in hemorrhagic disease of the newborn. Because vitamin K reduces the effectiveness of anticoagulant drugs, food sources of vitamin K (including enteral feedings) should be limited and consistently supplied." Hip fracture incidence is increased in elderly patients receiving warfarin therapy; thus, higher vitamin K intake has been suggested.
Toxicity Toxicity to phylloquinone is unusual in adults, and a UL for vitamin K has not been established. Vitamin K toxicity has been reported rarely in infants and pregnant women, with RBC hemolysis, jaundice, and brain damage as symptoms, and was thought to be due to the vitamin K preparation used (no longer available).
Indices Vitamin K status is detected by a lack of y-carboxyglutamate residues, formed by vitamin K activity, in prothrombin or osteocalcin." Plasma phylloquinone concentrations of clotting assays are insensitive to vitamin K activity.
CONCLUSION In summary, the start of the 21st century brings knowledge of and respect for new vitamin functions, the importance of vitamins to health, and complex, unexpected interrelationships between vitamin compounds. Future trials will be important in identifying further functions of vitamins and in clarifying these issues. Acknowledgement
The author gratefully acknowledges the editorial assistance of Carolyn T. Spencer, RD. REFERENCES 1. Committee on Dietary Reference Intakes, Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, and Choline. Washington, DC, National Academy Press, 1998. 2. Committee on Dietary Reference Intakes, Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids. Washington, DC, National Academy Press, 2000. 3. Committee on Dietary Reference Intakes, Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC, National Academy Press, 2000.
4. Whitney EN, Cataldo CB, Rolfes SR: Understanding Normal and Clinical Nutrition, 6th ed. Belmont, CA,Wadsworth Publishers, 2002. 5. Bender DA:Optimum nutrition: Thiamin, biotin and pantothenate. Proc Nutr Soc 1999;58:427-433. 6. Lieber CS: Alcohol: Its metabolism and interaction with nutrients. Annu Rev Nutr 2000;20:395-430. 7. Merkin-Zaborsky H, Ifergane G, Frisher S, et al: Thiamine-responsive acute neurological disorders in nonalcoholic patients. Eur NeuroI2ool;45:34-37. 8. Johri S, Shetty S, Soni A, Kumar S: Anaphylaxis from intravenous thiamine-Long forgotten? Am J Emerg Med 2000;18:643-644. 9. Powers HJ: Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc 1999;58: 435-440. 10. McKinley MC, McNulty H, McPartlin J, et al: Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. Am J Clin Nutr 2001;73:759-764. I\. Jacques PF, Kalmbach R, Bagley PJ, et al: The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J Nutr 2002;132:283-288. 12. McNulty H, McKinley MC,Wilson B, et al: Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: Implications for riboflavin requirements. Am J Clin Nutr 2002;76:436-441. 13. Blanck HM,Bowman BA,Serdula MK, et al: Angular stomatitis and riboflavin status among adolescent Bhutanese refugees living in southeastern Nepal. Am J Clin Nutr 2002;76:430-435. 14. Ou lB, Kuo ML, Huang JL. Anaphylaxis to riboflavin vitamin B2• Ann Allergy Asthma ImmunoI2001;87:430-433. 15. Gerritson MM, De Krom M, Struijs MA, et al: Conservative treatment options for carpal tunnel syndrome: A systematic review of randomised controlled trials. J Neural 2002;249:272-280. 16. Scott JM: Folate and vitamin B12• Proc Nutr Soc 1999;58:441-448. 17. Bailey LB, Gregory JF: Polymorph isms of methylenetetrahydrofolate reductase and other enzymes: Metabolic significance, risks and impact on folate requirements. J Nutr 1999;129:919-922. 18. Voutilainen S, Rissanen TH, Virtanen J, et al: Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study. Circulation 2001;103:2674-2680. 19. Title LM, Cummings PM, Giddens K, et al: Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll CardioI20oo;36:758-765. 20. Schnyder G, Roffi M, Pin R, et al: Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600. 21. Van Dijk RA, Rauwerda JA, Steyn M,et al: Long-term homocysteinelowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: A 2-year, randomized, placebo-controlled trial. Arterioscler Thromb Vase Bioi 2001;21:2072-2079. 22. Stanger 0, Semmelrock H-J, Wonisch W, et al: Effects of folate treatment and homocysteine lowering on resistance vessel reactivity in atherosclerotic subjects. J Pharmacol Exp Ther 2002;303: 158-162. 23. Kim V-I: Folate and cancer prevention: A new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutr Rev 1999;57:314-321. 24. Stabler SP, Lindenbaum J, Allen RH:The use of homocysteine and other metabolites in the specific diagnosis of vitamin BI2-deficiency. J Nutr 1996;125: 12665-1272S. 25. Ward PC: Modem approaches to the investigation of vitamin Bl2 deficiency. Clin Lab Med 2002;22:435-445. 26. Nexa E, Hvas A-M, Bleie 0, et al: Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clin Chem 2002;48:1768-1771. 27. Jacob RA, Sotoudeh G: Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5:66-74. 28. Blanchard J, Tozer TN, Rowland M: Pharmacokinetic perspectives on rnegadoses of ascorbic acid. Am J Clin Nutr 1997;66:
1165--1171.
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29. Loria CM, Klag MJ, Caulfield LE, et al: Vitamin Cstatus and mortalityin US adults. AmJ Clin Nutr2000;72:139-145. 30. Douglas RM, Chalker EB, Treacy B: Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews, 2002;4. 31. Benzie IFF: Vitamin C:Prospective functional markers for defining optimal nutritional status. Proc NutrSoc 1999;58,469-476. 32. Thumham 01, Northrop-Clewes CA: Optimal nutrition: Vitamin A and the carotenoids. Proc NutrSoc 1999;48:449-457. 33. CooperDA, Eldridge AL, PetersJC: Dietary carotenoids and certain cancers, heart disease, and age-related macular degeneration: A review of recent research. NutrRev 1999;57:201-214. 34. Russell RM: The vitamin A spectrum: From deficiency to toxicity. AmJ ClinNutr2000;71:878-884. 35. Reifen R: Vitamin A as an anti-inflammatory agent. Proc NutrSoc 2002;61:397-400. 36. Omdahl JL, Morris HA, May BK: Hydroxylase enzymes of the vitamin Dpathway: Expression, function, and regulation. Annu Rev Nutr2002;22:139-166. 37. Deluca HF, CantomaMT: Vitamin D: Itsroleand usesin immunology. FASEB J 2001;15:2579-2585. 38. Chatterjee M: Vitamin D and genomic stability. Mut Res 2001;275: 69-88. 39. Janssen H, Samson MM, VerhaarHJ: Vitamin D deficiency, muscle function, and falls in elderly people.Am J Clin Nutr2002;75:611-615.
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40. AminS, laValley MP, SimmwRW, FelsonDT: The role of vitaminD in corticosteroid-induced osteoporosis. Arthritis Rheum 1999;42: 1740-1751. 41. Brigelius-Flohe R, Kelly FJ, Salonen IT, et al: The European perspective on vitamin E: Current knowledgeand future research. Am J ClinNutr2002;76:703-716. 42. Liu M, Wallman A, Olsson-Mortlock C, et a1: Mixed tocopherols inhibit platelet aggregation in humans: Potential mechanisms. Am J ClinNutr2003;77:700-706. 43. Devaraj S, Traber MG: a-Tocopherol, the new vitamin E? AmJ Clin Nutr2003;77:530-531. 44. Beck MA. Handy J, Levander OA: The role of oxidative stress in viralinfections.Ann NY Acad Sci 2000;917:906-912. 45. BeckMA: Antioxidants and viralinfections: Hostimmune response and viral pathogenicity. J Am Call Nutr2001;20:3845-3885. 46. Vatassery GT, Bauer T, Dysken M: High doses of vitamin E in the treatment of disorders of the central nervous system in the aged. AmJ Clin Nutr 1999;70:793-801. 47. Morrissey PA, Sheehy PJA: Optimal nutrition:Vitamin E. Proc Nutr Soc 1999;58:459-468. 48. Booth SL, Centurelli MA: Vitamin K: A practical guide to the dietary management of patients on warfarin. Nutr Rev 1999;57:288-296. 49. Booth SL, SUllie JW: Dietary intake and adequacy of vitamin K. J Nutr 1998;128:785-788.
II Minerals and Trace Elements Myeongsik Han, MD Phyllis Schiavone-Gatto, MSN Charlene Compher, PhD, RD
CHAPTER OUTLINE Introduction Minerals Calcium Phosphorus Magnesium Iron Zinc Copper Sulfur
Trace Elements Chromium Cobalt Iodine Manganese Molybdenum Selenium
Arsenic, Boron, Nickel, Silicon, Vanadium, and Aluminum Arsenic Boron Nickel Silicon Vanadium Aluminum
Conclusion
INTRODUCTION Minerals are an integral part of the body structure and provide for specific vital functions. Total body content for various minerals varies widely, from kilogram (calcium is 1% to 2% of body weight) to milligram quantities. Trace minerals are those present in the human body in quantities of less than 50 mg/kg (0.005% body weight) and include copper, iron, manganese, and zinc. Ultratrace minerals have estimated dietary requirements of less than 1 Ilg/g diet or less than 1 rng/day.' At least 140
18 elements are considered as trace elements: aluminum, arsenic, boron, bromide, cadmium, chromium, fluorine, germanium, iodine, lead, lithium, molybdenum, nickel, rubidium, selenium, silicon, tin, and vanadium. These elements may be essential, because they prevent deficiency syndromes, but the evidence of essentiality varies considerably.l- Updated nutritional information about the function, metabolism, requirements, deficiency, toxicity, and monitoring of these elements will be presented in this chapter.
MINERALS
Calcium Function Calcium is the mineral in greatest concentration in the human body, with more than 99% present in the bones and teeth. Calcium exists in bone as hydroxyapatite, CalO(P04)60H2, a dynamic tissue undergoing bone remodeling, with osteoclastic bone resorption and osteoblastic bone formation.' Calcium within the bone provides a structural strength that allows the bone to support the body's weight and anchor the muscles, but also serves as a reservoir that can be tapped to maintain extracellular calcium concentration, regardless of intake. The 1% of remaining calcium is in the blood and extracellular fluids and within cells of all tissues, where the regulation of important metabolic functions occurs. Calcium influences the transport functions of cell membranes and is required for nerve transmission and regulation of cardiac muscle function. The proper balance of calcium, sodium, potassium, and magnesium ions maintains skeletal muscle tone and controls nerve irritability. In addition, calcium ions playa critical role in smooth muscle contractility.' Ionized calcium plays a role in initiation of blood clot formation by the stimulation of thromboplastin from blood platelets and by the conversion of prothrombin to thrombin, which helps in the polymerization of fibrinogen to fibrin and eventual blood clot formation.'
SECTION III • Nutrient Metabolism
Metabolism Absorption of calcium takes place in the small intestine by active transport under the action of 1,25-dihydroxyvitamin D or by passive diffusion, with high calcium intakes. If vitamin D intake is low or exposure to sunlight is inadequate, calcium absorption will be decreased, a factor in the elderly population. Fractional calcium absorption varies inversely with calcium intake and also varies throughout life. Absorption is highest during developmental stages with high calcium requirements for growth, including infancy and puberty, and absorption reduces with aging. Calcium is absorbed only if it is present in an ionic form, thus binding with dietary oxalate (spinach, sweet potatoes, rhubarb, and beans), phytate (unleavened bread, raw beans, seeds, nuts, grains, and soy), or free fatty acids will reduce calcium absorption, with unabsorbed complexes excreted in the feces. Renal calcium excretion is regulated by parathyroid hormone (PTH) level. Racial differences in calcium metabolism have been identified, with African-American children and women having reduced urinary calcium excretion and higher bone mass than whites.'
Diet The calcium content of a food is more important than bioavailability because the calcium in most foods is absorbed at similar rates. The strongest food sources are dairy products such as cheese, yogurt, and milk. Fortified milk also provides a reliable source of vitamin D, which aids in calcium absorption. Dairy fats such as butter, sour cream, and cream cheese are poor sources of calcium. The 25% of adults in the United States who are lactose-intolerant are at risk for calcium deficiency if they avoid milk products, because 73% of calcium in the U.S. food supply is from milk products. Dark green leafy vegetables, broccoli, sardines, clams, oysters, canned salmon, soybeans, cooked dried beans, peas, and cottage cheese are other good sources. High sodium chloride and protein intakes result in increased urinary calcium loss, and caffeine has a modest impact on calcium loss. The Recommended Dietary Allowance (RDA) for adults is 1000 mg/day until age 50 and 1200 mg/day thereafter.'
Deficiency Chronic calcium deficiency comes primarily from inadequate intake or malabsorption and results in reduced bone mass and osteoporosis. As the circulating ionized calcium concentration drops acutely, the parathyroid gland secretes PTH to trigger the kidney to reabsorb calcium, the intestine to increase calcium absorption, and the bone to release calcium. The need for normal ionized calcium effectively catabolizes bone calcium stores. Osteoporosis, defined as bone mineral density greater than -2.5 SD below the mean, increases bone fragility and the risk of fractures. Ethnic differences in osteoporosis have been described in postmenopausal women, affecting 21%of white and Asian women, 16% of Hispanic women, and 10% of African-American women.
141
Annually, 1.5 million fractures are associated with osteoporosis. Osteopenia, defined as bone mineral density -1 to -2.5 SD below the mean, affects 38%of American women older than age 50. Inadequate calcium intake may also modestly increase the risk of hypertension. Acute hypocalcemia occurs rarely in the setting of malabsorption and is associated with tetany, an involuntary muscle spasm.'
Toxicity Calcium toxicity manifests as hypercalcemia, a risk not usually seen with dietary calcium but which may occur with calcium supplement use. If it occurs acutely, which is rare, significant hypercalcemia can cause cardiac or respiratory failure. Three clinical risks of chronic hypercalcemia have been described. Nephrolithiasis may occur, particularly if calcium supplements are taken separately from meals (where part of the calcium would bind with dietary oxalates, providing protection against kidney stones). A syndrome of hypercalcemia and consequent renal insufficiency, sometimes with metabolic alkalosis was seen when both milk and antacids were used to treat peptic ulcer disease. This is rare at the current time, because therapy for ulcer disease has changed. Finally, there is competition between calcium and other divalent minerals (iron, zinc, magnesium, and phosphorus) for absorption, although negative balance of the other minerals has not been effectively documented.'
Monitoring Serum calcium concentration is not a good measure of calcium status because it is regulated by PTH. The most reliable measure of chronic calcium balance is a dual energy X-ray absorptiometry (DEXA) scan measure of bone mineral content or bone mineral density. Concurrent measurements of l,25-dihydroxyvitamin D, PTH, and calcium are sometimes used to represent calcium status. Urinary markers of bone resorption can also be measured.
Phosphorus Function Phosphorus is an essential constituent of all cells and tissues, with approximately 85% found as hydroxyapatite in bone. The remaining 15% is distributed throughout soft tissues. Asmall amount is inorganic phosphate, a body component that accepts newly absorbed dietary phosphorus or resorbed phosphate from bone and that supplies urinary and bone mineral phosphorus. Primary phosphorus roles include buffering acid or alkali excesses, energy storage as adenosine triphosphate (ATP), and enzyme activation via phosphorylation. Phosphorus also supports tissue growth and replaces excretory or dermal losses.3
Metabolism The absorption of phosphorus takes place along the length of the small intestine and is governed by vitamin D,
142
13 • Minerals and Trace Elements
which causes saturable active transport. Passive diffusion also is important for phosphorus absorption. Unlike calcium, there is no variance in absorption efficiency due to intake. Approximately 70% of phosphorus in the diet is absorbed. Phosphorus absorption is reduced by aluminum-containingantacids or pharmacologic doses of calcium carbonate. Phosphorus excretion is primarilyrenal.
Requirements Phosphorus bioavailability in most foods is good, except for plant seeds (nuts, beans, peas, and cereals) containing phytate. The phosphorus content of phytate is unavailable for absorption. In addition to the naturally occurring phosphate content of foods such as dairy, meat, poultry, fish, and egg products, food additives are often phosphate salts. The RDA for adults is 700 mg/day.'
Deficiency Inadequate phosphorus intake is seen as hypophosphatemia, with resultant anorexia, anemia, muscle weakness, bone pain, rickets and osteomalacia, debility, infection risk, paresthesias, ataxia, confusion, and death. More severe symptoms are only seen with severe hypophosphatemia. Hypophosphatemia is rare in healthy individuals but can occur with refeeding of severely malnourished individuals or on recovery from alcohol withdrawal or diabetic ketoacidosis. In these states, monitoring of phosphorus intake and repletion during recovery are vital to prevent severe hypophosphatemia."
Toxicity Hyperphosphatemia occurs with excess phosphorus intake from any source, with symptoms due to elevated inorganic phosphorus levels in the extracellular fluid. Symptoms of hyperphosphatemia include secondary disturbance of calcium balance as hormonal regulation occurs, ectopic calcifications (often in the kidney), and reduced calcium absorption due to formation of calciumphosphorus complexes in the intestine. High inorganic phosphate levels reduce urinary calcium excretion, reduce renal activation of vitamin D, reduce serum ionized calcium levels, and result in increased PTH levels. Ectopic calcifications are primarily limited to individuals with renal insufficiency. An upper intake level of 5 g/day was established for adults to avoid hyperphosphaternia."
Monitoring The serum phosphorus level is used clinically to monitor phosphorus status.
Magnesium Function Of the 25 g of total body magnesium, 50% to 60% resides in bone, and one third is freely exchangeable as a
reservoir for needed extracellular magneslum." Magnesium is a cofactor for more than 300 enzymes, including both anaerobic and aerobic energy metabolism and for mitochondrial oxidative phosphorylation, using the magnesium chelate of ATP and adenosine diphosphate as substrates for phosphate transfer. Magnesium plays a role in maintenance of adequate purine and pyrimidine nucleotides for DNA and RNA synthesis during cell replication, and new protein synthesis is sensitive to the magnesium supply. The activation of adenylate cyclase, for hormonal or neurotransmitter action, requires magnesium. The active transport of potassium via Na-Kt-adenosine triphosphatase requires magnesium. With magnesium depletion, intracellular calcium concentration increases, and muscle cramps, hypertension, and cerebral or coronary vasospasms may develop." Magnesium has a role, which is not fully understood, in bone mineral homeostasis, and magnesium supplementation may be helpful in osteoporosis. Magnesium depletion has resulted in insulin resistance, and magnesium supplements have improved glucose tolerance in elderly patients with type II diabetes mellitus."
Metabolism Most of the approximately 50% dietary magnesium is absorbed in the distal jejunum and ileum. Like that of calcium, fractional absorption of magnesium is inversely proportional to magnesium intake. Ingestion of magnesium-eontaining foods concurrent with oxalate, phytate, or bran will cause binding of the mineral and reduce its absorption. Magnesium homeostasis is governed primarily by renal excretion using a filtration-reabsorption process.' Excessive alcohol intake, diuretic use, and a high-protein diet cause renal magnesium wasting.'
Diet Magnesium is widely distributed in the food supply, with green leafy vegetables, nuts, and unprocessed grains being strong sources. Refined foods are poor sources of magnesium. The RDA for adults is 420 mg for men and 320 rng for women.'
Deficiency Moderate to severe magnesium deficiency is often detected by hypocalcemia, with neuromuscular hyperexcitability, latent tetany (with positive Chvostek and Trousseau signs), or seizures. Magnesium depletion can result in electrocardiogram changes, arrhythmias, and increased sensitivity to cardiac glycosides. In patients with cardiac disorders, added magnesium depletion may further predispose individuals to arrhythmias. Most hypocalcemic, hypomagnesemic patients have a low or normal PTH concentration, suggesting impaired synthesis or secretion of PTH.5 Hypokalemia can also occur with magnesium deficiency, correction of which requires correcting the magnesium deficit.
SECTION III • Nutrient Metabolism
143
Toxicity
Diet
Magnesium toxicity is not seen with food sources but may occur with magnesium supplements. The initial manifestation is an osmotic diarrhea that may be accompanied by nausea and abdominal cramping. Hypermagnesemia can also occur in patients with renal insufficiency or with pharmacologic doses of magnesium oxide, causing metabolic alkalosis and hypokalemia. The tolerable upper intake level for adults is 250 mg/day.'
Foods with the greatest concentrations of iron include beef, whereas poultry and fish provide partly non heme iron. Fortified grains and cereal products are rich sources of iron. Milk and milk products, unfortified snack foods, and carbonated beverages are poor sources of iron. For adult men and postmenopausal women the RDA is 8 mg/day, and for postmenopausal women it is 18mg/day. The average intake is approximately 12 mg/day for women and 16 to 18 mg/day for men.
Monitoring
Deficiency
Serum magnesium concentration may not reflect intracellular magnesium, but it is commonly available. Intracellular or plasma ionized magnesium may be a better guide.
Iron deficiency results in reduced physical work performance, developmental delay, cognitive impairment, and adverse pregnancy outcomes, including maternal and infant mortality and premature delivery. Host immune surveillance is reduced as evidenced by reduced cell-mediated immunity and phagocytosis. Clinical signs of iron deficiency may include angular stomatitis, glossitis, esophageal webs, gastritis, koilonychia, pica, pagophagia, cold intolerance, and pallor. Iron deficiency affects an estimated 40% of the world's population, approximately 2 billion people, and is second only to hunger as a major nutritional problem worldwide." Three stages of iron deficiency are described. The first stage is reduced iron stores, as measured by ferritin concentration. Early iron deficiency is identified by reduced transferrin saturation or excess free protoporphyrin or transferrin receptors. The most severe phase is a microcytic, hypochromic anemia, noted by a reduced erythrocyte hemoglobin and mean corpuscular volume."
Iron Function Iron is a key component of many proteins, including hemoglobin and enzymes. Approximately two thirds of body iron circulates as a component of hemoglobin in erythrocytes, 15% as myoglobin, and 25% in a readily available iron store. Interconversion of iron from ferrous (+2) to ferric (+3) to ferryl (+4) forms allows the transfer of electrons during energy metabolism. Of the 40 proteins in the respiratory (electron transport) chain, 6 contain heme, 6 have iron-sulfur centers, and 2 contain copper. As the core of the porphyrin ring in the heme molecule of hemoglobin, iron carries oxygen from the atmosphere to tissue sites. Other iron-eontaining proteins include the iron-sulfurenzymes (flavoproteins) and iron storage and transport proteins (ferritin, hemosiderin, transferrin, and lactoferrin), and several non heme enzymes.'
Metabolism Iron absorption varies with the food source and with metabolic need. Food sources providing heme iron (beef) are readily absorbed, whereas nonheme iron in vegetables, poultry, and fish is absorbed less efficiently. Ascorbic acid taken concurrently with non heme iron foods effectively increases iron absorption by converting the ferric to ferrous iron. The maximum amount absorbed from an average diet in the United States is about 1 to 2 mg in normal adults and 3 to 6 rng in patients with iron deficiency. Iron balance is maintained by the regulation of absorption. Once absorbed, iron is transported bound to transferrin and binds with a specific transferrin receptor on the plasma membrane of the cell. After binding, iron is internalized into the cell in clathrin-eoated pits and released into the cell for storage. Iron is stored either in ferritin or hemosiderin in liver, spleen, or bone marrow sites. Iron excretion is very limited other than during bleeding.'
Toxicity Iron toxicity most often occurs in small children who have accidentally ingested iron tablets, with severity of symptoms depending on the total dose ingested. Symptoms include vomiting, diarrhea, organ dysfunction (cardiovascular, neurologic, renal, hepatic, and hematologic) and even death.! Excess iron intake impairs zinc absorption. Secondary iron overload occurs with transfusions and intravenous iron supplementation. Excess iron stores have been suggested as a factor for increased risk of cardiac disease, but the data are inconsistent, although iron also cannot be ruled out as a factor. Excess iron intake has also been examined as a potential colon cancer promoter, but the data are not conclusive. Patients with hemachromatosis, a condition that results in severe iron overload, have a higher risk of developing ischemic heart disease. Excess iron accumulates in the liver and has been associated with increased hepatocellular cancer risk. The clinical signs of iron overload are sterility, hyperpigmentation of the skin, fatigue, cardiac arrhythmias, hypothyroidism, arthropathy, and testicular atrophy. Treatment for this condition is lifelong phlebotomies. A tolerable upper intake level of 45 mg/day was established, based on the gastrointestinal distress (nausea, vomiting, and diarrhea) associated with greater intake. Individuals with hemochromatosis or hemosiderosis should avoid excess iron intake.s
144
13 • Minerals and Trace Elements
Monitoring The most common measures of iron status are serum iron and ferritin (stores) levels, transferrin saturation, and hemoglobin.
diarrhea, and headaches. Long-term excess intake of zinc can lead to copper deficiency, suppressed immune response, and reduced levels of high-density lipoprotein cholesteroJ.2
Monitoring
Zinc Function Zinc functions in catalytic, structural, and regulatory roles. For almost 100 specific enzymes, the catalyst is zinc. Zinc removal results in loss of enzyme activitywhereas addition of zinc restores activity. These metalloenzymes include RNA polymerases, alcohol dehydrogenase, carbonic anhydrase, and alkaline phosphatase. With zinc binding, a "zinc finger" is formed in proteins with cysteine and histidine residues in key sites for binding. These proteins include transcription factors for gene regulation, retinoic acid and vitamin 0 receptors, and copper-zinc superoxide dismutase. Metallothionein expression is regulated by zinc binding to a transcription factor. Apoptosis and protein kinase C activity are also influenced by zinc.!
Metabolism Zinc is absorbed through the small intestine after liberation from food sources by digestion. Zinc absorption is increased, and release of zinc into pancreatic and intestinal cell secretions is reduced during zinc depletion. Zinc homeostasis is controlled by a balance between absorption and variable secretory losses. More than 85% of zinc is contained in skeletal muscle and bone,"
Diet Strong food sources of zinc include red meats, seafood, and whole grains. The metal is lost from grains during processing. Zinc absorption is greater with a high animal protein diet and is reduced by concurrent iron supplementation. The RDA for zinc is 8 mg/day for adult women and 11 mg/day for adult men. Women require less than men because of their lower body weight"
Deficiency Severe zinc deficiency is rare, but patients with malabsorption syndromes (Crohn disease, sprue, and short bowel syndrome) are at risk of deficiency due to malabsorption and increased urinary losses. Some clinical symptoms include slowed growth, reduced taste perception and appetite, birth defects, poor healing of wounds, impotence, spontaneous abortion, delayed sexual maturation, dermatitis, and alopecia.
Toxicity Zinc toxicity does not occur from food sources, but can occur with high intake of supplemental zinc. With acute intake of large doses of zinc, symptoms of toxicity include nausea, vomiting, metallic taste, abdominal cramps
Plasma or serum zinc concentrations are used to monitor status, but erythrocyte zinc concentrations can be contaminated with zinc from red blood cells. The zinc concentration in hair is not generally regarded as an accurate indicator.!
Copper Chemistry Copper has two oxidation states, Cu' and Cu2+, and may shift back and forth between the two during biologic action. Cu2+ is most often found in biologic systems.
Function Copper is a constituent of a number of metalloenzymes with roles in oxidation-reduction and electron transfer reactions involving oxygen. Copper has diverse physiologic roles, including elastin and collagen fiber synthesis (lysyloxidase), free radical scavenging (copperzinc superoxide dismutase), iron metabolism (ferroxidases), mitochondrial energy metabolism (cytochrome c oxidase), catecholamine and serotonin metabolism (monoamine oxidase), and peptide and peptide hormone metabolism (o-amidatlng rnonooxygenasej.! Copper also affects central nervous system function, synthesis of the pigment melanin, cholesterol metabolism, and cardiac function."
Metabolism The adult human body contains approximately 50 to 120 mg (0.79 to 1.9 mmol) of copper. About 20% to 70% of ingested copper is absorbed, primarily in the duodenum and a lesser amount in the stomach," Copper homeostasis is regulated primarily by the rate of absorption and excretion via bile. 2,9 Carried by albumin, copper is transported to the liver where it is bound to ceruloplasmin, for release into the bloodstream and transport to tissues. Liver and muscle contain, respectively, 10% and 30% of total body copper. Iron and copper share a common transport system, and excess intake of either element can cause deficiency in the other. Excessive dietary zinc impairs copper status by promoting the synthesis of intestinal metallothionein, which binds copper in the mucosal cells from where the metal is lost by enterocyte sloughing. High copper intake also reduces zinc absorption slightly, and a slight excess of molybdenum in the presence of sulfide produces molybdenum toxicity and secondary copper deficiency. When dietary copper is increased, molybdenum toxicity is ameliorated. Ascorbic acid supplements have been
SECTION III • Nutrient Metabolism
associated with copper deficiency, thought to be due to impaired ceruloplasmin production.'? Penicillamine chelates endogenous copper and antacids also decrease copper absorption.
145
methionine-and many other organic molecules in the body. Sulfur is involved in the formation of bile acids, which are needed for fat digestion and absorption. It is a constituent of bones and teeth, regulates coagulation, and activates certain enzymes.
Diet The copper content of foods varies with method of assay, cooking and preparation procedures, and the source of the food. Major sources include shellfish, seeds, legumes, nuts, meats, and liver. Patients with chronic malabsorption, prematurity, excessive diarrhea or fistulas (especially biliary-enteric and biliary-eutaneous), high-dose zinc supplementation, and bums may need increased copper intake. In liver disease, copper absorption may be reduced by the use of zinc supplements, due to competition with copper for transport. The RDA for adults is 900 ug/day.'
Deficiency Copper deficiency is rare in humans. The greatest risk for copper deficiency is in premature infants receiving milk formulas, patients with chronic diarrhea, and persons receiving total parenteral nutrition (TPN).2 Vitamin C interferes with copper absorption and can lead to copper deficiency. Copper deficiency is detected by low serum concentrations of copper and ceruloplasmin, with manifestations of anemia, neutropenia, leukopenia, and osteoporosis.i Other symptoms of deficiency may include arthritis, glucose intolerance, and altered immunity.'!
Toxicity Acquired copper toxicity usually occurs from accidental consumption by children, contaminated water sources, suicide attempts, and use of topical creams, which contain copper salts, for burn treatment. Clinical manifestations of acute toxicity are epigastric pain, vomiting, hepatic necrosis, oliguria, and death. In chronic exposure, liver damage with cirrhosis, hemolysis, and brain and nerve injury are observed. The tolerable upper intake level for copper is 10 mg/day.!
Requirements As yet, there is no Dietary Reference Intake established for sulfur. The American diet is rich in protein, a factor that gives adequate sulfur intake. Food sources include meat, poultry, fish, eggs, cooked dried beans and peas, broccoli, cauliflower, peanuts, clams, milk, and dairy products.
Deficiency Sulfur deficiency is not known, although a low-protein diet could theoretically produce a deficiency. While protein deficiency is treated, however, sulfur status would improve.
Toxicity Sulfur toxicity is not known or documented.
TRACE ELEMENTS Trace elements often function in metabolic processes or redox reactions in many body systems, and deficiency results in nonspecific, diverse symptoms with overlap among elements. Nowadays severe trace mineral deficiency with classical symptoms is rare; however, borderline deficiency would probably produce detrimental results. The margins of safety from usual intake levels of many trace minerals are relatively low, and there is a potential risk of trace element toxicity with the use of many vitamin-mineral supplements. Symptoms for intoxication by trace metals are also nonspecific. Dietary requirements for trace elements are listed in Table 13-1.
Chromium Monitoring Copper-eontaining enzymes in blood cells (erythrocyte copper-zinc superoxide dismutase and platelet cytochrome c oxidase) may be functional indicators of copper metabolism.! Serum copper and ceruloplasmin levels are static indicators of body copper status but do not reveal marginal deficiency," Hepatic dysfunction, malnutrition, and nephrosis may have independent effects on ceruloplasmin concentration. The copper concentration in hair is not a reliable index.
Sulfur Function Sulfur is a component of all body tissues, as a constituent of three amino acids-cystine, cysteine, and
Chemistry Chromium exists in multiple valence states (from Cr2 to Cr+6). Chromium from food or water is reduced by gastric acid to Cr+3, a form that binds with various ligands. The more oxidized form Cr" is a strong oxidizing agent and a potentially toxic substance,"
Function Chromium is recognized as a glucose tolerance factor that potentiates insulin action and restores normal glucose tolerance in laboratory animals, even though specific chromium-eontaining metalloenzymes have not been identified. Chromium potentates the action of insulin by increasing the number of insulin receptors in vivo and in oltro? In chromium deficiency, glucose intolerance is improved by chromium supplementation. Treatment of
Neutropenia, microcytic hypochromic anemia, cardiac arrhythmia, osteoporosis Glucose intolerance, i cholesterol and LDL, peripheral neuropathy, weight loss
310-420
8 (men) 18 (women)
8-11
900
25-35
Magnesium
Iron
Zinc
Copper
Chromium
Anorexia, anemia, osteomalacia, rickets, bone pain, muscle weakness, i risk of infection, paresthesia, confusion Cardiac arrhythmia, neuromuscular hyperexcitability, latent tetany or seizure, hypocalcemia, hypokalemia Developmental delay, prematurity and stillbirth, cognitive impairment, cold intolerance, koilonychia, glossitis, angular stomatitis, microcytic anemia, .,l. work performance Retarded growth, poor wound healing, .,l. taste and appetite, alopecia, dermatitis, impotence, birth defects
hypertension
700
None reported
Acute: nausea, metallic taste, abdominal cramps, diarrhea, nausea, headache Chronic: .,l. immunity, .,l. HDL cholesterol, copper deficiency Acute: abdominal pain, vomiting, ataxia, hepatic necrosis Chronic: cirrhosis, hemolysis, brain, nerve injury
Acute: vomiting, diarrhea, organ failure Chronic: hemochromatosis, increased risk of ischemic heart disease, zinc deficiency
Osmotic diarrhea, abdominal cramping, nausea, hypokalemia, metabolic alkalosis
.,l. Calcium absorption, .,l. urinary calcium excretion, i PTH, ectopic calcification
Renal insufficiency, hypercalcemia, respiratory and cardiac failure
i Bone mass, osteoporosis, hypocalcemia, i risk of
Phosphorus
Toxic Symptoms
Deficiency Symptoms
1000
RDA/AI (mg)*
Calcium
Element
_ _ Minerai Requirements of Adult Humans
Urinary Cr, plasma Cr, glucose tolerance test
Plasma copper and ceruloplasmin, erythrocyte superoxide dismutase/platelet cytochrome c oxidase activity
Serum zinc
Ferritin, transferrin, hemoglobin, serum iron
Serum magnesium, ionized Mg2. better
Bone density (DEXA) most reliable; 1,25-dihydroxyvitamin D, PTH, and serum calcium helpful Serum phosphate
Assessment
.,l. Antacid, .,l. vitamin C, .,l. Fe, .,l. Zn, t starch as CHO source, .,l. sucrose and fructose as CHO source i Aspirin, T oxalate i ascorbic acid, .,l. zinc, .,l. iron, .,l. antacids, .,l. phytate
.,l. Iron, .,l. calcium, .,l. phosphorus
.,l. Phytate, .,l. calcium, i animal meat
.,l. Phosphate, .,l. high protein, .,l. phytate
.,l. High sodium and protein intake (by i urinary calcium loss), .,l. caffeine
Dietary Interaction
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Manganese
Molybdenum
Selenium
Arsenic
Boron
Nickel
Vanadium
Aluminum
No reported case of deficiency
No reported case of deficiency
J-BUN/creatinine, J-serum ,Iucose, J. calcitonin, increased hemoglobin No reported case of deficiency
Hypothyroidism, goiter, and cretinism in children Dermatitis, hypocholesterolemia, bone and cartilage abnormality, anemia Intolerance to S-containing amino acids, hypouricemia, mental disturbance, coma Cardiomyopathy, immune deficiency, skeletal myopathy, risk of cancer Unknown Acute: encephalopathy, GI symptoms Chronic: hepatotoxicity, hematopoietic depression, neuritis, various dermatoses DI symptoms, dermatitis, scanty hair, weight loss, anemia, seizures Dermatitis, carcinogenesis, nephrotoxicity, immunosuppression Neurotoxicity, hepatotoxicity, nephrotoxicity, green tongue, muscle cramps, diarrhea Osteomalacia, microcytic hypochromic anemia, encephalopathy (seizures, ataxia, dementia)
Urine xanthine, plasma Mo
Hyperuricemia, arthritis, gastrointestinal symptoms, growth retardation, anemia Hair and nail loss, tooth decay, neuropathy, mental change
Blood and serum aluminum: not accurate
No adequate method
Blood level of nickel
Plasma boron
Plasma and RBC Se, selenoprotein in RBCs, glutathione peroxidase
Urine iron concentration, serum T 3, T 4, TSH Plasma and whole blood Mn, RBC Mn concentration-no consistent results, MRI
Goiter and hyper- or hypothyroidism Anorexia, weakness, ataxia, tremor, neurologic irritability
Vitamin E, r iodine
J. Fe, J. Cu, J-Zn
i AI containing antacids,
J. Fe, J. Cu
T Coffee and tea
t
J- Cu
J- Fe
Se (synergistic action)
*Recommended Daily Allowance (RDA) or Adequate Intake (AI). AI, aluminum; BUN, blood urea nitrogen; Cr, chromium; Cu, copper; 01, diabetes insipidus; Fe, iron; GI,gastrointestinal; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Mg, magnesium; MRI, magnetic resonance imaging; PTH, parathyroid hormone; RBC, red blood cell; S, sulfur; Se, selenium; T3, triiodothyronine; T4, thyroxine; TSH,thyroid-stimulating hormone; Zn, zinc. From Committee on Dietary Reference Intakes: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC, National Academy Press, 2001; Committee on Dietary Reference Intakes: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC, National Academy Press, 1997;Committee on Dietary Reference Intakes: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC, National Academy Press, 2000.
150
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13 • Minerals and Trace Elements
type II diabetes mellitus with chromium improves levels of blood glucose, insulin, and hemoglobin A1C. 12 Chromium improves lipid profiles by decreasing total and low-density lipoprotein cholesterol and trlglyceride.i
Metabolism Homeostasis of total body chromium is maintained through a change in small intestinal absorption by passive diffusion, a process that is reduced by the presence of zinc, iron, and phytates" but enhanced by ascorbic acid.' Humans fed adequate chromium daily absorb only 0.4% to 2%. Soluble at gastric pH, chromium may precipitate, which results in reduced absorption as the pH is increased. Chromium is transported bound to albumin and transferrin and rapidly stored in bone, liver, spleen, and soft tissues.' Cr+3 is excreted in urine, and organic chromium in bile.
Cobalt Function Cobalt compounds have industrial applications, but there is little evidence of a role in human nutrition other than as part of the vitamin BI2 molecule, where the element is bound in the center of a square plane.v"
Toxicity In patients treated with cobalt for anemia, toxicity manifested as goiter, myxedema, and cardiomyopathy was reported. The molecular mechanisms behind genotoxic and carcinogenic effects of cobalt ions have begun to be
identified."
Iodine Dietary Intake Processed meats, whole grain products, bran cereals, green beans, broccoli, and spices have a high concentration of chromium. In renal dysfunction, the chromium requirement is reduced owing to limited excretion. The RDA for chromium is 251lglday for women and 351lglday for adult men with a reduction by 5 Ilg after age 50.2
Deficiency Frank chromium deficiency is generally limited to hospitalized patients with increased demands or excess losses (burns) combined with limited intake as a result of malabsorption or TPN without appropriate trace element supplementation.'! In a case report of a patient receiving TPN, hyperglycemia, weight loss, ataxia, and peripheral neuropathy were linked with inadequate chromium intake, and the insulin requirement was reduced with optimized chromium intake."
Toxicity Trivalent chromium has limited toxicity with a wide margin of safety from usual intake levels. IS Higher doses of oral chromium are nontoxic due to poor bioavailability. The pentavalent and hexavalent forms of chromium, obtained from industrial exposure, are carcinogenic and toxic, causing dermatitis and skin ulcer manifestations. Airborne tetravalent chromium toxicity has been established as a work-related cause of lung cancer in stainless steel workers.'
Monitoring The circulating (serum) chromium concentration, although it responds to chromium supplementation, does not reflect the tissue concentration. Similarly, urinary chromium output is responsive to chromium supplementation but fails to correlate with glucose, insulin, or lipid concentrations, outcomes affected by chromium
balance.'
Function Iodine is predominantly found in the thyroid gland, as an integral part of thyroid hormones, where it is bound to tyrosine as monoiodothyronine (MIT), diiodothyronine (DIT), triiodothyronine (T3), and thyroxine (T4)' T3, the metabolically active form of thyroid hormone, regulates protein synthesis and enzyme activity in multiple tissues, including developing brain, muscle, heart, kidney, and pltuitary.'
Metabolism The healthy human adult body contains 15 to 20 mg of iodide, of which 70% to 80% is in the thyroid gland. Ingested iodide is absorbed readily and is taken up from the circulation by the thyroid gland. Any excess iodine is excreted renally. The thyroid must trap about 60 ug/dey of iodide to maintain an adequate T4 supply. In the thyroid gland, iodide trapping from the extracellular space into the thyroid cells is regulated by thyroid-stimulating hormone (TSH) through an active Nat-Kt-dependent energy-requiring process. Within the thyroid cell, iodide is oxidized by thyroid peroxidase and combines with tyrosine to form MIT and OIT, both bound to thyroglobulin. By another oxidation reaction and in coupling of MIT and OIT, T3 and T4 are formed and secreted into the bloodstream toward their target. 18
Diet Iodine is a trace element in the crust of the earth with variable geographic distribution. Although soils have sufficient to excessive iodine in coastal regions, minimal iodine is found in soil from mountainous and inland regions. Iodine occurs in soil and the sea as iodide. Significant food sources of iodine include seaweed, bread, dairy products, and iodized table salt. Iodized salt, the strongest source in the United States and Canada, supplies 76 Ilg of iodide per g of salt. Iodine bioavailability is more than 90%. The RDA for adults is 150 Ilg/day, and average intake is more than 1 mg/day.! In countries
SECTION III • Nutrient Metabolism
where iodized salt is not available, iodine deficiency represents the most common worldwide cause of goiter, hypothyroidism, and mental retardation.
149
synthetase)." In addition, manganese is a component of metalloenzymes, such as manganese superoxide dismutase (antioxidant protection), arginase (urea formation), and pyruvate carboxylase (energy metabolism).
Deficiency Iodine deficiency disorders result from an amount of iodine that is inadequate to permit adequate thyroid hormone production. Fetal hypothyroidism results in cretinism, characterized by mental retardation, short stature, deafmutism, and spasticity.' Diffuse and nodular goiter is the most obvious manifestation of childhood and adult iodine deficiency. If very low intake persists, reduced fertility with increased stillbirth and neonatal and infant mortality may occur.
Toxicity Iodine supplementation may result in different reactions, according to the status of the thyroid gland. Healthy subjects without iodine deficiency can maintain normal thyroid function even with high iodine intake. With iodine deficiency, there is a risk of iodine-induced hyperthyroidism, but chronic excessive iodine intake greater than 2000 ug/day causes goiter and hypothyroidisrn.! Chronic thyroid gland stimulation by TSH is associated with thyroid neoplasms and papillary cancers.i The upper intake level for adults is 1100 ug/day.
Monitoring The concentration of iodine in either 24-hour urine or random urine samples is a reliable marker for iodine status. The plasma TSH level provides a good indicator of functional iodine status, with elevated TSH levels noted as the first effect with iodine excess.'
Manganese Chemistry The characteristic oxidative state of manganese in solution, in metalloenzymes, and in metal-enzyme complexes is divalent manganese (Mn2+) . The chemistry of Mn2+ is similar to that of Mg2+, and many enzymatic reactions activated by Mn2+ can also be activated by Mg2+.2 Mn3+ is also important in biologic activity.
Metabolism The bioavailability of manganese from dietary sources is greater than 5% of the 2 to 4 mg usually ingested, with absorption throughout the small intestine.f Once absorbed, it is transported to the liver where a small amount is oxidized from Mn2+ to Mn3+, bound to transferrin, and transported to the tissues. 19 Within cells, manganese is found predominantly in the mitochondria; thus, organs such as brain, kidney, pancreas, and liver have high manganese contents. The plasma manganese concentration is extremely low, and homeostasis is regulated mainly by variable fecal excretion.'
Diet Unrefined cereals, nuts, leafy vegetables, and tea are rich in manganese. Manganese, like copper, is eliminated predominantly through the hepatobiliary system, and patients with hepatobiliary disease may have impaired excretion of these minerals and a predisposition to manganese toxicity. Catabolic states, diarrhea, and malabsorption may increase manganese requirements. Manganese contamination of parenteral nutrition solutions must be considered as a source of intake. The adequate intake level for manganese, based on median intake in healthy people, is 2.3 and 1.8 mg/day in adult men and women.'
Deficiency Deficiency can impair the production of hyaluronic acid, chondroitin sulfate, and other mucopolysaccharides needed for growth and maintenance of connective tissue, cartilage, and bone." The most common manifestations are skeletal abnormalities caused by defective synthesis of the mucopolysaccharide organic matrix of cartilage. Dermatitis, hair depigmentation, slowed growth of hair and nails, nausea and vomiting, and moderate weight loss are also described." Hypocholesterolemia, impaired glucose tolerance, and altered lipid and carbohydrate metabolism occur with manganese deficiency!
Toxicity Function The human body contains 12 to 20 mg of manganese, mostly in the bone and in metabolically active organs such as brain, kidney, pancreas, and liver,where it is distributed in tissues as manganese-containing metalloenzymes. Manganese is a cofactor for many enzymes that facilitate metabolic processes, particularly those involved with formation of bone and with amino acid, lipid, and carbohydrate metabolism. These include hydrolases, kinases, decarboxylases, and transferases (glycosyltransferase, phosphoenolpyruvate carboxylase, and glutamine
Although oral intake is less toxic than intravenous administration, it can cause toxicity in patients with hepatic dysfunction or compromised homeostatic mechanisms and in infants. In those who inhale manganese dust, central nervous system pathologic conditions, including extrapyramidal motor system (globus pallidus or substantia nigra) symptoms similar to those of Parkinson disease are seen," Manganese toxicity presents clinically as muscle weakness, stiffness, tremors, ataxia, asthenia, and difficulty with speech. A tolerable upper intake level of 11 mg/day was set for adults.!
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13 • Minerals and Trace Elements
Monitoring
Toxicity
Potential indices include concentrations of serum or plasma manganese, mononuclear blood cell manganese, and manganese superoxidedisrnutase activity of lymphocytes.' Whole blood manganese is more often associated with tissue accurnulation-? and may be the best marker of toxicity. A magnetic resonance image showing manganese deposition in brain or liver may be the best indicator for toxicity, but expense limits its usefulness.
Molybdenum has limited toxicity in humans. Large oral doses may be associated with hyperuricemia and arthralgias. Reproductive loss and growth failure are also seen in animal models. The tolerable upper intake level is 2 rng/day, based on impaired reproduction and growth in animals.!
Molybdenum
Monitoring Plasma and serum molybdenum concentrations do not reflect molybdenum status, and urinary excretion varies with intake but does not reflect status" Molybdenum requirements are based on balance studies.
Chemistry Molybdenum may exist in multiple oxidation states (+3,
+4, +5, and +6) and can thus facilitate electron transfer in oxidation-reduction reactions." It is present in the body as a molybdenum cofactor at the active site of enzymes and molybdate ion (MoOl-), which is the main form in the blood and urine.
Function Metabolically active organs, such as liver and kidney, have the highest molybdenum concentrations. Molybdenum facilitates electron transfer reactions in a diverse range of enzymes such as the metabolism of xanthine (xanthine oxidase), sulfur (sulfite oxidase), and carbon (aldehyde oxidasej.i
Selenium Function Most selenium in biologic systems complexes with amino acids called selenoproteins, including selenomethione and selenocysteine, a component of glutathione peroxidase, iodothyronine deiodinase, and selenoprotein P.24 Four or more selenium-dependent glutathione peroxidases defend against oxidative stress, and three iodothyronine deiodinases regulate thyroid hormone metabolism." Three thioredoxin reductases have been identified, with function in intramolecular disulfide bond reduction and regeneration of ascorbic acid from an oxidized state."
Metabolism Metabolism Molybdenum, in food and in the form of soluble complexes, is easily absorbed in the stomach and upper jejunum and is excreted in the urine (90%) and bile (10%). Absorption efficiency is 28% to 77% of that ingested" and is inhibited by copper. Molybdenum is transported after specific binding with a.2-macroglobulin, and the major homeostatic control of molybdenum may be variable renal excretion.'
Selenium is absorbed throughout the small intestine, with more than 50% bioavailability in foods and near 100% as selenornethionine.P Selenium present as selenomethionine is regulated by methionine metabolism, not by selenium need. Hepatic glutathione peroxidase is reduced with limited dietary selenium, freeing selenium for the synthesis of other selenoproteins." The primary homeostatic regulatory mechanism for selenium is renal excretion.
Diet
Diet
Legumes, grains, and nuts are good dietary sources of molybdenum, although content will vary with soil molybdenum content. The RDA for adults is 45 J..lg/day, and average intake is 180 J..lg/day.2
The selenium content of foods varies with the selenium content of the soil, with up to lo-fold differences in the same food item. The best dietary sources are meat and seafood, grains, and vegetables (onion and garlic). Selenium content of wound and pus is high, suggesting that selenium requirements may be increased in patients with wounds and enteric fistulas. In renal dysfunction, the selenium requirement is decreased. The RDA for adults is 55 J..lg/day, with reported mean intake of 106 to 220 J..lg/day.25
Deficiency Acquired molybdenum deficiency was reported only in one patient during administration of TPN,23 with a manifestation of hypermethioninemia, hypouricemia, low urinary sulfate excretion, and mental disturbance that progressed to coma. Supplementation of 300 J..lg/day of ammonium molybdate reversed the sulfur-handling defect and normalized uric acid production.
Deficiency Experimental models of selenium deficiency result in reduced selenoenzyme activities with limited clinical
SECTION III • Nutrient Metabolism
sequelae. Human selenium deficiency rarely causes overt illness in isolation but can predispose patients to severe illness when combined with other deficiencies or stresses.P Keshan disease, found in China, is a cardiomyopathy that occurs with selenium deficiency in children that is also associated with a second infectious trigger. In an animal model of selenium deficiency, a nonpathogenic strain of Coxsackievirus B3 was mutated to a cardiomyopathy-producing strain." Kashin-Beck disease, also found in China, is an osteoarthritis occurring during preadolescence and adolescence that is characterized by dwarfism and joint deformities from cartilage abnormalities but may not respond to selenium supplementarion." The number of randomized trials conducted is still limited, but results suggest that selenium supplementation beyond the intake level needed to maintain selenoenzyme status may protect against prostate and colon cancer."
Toxicity Chronic selenosis occurs with excess dietary intake, either through diets naturally high in selenium or "rnegadose" supplementation. Chronic consumption of approximately 5 mg/day from a plant-based diet resulted in loss of hair and nails, tooth decay, dermatologic lesions, and neurologic effects." With accidental or suicidal selenium poisoning, severe gastrointestinal and neurologic disturbances, myocardial infarction, and acute renal failure result with gut and renal necrosis. A tolerable upper intake level for adults of 400 Ilg/day has been established."
Monitoring
151
Metabolism Arsenic has good bioavailability, particularly in solutions, is transported to the liver for reduction to arsenite and methylation, and is excreted renally.
Diet Strong food sources of arsenic include milk, meat, fish, poultry, grains, and cereal products.!
Toxicity Acute effects of arsenic poisoning, with ingestion of more than 10 mg/kg/day, include encephalopathy and gastrointestinal symptoms. Chronic ingestion of 1 mglkg/day can also result in anemia and hepatotoxicity! Blackfoot disease, an occlusive peripheral neuropathy with gangrenous extremities, has been described but may involve zinc deficiency in addition to arsenic toxicity. Epidemiologic studies suggest an association of increased cancer risk in populations with elevated exposure to arsenic.i although data are too limited to establish a tolerable upper intake level.
Boron Chemistry Boron is found in the body as boric acid in B(OH)3 and B(OH)4-. Boric acid forms esters with organic compounds, including sugars and polysaccharides, adenosine 5'-phosphate, pyridoxine, riboflavin, dehydroascorbic acid, and pyridine nucleotides.'
Plasma selenium and glutathione peroxidase activity in blood or tissue are sensitive to selenium intake and can be used to assess the need for this element. 24,25.26
Function
ARSENIC, BORON, NICKEL, SILICON, VANADIUM, AND ALUMINUM
The functions of boron in humans are not clear. In animal models, boron often shows physiologic effects only with combined nutrient deficiencies or stressors.
Although these elements have beneficial roles in physiologic processes in some species, the available scientific data in humans are limited, and thus no Dietary Reference Intake values have yet been established. Because deficiencies are observed, usually shown by impaired growth and development, further studies are needed to determine specific metabolic roles, sensitive indicators, and a full description of physiologic functions.' We will consider these elements as a group.
Metabolism More than 90%of boron, sodium borate, and boric acids in foods is absorbed, converted into B(OH)3, and excreted mostly in the urine.' Boron is distributed throughout tissues and organs, particularly bone, nails, and teeth.
Diet
Arsenic Function Arsenic may play a role in methionine metabolism, in growth and reproduction, and in gene regulation."
In the 19th and 20th centuries, boric acids were used as food preservatives, a practice that was banned after reports of human toxicity. Foods from plant origin, wine, cider, and beer are strong sources of boron.' The mean intake for an adult male is approximately 1 to
2 mg/day."
152
13 • Minerals and Trace Elements
Deficiency
Diet
In animals, boron deficiency impairs calcium metabolism, brain function, and energy metabolism," although usually with other stressors present."
Plant foods provide significant silicon content, as well as beer, coffee, and water.
Toxicity Toxicity Boron has limited toxicity when administered orally, but toxicity results from acute ingestion of large doses, with symptoms of anorexia, indigestion, derriatitis, and alopecia. 2 A tolerable upper intake level for adults was set at 20 mg/day.
Nickel Function Nickel may function as a cofactor in specific metalloenzymes, including hydrolysis and oxidation-reduction reactions, gene expression, and iron metabolism."
Metabolism Nickel absorption is 20% to 25% of that ingested. After absorption, nickel is principally bound to albumin and transported in the blood." Nickel is not accumulated in specific organs or tissues, but the thyroid and adrenal glands have relatively high nickel concentrations. Most ingested nickel is efficiently excreted in the urine, through which nickel homeostasis is maintained.'
To date no clear evidence of adverse health risks of food sources of silicon has been found.
Vanadium Function In animal studies, vanadium has insulin-mimetic action" and stimulates cell proliferation, differentiation, and phosphorylation-dephosphorylation.
Metabolism Less than 5% of ingested vanadium is absorbed. Vanadium is rapidly removed from plasma and retained in the highest amounts in the kidney, liver, testes, and spleen and with bone as the major sink. Excretion is primarily via urine."
Diet Foods rich in vanadium are shellfish, mushrooms, parsley, dill seed, and black pepper. Vanadium intake in adults is 6 to 18 ug/day,"
Diet
Toxicity
Plant foods with significant nickel content are chocolate, nuts, legumes, and grains. The average intake in adults is 74 to 100 Ilg/day.2
Vanadium from food sources is nontoxic, and acute toxicity in humans has not been reported.' In rodents, neurologic, hemorrhagic, endothelial, nephrotoxic, and hepatotoxic manifestations have been reported. Green tongue, cramps, and diarrhea were inconsistently reported with excessive intake in humans.'
Toxicity Because of limited absorption, the toxicity of nickel compounds is relatively limited when they are administered orally. Accidental ingestion of up to 2.5 g in contaminated water resulted in nausea, diarrhea, abdominal pain, and dyspnea. 1 A tolerable upper intake level of 1 rug/day of nickel salts was established.'
Aluminum The impact of aluminum on biologic systems has been debated in the past few decades, leaving no clear evidence that aluminum plays an essential role in live organisms29.30 but there is a clearly accepted risk of toxicity.
Silicon Function The functions of silicon in humans have not been established, but animal models suggest a role in collagen formation with structural abnormalities of skull and long bones during deficiency.
Function In vitro, aluminum activates adenylate cyclase, cytochrome c succinate dehydrogenase, DNAsynthesis, and osteoblasts. Aluminum accumulates within organelles, particularly the lysosome, nucleus, and chromatin." An association between intranuclear aluminum and aluminum neurotoxicity has been suggested.
Metabolism Little is known about silicon absorption, but it is not protein-bound in the bloodstream and shows primary renal excretion.
Metabolism Although intestinal absorption of aluminum is negligible (=0.1 %),31 concurrent intake of citrate can increase
SECTION III • Nutrient Metabolism
absorption and intake of salicylic acid can inhibit absorption. Absorbed aluminum is quickly removed from the bloodstream and excreted or stored in tissues, primarily skeleton, brain, kidneys, muscle, and heart. Aluminum can reduce the bioavailability of calcium and magnesiurn'" and negatively impact tissue concentrations of iron, zinc, copper. 33,34
Diet Aluminum is the most widely distributed metal in the environment and is naturally present in many foods, particularly from plant sources and drinks stored in aluminum cans. Aluminum intake from food sources is approximately 2 to 5 mg/day in adults with less than 0.3% to 0.5% absorption. Although aluminum requirements have not been established, they will probably be less than 1 mg/day."
Deficiency There is no clear evidence of human deficiency, although aluminum plays essential roles in live organisms. In animals, aluminum deficiency results in lack of coordination, weak limbs, slower growth rate, and shorter life span. 29.30
Toxicity Healthy individuals run no risk of aluminum poisoning from the diet, although patients with end-stage renal disease are susceptible to toxicity from aluminum contaminants in dialysate and phosphate binders, described as dialysis dementia syndrome." Casein hydrolysates in early parenteral nutrition solutions were contaminated with aluminum and associated with osteomalacia, although aluminum content was reduced with the change to crystalline amino acids. Encephalopathy due to aluminum poisoning is characterized by uncoordinated muscle contraction, ataxia, convulsions, and dementia. Aluminum has been suggested as a possible factor in Alzheimer
dementia." Monitoring Serum and whole blood aluminum levels do not accurately reflect the aluminum status because most aluminum is stored in tissues.
CONCLUSION In summary, minerals and trace elements provide vital structural, hormonal, and metabolic support of human body functions. An imbalance can be achieved with excess intake of individual mineral elements (most often through supplement use), and symptoms of toxicity are similar across elements. This exciting area of nutrition science will undoubtedly be elucidated by future research.
153
REFERENCES I. Nielsen FH: Ultratrace minerals. In Shils ME, Olson JA, Shike M, Ross CA (eds): Modem Nutrition in Health and Disease, 9th ed. Baltimore, Williams & Wilkins, 1999, pp 283-303. 2. Committee on Dietary Reference Intakes: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC, National Academy Press, 2001. 3. Committee on Dietary Reference Intakes: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin 0, and Fluoride. Washington, DC, National Academy Press, 1997. 4. Weaver CM, Heaney RP: Calcium. In Shils ME, Olson JA, Shike M, Ross CA (eds): Modem Nutrition in Health and Disease, 9th ed. Baltimore, Williams & Wilkins, 1999, pp. 141-156. 5. Shils ME: Magnesium. In Shils ME, Olson JA, Shike M, Ross CA (eds): Modem Nutrition in Health and Disease, 9th ed. Baltimore, Williams & Wilkins, 1999, pp. 169-192. 6. Fairbanks VF: Iron in Medicine and Nutrition. In Shils ME, Olson JA, Shike M, RossCA (eds): Modem Nutrition in Health and Disease, 9th ed. Baltimore, Williams & Wilkins, 1999, pp. 193-222. 7. Milne DB: Copper intake and assessment of copper status. Am J Clin Nutr 1998;67:1041£-1045S. 8. Schumann K, Classen HG, Dieter HH, et al: Hohenheim consensus workshop: Copper. Eur J Clin Nutr 2002;56:469-483. 9. Tumlund JR,WeaverCM,Kim SK,et al: Molybdenum absorption and utilization in humans from soy and kale intrinsically labeled with stable isotopes of molybdenum. Am J Clin Nitr 1999;69:1217-1223. 10. Spiegel JE, Willenbucher RF: Rapid development of severe copper deficiency in a patient with Crohn's disease receiving parenteral nutrition. JPEN J Parenter Enteral Nutr 1999;23:169-172. 11. Bonham M, O'Connor JM, Hannigan BM, et al: The immune system as a physiologic indicator of marginal copper status? Br J Nutr 2002;87:393-403. 12. Lamson OS, Plaza SM: The safety and efficacy of high-dose chromium. Altern Med Rev 2002;7:218-235. 13. Steams OM: Is chromium a trace essential metal? Biofactors 2000; 11;149-162. 14. Jeejeebhoy KN, Chu RC, Marliss EB, et al: Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr 1977;30:531-538. 15. Lukaski HC: Chromium as a supplement. Annu Rev Nutr 1999; 19:279-302. 16. Harris ED: Inorganic cofactors.ln Sadler MN, Strain JJ,Carbarello B (eds): Encyclopedia of Human Nutrition. San Diego, CA, Academic Press, 1999, p 399. 17. Lison 0, Boeck MD, Verougstraete V, et al: Update on the genotoxicity and carcinogenicity of cobalt compounds. Occup Environ Med 2001;58:619-625. 18. Hetzel BS, Clugston GA: Iodine. In Shils ME, Olson JA, Shike M, Ross CA (eds): Modern Nutrition in Health and Disease, 9th ed. Baltimore, Williams & Wilkins, 1999, pp 253-264. 19. Dickerson RN: Manganese intoxication and parenteral nutrition. Nutrition 2001;17:689-693. 20. Takagi Y, Akada A, Sando K, et al: On-off study of manganese administration to adult patients undergoing home parenteral nutrition: New indices of in vitro manganese level. JPEN J Parenter Enteral Nutr 2001;25:87-92. 21. Chan S, Gerson B, Subramaniam S: The role of copper, molybdenum, selenium and zinc in nutritional health. Clin Lab Med 1998; 18:673-685. 22. Tumlund JR, Keyes WR, Peiffer GL: Molybdenum absorption, excretion, and retention studied with stable isotopes in young man during depletion and repletion. Am J Clin Nutr 1995; 61:1102-1109. 23. Abumrad NN, Schneider AJ, Steel 0, et al: Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdenum therapy. Am J Clin Nutr 1981;34:2551-2559. 24. Committee on Dietary Reference Intakes: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC, National Academy Press, 2000. 25. Holben DH, Smith AM: The diverse role of selenium within selenaproteins. J Am Diet Assoc 1999;97:836-843. 26. Arthur JR: Functional indicators of iodine and selenium status. Proc Nutr Soc 1999;58:507-512.
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27. Nielsen FH: The emergence of boron as nutritionally important throughout the life cycle. Nutrition 2000;16:512-514. 28. Crans DC: Chemistry and insulin-like properties of vanadium (IV) and vanadium M compounds. J Inorg Biochem 2000;80: 123-131. 29. Campbell A, Bondy SC: Aluminum induced oxidative events and its relation to inflammation: A role for the metal in Alzheimer's disease. Cell Mol Bioi 2000;46:721-730. 30. Nayak P: Aluminum: Impact and disease. Environ Res 2002;89: 101-115. 31. Flaten TP: Aluminum as a risk factor in Alzheimer's disease, with emphasis on drinking water. Brain Res Bull 2001;55:187-196.
32. Williams RJ: What is wrong with aluminum? The JD Birchall Memorial Lecture. J lnorg Biochem 1999;76:81-88. 33. Dlugaszek M, Fiejka MA, Graczyk A, et al: Effects of various aluminum compounds given orally to mice on Al tissue. Pharmacol ToxicoI2oo0;86: 135-139. 34. Priest ND: Aluminum. Occurrence and toxicity. In Sadler MN, Strain JJ, Carbarello B (eds): Encyclopedia of Human Nutrition. San Diego, CA,Academic Press, 1999, pp 59-66. 35. Davis A, Spillane R, Zublena L: Aluminum: a problem trace metal in nutrition support. Nutr Clin Pract 1999;14:227-231.
III Non-Nutritive Supplements: Dietary Fiber Donna Zimmaro Bliss, PhD, RN, FAAN Hans-Joachim G. Jung, PhD
CHAPTER OUTLINE
INTRODUCTION
Introduction Definition of Dietary Fiber Composition of Dietary Fiber
It can be argued that dietary fiber is not an essential nutrient; however, research has shown that inclusion of greater amounts of dietary fiber in typical Western diets offers health benefits. There are no classical deficiency symptoms, as observed for inadequate intake of a vitamin or mineral, associated with consumption of minimal amounts of dietary fiber. Plant cell walls provide the bulk of dietary fiber in human diets. These cell walls are complex chemical structures composed of polysaccharides (cellulose, hemicellulose, and pectin), lignin, and several minor constituents such as proteins, hydroxycinnamic acids, and cutin. Although fiber has been referred to as a non-nutritive dietary ingredient because humans do not secret the enzymes needed for cell wall polysaccharide digestion, the bacterial population in the human colon does degrade and ferment plant cell walls. This fermentation produces short-ehain fatty acids that have important effects on colon function and health, and a substantial portion of these short-ehain fatty acids are absorbed and metabolized to yield energy for bodily functions. In this chapter we will explain the composition of dietary fiber, provide an overview of the effects of dietary fiber and short-ehain fatty acids on physiologic health of the gut, and review clinical studies related to the therapeutic use of dietary fiber and short-ehain fatty acids.
Polysaccharides Lignin
Analytical Methods Prosky Method Uppsala Method Solubility of Dietary Fiber
Fiber Fermentation Short-Chain Fatty Acids SCFAs: Substrates for Intestinal Cell Metabolism
Intestinal Effects of Dietary Fiber and Short-Chain Fatty Acids Intestinal Trophic Effects Anti-Inflammatory Effects Anti-Neoplastic Effects Effects on Sodium and Water Absorption Effects on Bacterial Growth and Pathogen Suppression Preventing Translocation of Bacteria and Mucosal Damage Effects on Segmental Gastrointestinal Motility and Oral-Anal Transit Effects on Stool Weight
Clinical Applications of Dietary Fiber and SCFAs Therapy for Ulcerative Colitis Therapy to Stimulate Intestinal Adaptation and Strengthen the Gut Barrier Protection Against Cancer Relief of Constipation Reduction of Diarrhea
Limitations of Some Clinical Studies Administering Fiber-Containing Formulas via Feeding Tubes Conclusion
DEFINITION OF DIETARY FIBER Dietary fiber has been a very difficult nutrient to define. I It is neither a specific chemical compound nor a homogeneous component of food. Although the concept that plant cell wall material should be considered an integral component of dietary fiber has always been accepted, the definition of dietary fiber has evolved over time. The primary sources of debate in defining dietary fiber have revolved around empirical (method) versus chemically based definitions, and questions of mammalian physiology versus botanical traits. Dietary fiber was originally 155
156
14 • Non-Nutritive Supplements: Dietary Fiber
measured by the crude fiber method that quantified the residue remaining after sequential extraction with dilute acid and base.' Crude fiber recovered almost all of the cellulose present in plants whereas the recoveries of the hemicellulose, pectin, and lignin fractions of cell walls were poor and variable among foods and animal feeds. Van Soesf introduced the neutral detergent fiber method for evaluating dietary fiber in forages fed to livestock as an alternative method that provided more complete recovery of the plant cell wall components than did crude fiber. However, the pectin fraction of cell walls is poorly recovered in neutral detergent fiber. This lack of recovery of pectin was judged not to be a problem by Van Soest because he introduced the concept of dietary fiber representing the incompletely digestible fraction of plant-derived feeds. Because forage pectins are highly digestible by ruminant livestock, lack of inclusion of this cell wall polysaccharide in neutral detergent fiber was not a problem. After the introduction of a nutritional definition of dietary fiber for livestock by Van Soest, dietary fiber was redefined for human nutrition as the portion of plantbased foods that was resistant to digestion in the human gastrointestinal tract.l ln this definition of dietary fiber for humans, plant cell walls were still considered to be the source of dietary fiber. More recently this definition has been broadened to include gums, industriaIly modified celluloses, and oligosaccharides resistant to hydrolysis in the mammalian gut. The current working definition for official methods of dietary fiber determination according to the Association of Official Analytical Chemists (AOAC) states that "Dietary fiber consists of the remnants of plant cells, polysaccharides, lignin, and associated substances resistant to hydrolysis (digestion) by the alimentary enzymes of humans."!
COMPOSITION OF DIETARY FIBER The majority of dietary fiber consumed by humans comes from plant cell waIls found in foods. Plant ceIls are surrounded by a complex wall structure that provides physical support, just as the skeletal system does for animals, and defense against attack by pest organisms. The physical and chemical structures of ceIl waIls among the various tissues comprising plant organs differ, but some important generalities exist. The most abundant components of plant cell walls are various polysaccharides and lignin, a phenolic polymer." Three classes of polysaccharides are found in plant cell walls: ceIlulose, a homogeneous polymer of glucose residues; hemicelluloses, polysaccharides comprising several different combinations of xylose, glucose, arabinose, mannose, fucose, and glucuronic acid residues; and pectin, a diverse assemblage of polysaccharides containing galacturonic acid, galactose, arabinose, and rhamnose units. Hemicellulose and pectin are heterogeneous classes of polysaccharides because they have been defined by the traditional methods for their isolation rather than based on specific chemical structures. Solubility and other nutritionally relevant characteristics of the many polysaccharides comprising the hemicellulose and pectin fractions make
the value of this traditional nomenclature questionable. More chemicaIly exact descriptions of the individual noncellulosic cell wall polysaccharides are generally preferred.
Polysaccharides The major cell wall polysaccharide structures in plant ceIl walls are illustrated in Fig. 14-1. CeIlulose is a linear, homopolymer of glucose residues with pIA linkages.' Unlike the other ceIl wall polysaccharides, ceIlulose has no branching points or substitutions. Individual cellulose molecules are very large in size, and numerous cellulose molecules are hydrogen bonded together to form microfibril bundles. A major form of hemicellulose is the xylans. These polysaccharides have a xylose backbone chain and various branching substitutions. The arabinosecontaining xylans are predominant in foods derived from grass species. Xyloglucans are a group of hemicellulosic polysaccharides most abundant in dicotyledonous plants (e.g., leafy vegetables) that have a pIA-linked glucose backbone similar to that of ceIlulose, but much shorter in length, with xylose substitutions as branch points. Oat and barley grains contain very little xyloglucan but can contain significant amounts of p-glucons (glucose chains with p I A linkages and periodic interspersed pI ,3 linkages), another form of hemiceIlulose. Mannans are pIA-linked polymers of man nose residues and are also included among the hemiceIlulosic polysaccharides. When mannan backbones have galactose substitutions attached as branches they are typicaIly referred to as gums because of their physical properties in solution. The hemicellulosic polysaccharides are intertwined around the ceIlulose microfibrils, forming a net-like covering. Cellulose and hemiceIluloses are abundant in all dietary fiber sources. Pectic polysaccharides consist of a series of polymers with galactose, galacturonic acid, or mixed galactose and rhamnose backbone chains and several different branching structures. Pectin appears to accumulate only in plant ceIl walls that do not deposit lignin during their development. Fruits are an especially rich source of pectin.
Lignin Lignin is a very complex, three-dimensional polymer that has no identifiable repeating structure. Lignin is constructed from coniferyl alcohol and other phenylpropanoid precursors." The complex structure of lignin results from the nonenzymatic, free-radical reactions that occur during lignin polymerization, unlike the enzymatically controIled reactions in polysaccharide assembly. Accumulation of lignin is seen in vegetative plant parts and seed coats; therefore, the lignin content of most dietary fiber in human food is low. The arabinoxylans in cereal brans are substituted with ferulic acid molecules that are ester-linked to arabinose residues. Some of these ferulic acid molecules will bind with one another and create cross-linking structures between arabinoxylans and lignin. Both total lignin and ferulate cross-links of
SECTION III • Nutrient Metabolism Cell Wall Polysaccharides
Backbone Linkages
Cellulose
~[I3-D-Glc-(1 ~4)-I3-D-Glc]~
157
Branch Linkages
Hemicellulose
XylansArabinoxylans
~[I3-D-Xyl-(1 ~4)-I3-D-Xyl]~
Glucuronoxylans
~[I3-D-Xyl-(1 ~4)-I3-D-Xyl]~
a-D-GlcA-(1 ~2)-I3-D-Xyl
Glucuronoarabinoxylans
~[I3-D-Xyl-(1 ~4)-I3-D-Xyl]~
a-L-Ara-(1 ~2 or 3)-I3-D-Xyl
a-L-Ara-(1 ~2 or 3)-I3-D-Xyl
a-D-GlcA-(1 ~2)-I3-D-Xyl Xyloglucans
~[I3-D-Glc-(1 ~4)-I3-D-Glc]~
a-D-Xyl-(1 ~6)-I3-D-Glc a-L-Fuc-(1 ~2)-I3·D-Gal-(1 ~2)-I3-D-Xy
~[I3-D-Man-(1 ~4)-I3-D-Man]~
Mannan Pectin
Galacturonans
~[a-D-GaIA-(1 ~4)-a-D-GaIAl~
Arabinogalactins
~[I3-D-Gal-(1 ~3,
Rhamnogalacturonans
~[I3-D-Gal-(1 ~4)-a-D-GaIA]~
I3-D-Gal-(1 ~4)-I3-L-Rha
Arabinorhamnogalactans
~[a-D-Gal-(1 ~2)-I3-L-Rha]~
a-L-Ara-(1 ~4)-I3-L-Rha
4, or 6)-I3·D·Gal]~
a-L-Ara(1 ~2, 3, or 6)-I3-D-Gal
FIGURE 14-1. Chemical composition and linkage structures of the major polysaccharides found in plant cell walls.
arabinoxylan to lignin are known to inhibit cell wall polysaccharide digestion in ruminant animals.v" All plant cell walls contain small amounts of protein, with more protein found in legumes than in cereals; however, dietary fiber methods specifically exclude this cell wall fraction. Plants deposit a waxy material known as cutin on their epidermis. Species that evolved in a desiccating environment have a thicker cutin layer than plants from cooler and wetter environments, but all plants have some cutin as protection against water loss and pathogen attack. Although not part of the plant cell wall, oligosaccharides such as raffinose and stachyose (containing glucose, galactose, and fructose residues) fall within the dietary fiber definition because mammalian digestive enzymes cannot degrade these compounds. These digestion-resistant oligosaccharides are most common in legume seeds. "Resistant starch" is another non-eell wall polysaccharide that technically meets the dietary fiber definition. This form of starch results from food processing and is resistant to mammalian enzymatic digestion, although it is rapidly and completely degraded by the gastrointestinal microflora.
ANALYTICAL METHODS The crude and neutral detergent fiber methods have been largely displaced for analysis of dietary fiber in human foods by enzymatic-gravimetric and enzymatic-chemical methods of analysis to capture all the plant cell wall constituents and most of the other components included in the current definition of dietary fiber. Although there are numerous variations of these
dietary fiber methods, the basic analytical scheme is similar (Fig. 14-2). Food samples must be dried and finely ground before analysis. Foods rich in fat (>10%) must be pre-extracted with ether to remove lipid material that can interfere with subsequent analysis. Samples are then treated with heat-stable a-amylase and amyloglucosidase to hydrolyze starch to glucose. Because the starchdegrading enzymes typically used for dietary fiber determination are bacterial in origin, resistant starch is degraded during dietary fiber analysis. Measurement of resistant starch requires the use of mammalian amylolytic enzymes. The remaining large oligosaccharides, polysaccharides, and lignin are precipitated by addition of ethanol. The resulting residue is then weighed to determine dietary fiber content of the food item or subjected to chemical hydrolysis of the cell wall polysaccharides with subsequent measurement of the individual sugar residues. Official AOAC methods have been established using both approaches, and several variations of each have been developed. A difficulty with both methods is that digestion-resistant oligosaccharides that meet the dietary fiber definition will only be recovered by these methods if their degree of polymerization (number of sugar units per molecule) is at least five. Therefore, foods known to be rich in small oligosaccharides that meet the dietary fiber definition require special analysis for these oligosaccharides.
Prosky Method The most common method of dietary fiber analysis is the Prosky method," an enzymatic-gravimetric analytical
158
14 • Non-Nutritive Supplements: Dietary Fiber Dried, Ground Sample • • • •
I Filtrate:
that there is no protein removal step during starch hydrolysis and the dietary fiber residue is subjected to acid treatment to hydrolyze the cell wall polysaccharides to their component sugars (see Fig. 14-2). The neutral sugar residues are measured using gas or liquid chromatography. The acidic sugar residues (glucuronic and galacturonic acids) are measured colorimetrically. Lignin is quantified as the ash-free, non hydrolyzable residue after acid treatment. Total dietary fiber is calculated as the sum of the individual sugars plus lignin minus the insoluble mineral ash. Protein is not quantified in this procedure.
I
Extract w/ether (if fat> 10%) Degrade starch Degrade protein (Prosky Method) Filter Insoluble dietary fiber
• Precipitate in 80% ethanol • Filter Soluble f----+ dietary fiber
Prosky Method • Weigh dietary fiber residues • Correct dietary fiber values for protein (N x 6.25) and ash
Solubility of Dietary Fiber
I
Uppsala Method
I
• Sulfuric acid hydrolysis of residues • Filter
I Filtrate
I Residue I
GC or HPLC
Neutral sugars
I
Colorimetry
Uronic acids
I
• Weigh • Ash • Weigh
I Klason lignin
Dietary fiber = neutral sugars + uronic acids + Klason lignin FIGURE 14-2. Basic schemes for analysis of soluble and insoluble fiber by the enzymatic-gravimetric (Prosky) and enzymaticchemical (Uppsala) methods for dietary fiber determination.
method (see Fig. 14-2). Most protein is removed from the food sample using base and a protease addition between the a-amylase and amyloglucosidase steps in the procedure. After precipitation of the dietary fiber with alcohol, following starch hydrolysis, glucose and cytosolic carbohydrates are removed by filtration. The resulting dietary fiber residue is dried and weighed. Replicate dietary fiber residues are analyzed for crude protein (N x 6.25) and ash to allow correction of the dietary fiber concentration for these non fiber components. Although the Prosky method provides an estimate of dietary fiber concentration, it does not provide any information about dietary fiber composition.
Uppsala Method To provide compositional information for dietary fiber, Theander and co-workers? developed the Uppsala method. This method differs from the Prosky method in
The Prosky and Uppsala dietary fiber methods both provide estimates for total dietary fiber. Using solubility in warm water as a criterion, total dietary fiber can be subdivided into soluble and insoluble fibers (see Fig. 14-2). Both analytical procedures are modified in the same manner to separate soluble and insoluble dietary fiber.' Rather than adding alcohol to the sample after completion of the starch hydrolysis procedure to precipitate all remaining polysaccharides, the aqueous solution is filtered immediately. Insoluble dietary fiber is recovered as the precipitate at this step and analyzed according to the remaining steps of each method's protocol. Alcohol is added to the filtrate to precipitate the soluble fiber, which issubsequently recovered and analyzed as before. Crude fiber and neutral detergent fiber are measures of the insoluble fiber fraction because only insoluble fibers are recovered by these methods. Cellulose, most hemicellulosic polysaccharides, and lignin are not soluble in warm water. Pectin is the major source of soluble fiber in many foods (especially fruits), although J3glucans in cereal grains (particularly oats and barley) are an important source of soluble fiber. Gums can be important soluble fiber constituents in processed foods to which these gums have been added. Soluble fiber will often form gels that can be stable or transient, depending on their chemical structure and the temperature and mineral composition of the aqueous solvent used. The dietary fiber content of some typical food items is shown in Table 14-1. Among the common food items, vegetables contain the highest concentration of total dietary fiber. Legume seeds (beans and peas) and root crop vegetables (potatoes and carrots) have lower dietary fiber content than some other vegetables because these food items are rich in storage carbohydrates such as starch and oligosaccharides. Breakfast cereals and baked goods have lower dietary fiber concentrations, with the exception of bran cereal. The higher concentration of dietary fiber in whole wheat bread results from the presence of bran in whole-wheat flour. Overall vegetables have the lowest soluble fiber content as a percentage of total dietary fiber. Fruit and cereal grainderived foods have higher, but variable, levels of soluble fiber. However, in no food item does soluble fiber exceed 40% of the total dietary fiber. Because of large differences in moisture content among food items (fable 14-1),
SECTION III • Nutrient Metabolism
159
_ _ Concentration of Dietary Fiber and Percentage of Soluble Fiber in Some Common Food Items
Baked goods Bread, white!" Bread, whole wheat III Cinnamon roll!" Doughnut, cake!" Breakfast cereals All bran!' Corn flakes 11
Oatmeal!' Fruits Apple, unpeeled'?
Banana'< Orange" Vegetables Beans, green!' Broccoli!" Carrot III Lettuce!'
Peas!" Potato, French fries!"
Moisture ("/0)
Total Dietary Fiber ("/0 Dry Weight)
("/0 Total Dietary Aber)
37.1 39.7 26.4 24.5
4.3 12.9 3.0 2.3
34.4 14.0 27.3 33.5
5.7 10.9 84.2
31.9 4.8 12.0
7.0 11.6 36.8
83.6 75.7 85.5
12.2 7.0 6.9
10.0 29.4 17.6
90.2 90.2 87.2 94.5 82.3 68.3
26.5 35.7 19.5 25.5 19.8 7.3
4.2 11.4 8.0 5.0 8.9 17.4
the actual amount of dietary fiber consumed in a typical serving of each food is poorly related to the concentration of dietary fiber as measured on a dry matter basis.
Dietary Fiber in Liquid Enteral Formulas There are two types of commercially available enteral formulas that contain dietary fiber: formulas ground in a blender from whole foods and defined formula diets supplemented with a single or mixed purified fiber source (Table 14-2). Most commercially available formulas contain soy polysaccharide, which has up to 94% insoluble fiber" and has been shown to be moderately fermented in oitro," Because highly fermentable soluble dietary fibers, such as pectin and guar gum, raise the viscosity of liquid solutions, they have been unsuitable for inclusion in enteral formulas. However, technologic advances have enabled the addition of partially hydrolyzed guar gum to enteral formulas.P'" Fiber-eontaining liquid enteral formulas provide a more complete diet to patients who would otherwise lack the dietary fiber component. They offer patients dependent on tube feedings potential physiologic and metabolic benefits from fiber and its fermentation products, short-chain fatty acids.
FIBER FERMENTATION Although mammals do not possess the enzymes necessary for degradation of plant cell walls, dietary fiber is fermented as the result of microbial action in the human gastrointestinal tract. Approximately 75% of the dietary fiber in a typical Western diet is fermented." Soluble dietary fiber such as pectin is more highly fermented than are the insoluble dietary fibers, cellulose and xylan.
Soluble Aber
Resistant starch can contribute significantly to this total dietary fiber fermentability because 3% to 20% of ingested starch escapes the small intestine undigested. Estimates of the contribution of metabolizable energy from dietary fiber range from 0.7 to 3 kcal/g of fiber consumed. Generally, lower values are from cereal and grain sources whereas higher values are from mixed diets that include fruits and vegetables. If increased losses of fat and protein occur because of elevated fiber intake, the net energy value lessens. 18 Fermentation of dietary fiber occurs through the action of the indigenous bacteria that reside in the intestines, primarily in the colon. The bacteria responsible for dietary fiber fermentation are anaerobic species that degrade the cell wall polysaccharides to their sugar constituents, and these degradation products are then fermented by the bacterial microflora. Short-ehain fatty acids (primarily acetate, propionate, and butyrate) are the end products of fermentation. Pectin fermentation results in very high proportions of butyrate, whereas cellulose and xylan fermentation yield more acetate and propionate than butyrate." Starch fermentation results in relatively higher levels of propionate production and lactate. Polysaccharide degradation requires a variety of enzymatic activities to hydrolyze the many different glycosidic linkages present in the cell walJ.20 At least three enzymatic activities are required for the degradation of cellulose: endoglucanase to cleave ~ 1,4 linkages within the cellulose polymer, exoglucanase for end-wise cleavage of cellulose fragments to cellobiose, and cellobiosidase to complete the degradation of cellobiose to glucose residues. Similar sets of enzymes are required to deal with the xylan, mannan, galactan, and galacturonate backbones of the noncellulosic polysaccharides. In addition, these noncellulosic polysaccharides require numerous additional enzymes to cleave the branching side-ehain structures. Most of the cell wall-degrading
160
14 • Non-Nutritive Supplements: Dietary Fiber
_ _ Fiber-Containing Liquid Enteral Formulas and Their Dietary Fiber Content IDF (gJL)
14.4
11.1
3.3
4.3 10
3.2 2.8
1.1 7.2
0 10 10
0 7.5 7.5
10.0 2.5 2.5
13.5 5
0.9 10
10
5
5
10
4.8
5.2
14.4 12.0 12.0 6.3 0 14
13.5 9.0 9.0 1.9 0 14
0.9 13.0 13.0 4.4 15.6
Soy polysaccharide
6
6
FOS Soy
0 5.0
0 4.7
Inulin and fructo-oligosaccharide
4
Manufacturer
flber Source *
Choice DM® TF (unsweetened) Compleat" Diabetlsource'" AC
Mead Johnson
Equalyte" Flbersource'> Standard Flbersource'?' HN
Ross Novartis Novartis
Glucerna" Glytrol" Impact" with Fiber
Ross Nestle, Clinical Nutrition Novartis
lsosource"
Novartis
Jevity" I Cal Jevity" 1.2 Cal Jevlty" 1.5 Cal Kindercal" with Fiber Nepro" Nutren" 1.0 with Fiber
Ross Ross Ross Mead Johnson Ross Nestle Clinical Nutrition Nestle Clinical Nutrition Ross Ross
Soy fiber, acacia, microcrystalline cellulose Fruits and vegetables Partially hydrolyzed guar gum, polysaccharides, fruits and vegetables FOS Soy fiber and hydrolyzed guar gum Soy fiber and partially hydrolyzed guar gum Soy Gum arabic, pectin, and soy polysaccharide Soy polysaccharide and partially hydrolyzed guar gum Soy polysaccharide and partially hydrolyzed guar gum Soy FOS, patented fiber blend FOS, patented fiber blend Gum arabic, soy fiber FOS Soy polysaccharide
Nutren Junior" with Fiber Optlmental" Pediasure" Enteral Formula with Fiber Peptamen with Preble"
Peratlve" Probalance"
Promote" with Fiber Protain XL'" Replete" with Fiber
Novartis Novartls
Nestle Clinical Nutrition Ross Nestle Clinical Nutrition Ross Mead Johnson Nestle Clinical Nutrition Novartis
Resource" Diabetic (closed system) TwoCal® Ultracal"
Ross Mead Johnson
Ultracal" HN Plus
Mead Johnson
Uquld Supplement
Manufacturer
Advera" Boost" with Fiber
Ross Mead Johnson
Choice DM'"Beverage
Mead Johnson
Ensure" Fiber with FOS Glucerna" Shake Nutrlfocus" ProSure'"
Ross Ross Ross Ross
SDF (gJL)
TDF (g/L)
Uquld Enteral Diet
14.4 15
FOS Gum arabic and soy polysaccharide
0 10
Oat, soy Soy fiber, microcrystalline cellulose Soy polysaccharide Soy polysaccharide and partially hydrolyzed guar gum FOS Soy fiber, acacia, microcrystalline cellulose Soy fiber, acacla, microcrystalline cellulose flber Souree" Soy Soy fiber, acacia, microcrystalline cellulose Soy fiber, acacia, microcrystalline cellulose FOS, soy, oat FOS, soy, maltodextrin FOS, patented fiber blend! FOS, gum arable, soy
5.0 0.3 4
0 7.5
6.5 2.5
14.4 9.1 14
13.5 8.6 14
0.9 0.5
12.8
6.4
6.4
0 14.4
0 10.1
5.0 4.3
7.3
2.7
10 TDF (gJ8 0 oz) 2.1 11.1
IDF (gJ8 0 oz)
SDF (gJ8 0 oz)
2.0 8.8
0.1 2.3
2.6
1.89
0.71
2.8 3.0 5 4.8
1.8 1.0 1.9 0.3
1.0 2.0 3.1 4.5
*Fiber source and content per manufacturer's data. lPatented fiber blend = oat fiber, soy fiber, carboxymethylcellulose, and gum arabic. TDF,total dietary fiber; IDF, insoluble dietary fiber; SDF,soluble dietary fiber; FOS, Iructo-oligosaccharides (Nutraflora" Brand FOS).
enzymes are bound to bacterial cells rather than being excreted into the general digesta. As a result, most cell wall-degrading bacteria must physically attach to dietary fiber particles with glycocalyx structures before degradation can occur. Unlike the polysaccharides in plant cell walls, lignin cannot be degraded by gastrointestinal
bacteria because the only known enzymatic system for lignin degradation requires the participation of O2, which is absent from the anaerobic gUt,21 The bacterial population of the human gastrointestinal tract is very complex. Finegold and assoclatesf estimated that there may be 400 to 500 bacterial
SECTION III • Nutrient Metabolism
161
species in residence in the human gut at anyone time, although many of these species will be present in very low numbers. Common colonic bacterial genera include Bacteroides, Eubacterium, Bifidobacterium,
Lactobacillus, Ruminoccocus, Peptococcus, Peptostreptococcus, and Clostridium, which are present at concentrations of 10 x 1010 or greater cells per g of dry weight of feces or digesta. The human gut microflora is relatively unique because of the virtual absence of Spirochaeta and relatively high numbers of Enterobacter and Clostridium compared with the microflora of animals." Mostof the human colonic bacteria can degrade and ferment carbohydrates, but only a limited number of species degrade dietary fiber. Some of the major rumen bacteria involved in cell wall degradation and fermentation, such as Ruminococcus albus, are found in the human colon along with many bacterial species unique to this environment." However, surprisingly little is known about the microbiology of dietary fiber degradation in the human colon with regard to capacity of specific bacterial species to degrade the variety of cell wall polysaccharides and other dietary fiber components reaching the colon. Compared with degradation and fermentation rates of starch, many of the polysaccharides in dietary fiber are degraded very slowly." Typical rates of starch degradation by bacterial action are 8% to 12% per hour, compared with cellulose and xylan degradation rates of 4% to 6% per hour. Generally, soluble fibers such as pectins are more rapidly degraded (10% to 20% per hour) in the proximal colon than are insoluble fibers. However, not all soluble fiber is rapidly degraded as evidenced by the slow rate of arabinogalactan degradation compared with that of other pectins." Because of the slow rate of cellulose and xylan degradation by gastrointestinal bacteria, the rate of passage of digesta through the colon has a major impact on extent of dietary fiber degradation." Dietary fiber sources with high concentrations of insoluble fibers will be less extensively degraded when digesta passage rates are rapid, such as when food intake is high or pathologic conditions result in greater colon peristalsis.
SHORT-CHAIN FATTY ACIDS Short-chain fatty acids (SCFAs) are the fermentation end products of bacterial degradation of dietary fiber in the colon. They are straight-chained organic fatty acids with one to six carbons. The major SCFAs of physiologic significance in humans and other mammals are acetate, propionate, and butyrate. Isobutyrate, valerate, isovalerate, and hexanoate, which comprise only about 10% of total SCFAs, exert less influence. SCFAs are used as an energy substrate by intestinal epithelial cells or colonic bacteria, absorbed into the portal circulation, or excreted in feces (Fig. 14-3). The normal concentration of SCFAs in human feces ranges from 70 to 100 mmol although the molar ratios of the individual acids vary, depending on the fiber source."
FIGURE 14-3. Fate of short-chain fatty acids (SCFAs), products of fiber fermentation.
SCFAs are absorbed in the ionized and non ionized (protonated) forms. Several mechanisms of absorption of SCFAs have been proposed, including simple diffusion of ionized SCFAs and carrier-mediated anion exchange." Absorption of SCFAs appears to occur principally via a transcellular pathway. Absorption of SCFAs is associated with sodium absorption and luminal bicarbonate appearance. The absorption of SCFAs appears to vary between colonic segments, and more rapid absorption occurs in the proximal colon.
SCFAs: Substrates for Intestinal Cell Metabolism Colonocytes derive as much as 70% of their energy from metabolism of SCFAs. Butyrate is the most important fuel for human colonocyte oxidation, preferred over Lglutamine and o-glucose, Butyrate is metabolized to CO2 and the ketones, acetoacetate, and j3-hydroxybutyrate. SCFAs that are not metabolized by colonic mucosal cells are transported via the portal circulation to the liver. In the liver, acetate is metabolized to the amino acid, glutamine, and ketone bodies, which in turn are used as respiratory fuels by the small intestinal mucosa. The dependence of colonocytes on SCFAs as oxidative substrates increases segmentally from the proximal colon to the rectum. Deprivation of SCFAs leading to reduced adenosine 5'-triphosphate (ATP) production may impair colonocyte function and mucosal integrity with the distal colon being at highest risk. Abnormally high luminal concentrations of butyrate were found in patients with ulcerative colitis and were associated with deficiencies in energy metabolism by inflamed colonocytes.A'?
162
14 • Non-Nutritive Supplements: Dietary Fiber
. . , Intestinal Effects of Dietary Fiber and . . Shon-Chaln Fatty Acids Stimulate structural and functional trophism of mucosa Promote healthy bacterial ecosystem Attenuate mucosal inflammation Arrest tumor cell growth Enhance sodium and water absorption Prevent bacterial translocation Modulate intestinal transit Bulk stools
INTESTINAL EFFECTS OF DIETARY FIBER AND SHORT-CHAIN FATTY ACIDS Dietary fiber affects the morphology and function of the gastrointestinal (Gl) tract (Table 14-3). Many of the physiologic effects of soluble dietary fiber appear to be mediated by its metabolic products, SCFAs. Soluble dietary fiber and SCFAs stimulate trophism of the intestinal mucosa, enhance sodium and water absorption in the colon, support a normal profile of indigenous bacteria, influence segmental motility of the gastrointestinal tract, and have anti-inflammatory and antineoplastic effects. Unfermented dietary fiber contributes to maintenance of the gut mucosal barrier and has water-holding capabilities that bulk stools, dilute intestinal contents, and normalize stool consistency and frequency.
Intestinal Trophic Effects Dietary fiber is essential in maintaining the normal structure and function of the intestine. Administration of total parenteral nutrition (TPN) or a fiber-free enteral formula results in atrophy of the intestinal mucosa and diminished intestinal function. 31.32 Including soluble dietary fiber in the diet stimulates mucosal hyperplasia. A diet supplemented with a purified source of pectin or germinated barley foodstuff induced hyperplastic changes in the small and large intestines of rats with normal or resected intestines compared with a fiber-free diet. 33-35 Measures of intestinal mucosal trophism showed greater villus height, crypt depth, mucosal mass, and DNA, RNA, and protein content. Germinated barley foodstuff, which is derived from the aleurone and scutellum fractions of germinated barley, is rich in low-lignified hemicellulose and fermented to SCFAs. SCFAs stimulate colonic mucosal growth and differentiation. They exert a dose-dependent stimulatory effect on the proliferation of the basal compartments of crypt cells in the following order of effectiveness: butyrate> propionate > acetate. Intracolonic infusions of SCFAs increased colonic mucosal height and DNA content in parenterally fed rats" and in cecectomized rats fed a fiber-free diet." The salutary effect of butyrate alone on colonic mucosal growth was as great as that with a combination of acetate, propionate, and butyrate." SCFAs enhance functional performance of the colonic mucosal epithelium in animals. Administered either via
intracolonic or enteral infusion, SCFAs resulted in a stronger colonic anastomosis and reduced spontaneous dehiscence in resected or ischemic colonic segments in rats.38.39 There was an increase in water absorption by the retained colonic segment of rats that underwent cecal resection and were fed fiber compared with those fed a fiber-free diet." The trophic effects of SCFAs are not confined to the colon. SCFAs retarded atrophy of the small intestinal mucosa associated with feeding an elemental, fiber-free enteral diet and after small bowl resection when total parenteral nutrition was administered. Changes induced by SCFAs included increases in villus height, crypt depth, mucosal weight, or DNA content in the jejunum and ileum. 41,42 Intestinal functional improvements, evidenced by increased ileal uptake of glucose, were seen in rats with extensive small bowel resection that were given SCFA-supplemented TPN.43 The enterotrophic effects of SCFAs are probably mediated by enhanced mesenteric blood flow and hormonal and neuronal mechanisms. SCFAs have a dose-dependent dilatory effect on colonic arteries that appears to be independent of the effects of other relaxants such as prostaglandins. SCFAs increase colonic blood flow in the colon of dogs and in the rectum of humans.r' Increases in plasma enteroglucagon and colonic tissue levels of peptide YY are associated with intestinal proliferation stimulated by fermentable soluble fiber.41,45 The autonomic nervous system mediates the trophic effects of cecal SCFAs on the jejunum. Extrinsic denervation of the rat cecum abolished the jejunotrophic effects of a cecal infusion of SCFAs, illustrating the importance of afferent innervation."
Anti-I nflam matory Effects Mucosal inflammation and damage is a hallmark of colonic diseases, such as ulcerative colitis and radiationinduced enterocolitis. The fiber fraction of germinated barley foodstuff and the SCFA, butyrate, have been shown to attenuate inflammatory mediators that may playa role in inflammatory diseases of the colon. In an animal model of colitis induced by dextran sulfate sodium, germinated barley foodstuff attenuated the activity of the transcription factor of the proinflammatory cytokine, nuclear factor K8, more so than cellulose or cellulose plus sulfasalazine." Sulfasalazine is part of the standard therapy for ulcerative colitis in humans. Some human studies report reductions in colonic mucosal inflammation and symptomatic improvement of ulcerative colitis in response to rectal irrigations of SCFAs.48 In isolated crypt cells, butyrate inhibited secretion of the proinflammatory cytokine, interleukin-8, which is enhanced in inflammatory bowel diseases."
Anti-Neoplastic Effects SCFAs modulate numerous cellular mechanisms including apoptosis (programmed cell death), cell differentiation, invasion and adherence, and cell gene cycles that
SECTION III • Nutrient Metabolism
may confer protection against cancer in the large intestine. Apoptosis is an important cell control mechanism for maintaining tissue homeostasis, eliminating damaged cells, preventing tumor progression, and determining response to therapy for cancer. The highly fermentable fiber, pectin, and the SCFAs, acetate, propionate, and butyrate, were capable of inducing apoptosis in colorectal tumor cells. 50,51 Butyrate has been shown to induce apoptosis at lower concentrations than other SCFAs.51 Although SCFAs stimulate proliferation of normal intestinal cells, they have an opposite effect in tumor cells. Butyrate arrests cell growth in various tumor cell llnes.P Cancer cells are often undifferentiated and have altered, uncontrolled patterns of proliferation outside the basal areas of the crypts. As normal colonocytes migrate from the lower crypts to the upper epithelial surface, they cease proliferating and fully differentiate. Butyrate promotes a physiologically normal pattern of proliferation in the lower zones of the crypts and potentiates differentiation of colonic cells in rats.52,53 SCFAtreated cells inhibited invasion and adherence by invasive human colon cancer cells. 54 Colon cells of the rat pretreated with butyrate were more resistant to DNA oxidative damage due to the genotoxic compound, hydrogen peroxide, than were nontreated cells." The mechanisms by which butyrate exerts its cellular effects are not well understood. Butyrate up-regulates the cell gene cycle inhibitor, p21, which may be one mechanism by which it inhibits the growth of colon cancer cells" and induces the acetylation of histones, which affects gene function." Treatment with butyrate stimulates transglutaminase activity, which appears to be involved in apoptosis and may promote remodeling of damaged tissue." Greater understanding of the role of dietary fiber and butyrate in the morphologic and functional changes that occur in normal versus adaptive or neoplastic processes is needed.
Effects on Sodium and Water Absorption SCFAs absorption is associated with water and electrolyte transport.P-" Butyrate is the most effective SCFA for stimulating absorption of water and sodium by colonocytes. SCFAs appear to be absorbed across the apical membrane in exchange for bicarbonate. Inside the colonocyte, protonated SCFAs dissociate and release hydrogen ions. The hydrogen ions are exchanged for sodium ions by an antiport mechanism. The absorption of sodium drags along water. Ionized SCFAs are partly recycled into the intestinal lumen in exchange for chloride. In addition to their proabsorptive properties, SCFAs appear to have antisecretory effects. An intracolonic infusion of SCFAs reversed the fluid secretion observed in the ascending colon of humans who were receiving intragastric tube feeding'" SCFAs inhibited chloride secretion mediated by adenosine cyclic 3':5'-monophosphate (cAMP) in rat colonocytes exposed to secretagogues such as cholera toxin."
163
Effects on Bacterial Growth and Pathogen Suppression Indigenous colonic bacteria interact with the human host to maintain colonic and systemic health. Bacteria constitute up to 55%of the dry weight of feces in persons ingesting a typical Western diet that contains approximately 10 to 20 g of mixed sources of dietary fiber. 62 Consumption of fermentable dietary fiber stimulates colonic bacterial growth. Increases in bacterial mass in healthy subjects and patients resulted from consumption of a single food source of fiber (e.g., cabbage), mixed food sources, or purified fiber sources, such as gum arabic or oat bran. 63-65 The amount and type of fiber substrate available and transit time determine fecal bacterial mass and composition. Fermentation of dietary fiber and production of SCFAs support a normal profile of bacteria in the colon. Colonic bacteria compete for nutrients and epithelial adherence. Some bacterial strains produce compounds that inhibit the growth of others. Clostridium difficile is the enteric pathogen most often responsible for infectious diarrhea in hospitalized patients. C. difficile is an opportunistic pathogen that causes clinical disease in some patients but not in others, and some strains appear to be more virulent than others. Ecologic factors within the gut appear significant in the establishment, proliferation, resistance, and clearance of C. difficile. SCFAs and an acidic pH suppressed C. difficile colonization and growth in vitro. 66,67 A direct correlation was found between clearance of C. difficile and a rise in SCFA concentrations in mice colonized with C. difficile whose diet was supplemented with fermentable wheat bran fiber.68 Hospitalized patients receiving a fiber-free formula via postpyloric tube feeding were three times as likely to acquire C. difficile organisms than non-tube-fed patients." A liquid enteral formula containing soy polysaccharide prolonged the survival of hamsters with experimental ileocecitis caused by C. difficile compared with a fiberfree formula.?"
Preventing Translocation of Bacteria and Mucosal Damage A defective intestinal mucosal barrier has been theorized to be partly responsible for several clinical problems including infections, sepsis, hypermetabolism after trauma, ulcerative colitis, radiation enteritis, and multiorgan failure syndrome. In susceptible individuals, increased intestinal permeability and diminished intestinal immune activity may lead to the translocation of pathogenic bacteria, toxins, and other antigenic substances and proteolytic enzymes from the intestinal lumen that can overwhelm host defense mechanisms, perpetuate inflammatory responses, or damage tissues. Dietary fiber and SCFAs are thought to be essential for maintaining an intact intestinal mucosa, containing bacteria and antigens within the intestinal lumen, and mounting an appropriate immune reaction. They have also been shown to
164
14. Non-Nutritive Supplements: Dietary Fiber
promote healing of injured intestinal tissues. Translocation of bacteria outside the intestine to lymph nodes, for example, was demonstrated in animals fed a parenteral nutrition formula (fiber-free) that was administered enterally or parenterally but not in those fed chow,?I.72 The nonfermentable fiber, cellulose, reduced ileal permeability and translocation of bacteria to mesenteric lymph nodes in rats." Intestinal mucosal damage associated with methotrexate-induced enteritisin rats was prevented by an enteral diet supplemented with the fermentable fibers pectin73 or germinated barley foodstuff."
Effects on Segmental Gastrointestinal Motility and Oral-Anal Transit Soluble fiber and SCFAs influence gastric and segmental intestinal transit in various animal models and humans in a manner that appears to optimize normal digestive and absorptive processes. Relaxation of the proximal stomach, which can slow transit through the stomach, occurred after intracolonic infusion of SCFAs, oral administration of lactulose or gastric administration of a mixed fiber diet (15 gil) containing 50% soluble fiber and 50% insoluble fiber in healthy volunteers.P:" Consumption of coarse bran slowed gastric emptying without affecting the motility of the fundus,suggestingaccumulation of the bran and chyme.I" Fibers that form gels, such as pectin, guar, and a chemically modified "liquid fiber," composed of the polysaccharide ethyl-hydroxyethylcellulose and the surfactant, sodium dodecyl sulfate, increased the viscosity of chyme and slowed gastric emptying. 79,BO The effects of dietary fiber on upper small intestinal transitseem related to the type of fiberconsumed. Coarse wheat bran, an insoluble fiber, as well as inert plastic particles accelerated small bowel transit in healthy volunteers." Stimulation of enteric nerves was proposed as a mechanism behind the faster transit.A liquid enteral diet composed of 50% soluble fiber and 50% insoluble fiber had no effect on duodenal motor activity in healthy volunteers." Conflicting results about the ability of soluble fibers, such as guar gum, to slow proximal intestinal transit have been reported. These varying responses seem to depend on the consistency of the meal (liquid or semisolid) to which the fiber was added and the dose, purity, and fermentability of the fiber source. 81.82 The potential clinical benefits of slowed gastric emptying and prolonged absorption are lowered postprandial serum glucose levels in diabetics and increased satiety and weight loss in obese patients.83-85 Findings from clinical studies of these metabolic effectsare still inconclusive. The motility effects of soluble fiber and SCFAsseem to be in concert with normal upper GI tract functions of mixing and digesting food and propelling it toward the large intestine. SCFAs stimulate ileal motility in the fasting and postprandial phases and promote propulsion and emptying of the distal ileum.86,87 The potency of SCFAs on ileal motility is concentration dependent and inversely related to their chain length."
Colonic transit time in rats is related to the fermentability of dietary fiber. The shortest transit times were found when rats were fed fibers that resist digestion, such as wheat bran or cellulose, and lengthened with the more fermentable fibers, oat bran, guar gum, and pectin." Colonic transit times were prolonged in humans consuming a liquid enteral diet supplemented with guar (21 g/L).82 Effects of SCFAs on colonic motility are unclear. SCFAs stimulated longitudinal contractions in isolated muscle strips of the mid and distal colon of the rat.90 When the whole intact or isolated colon was studied, SCFAs decreased colonic motility" or had no effect.92 Colonic transit time has implications for the extent and rapidity of dietary fiber fermentation and the turnover of colonic bacteria. Oral-anal transit time in healthy human volunteers appears to be influenced by the type of dietary fiber. A fiber-free liquid diet was associated with slow transit." Transit time was unaffected by liquid diets supplemented with different amounts of soy polysaccharide.17,93 Dietary fibers that resist complete or rapid fermentation, such as wheat bran or ispaghula, accelerated oral-anal transit time."
Effects on Stool Weight Insoluble dietary fiber as well as soluble fibers that are moderately or poorly fermented increase stool weight and bulk. The increase in stool bulk is thought to be a result of the residual, unfermented fiber as well as waterholding or gel formation by the unfermented fiber. Increases in bacterial mass make appreciably smaller contributions to wet stool weight. A fiber-free liquid diet is associated with low fecal output in man." A fiber such as wheat bran that is only 56% fermented increased stool weight primarily owing to residual plant fiber." Guar, a rapidly and completely fermented fiber, did not increase stool output." Liquid enteral formulas supplemented with soy polysaccharide or a mix of soluble fibers result in stool weights that do not differ appreciably from those of a self-selected Western diet." Unfermented fiber is thought to form a matrix in feces that traps water. Evidence presented for a fiber-stool matrix includes retention of the viscosity of fiber solutions after they had been fermented in vitro, greater viscosityof feces, and higher water-holdingcapacity of stool solids.98,99 Psyllium was shown to increase the waterholding capacity of stool solids in patients who were incontinent of loose/liquid stool'P' and in normal subjects who had diarrhea induced by phenolthalein.'?' Dietary fibers that retain some water-holding capacity after they are fermented tend to produce larger stools.102 Consumption of wheat bran increases the wet weight of stool and dilutes intestinal markers.P Water holding appears to contribute to stool bulk and normal stool consistency. Gel formation may be another mechanism by which dietary fiber bulks stools. Gel formation was proposed to explain an increase in the weights of wet stool and the
SECTION III • Nutrient Metabolism
soluble fraction of stool after a mixed fiber source was consumed and the water-holding capacity of insoluble stool solids was low.103 A gelatinous fraction of feces was observed after a supplement of psyllium, a moderately fermentable fiber, was consumed but not after consumption of an unsupplemented basal diet.'?' Stool weight increased, and an aqueous extract of the stools had a greater viscosity after the psyllium was ingested.
CLINICAL APPLICATIONS OF DIETARY FIBER AND SCFAs Therapy for Ulcerative Colitis Ulcerative colitis (UC) is a form of inflammatory bowel disease that can affect only the distal rectum or the entire colon; its cause is unknown. Ulcerative colitis is characterized by diarrhea, rectal bleeding, abdominal pain, fever, protein-energy malnutrition, weight loss, and sigmoidoscopic and histologic abnormalities. Standard treatment of UC with 5-aminosalicylic acid or steroids results in clinical improvement in up to 80% of patients and remission in up to 50%.105 Reduced butyrate oxidation in colonic mucosal cells and elevated luminal levels of SCFAs in patents with ulcerative colitis prompted Roediger and colleagues" to propose that UCrepresents an energy-deficient condition of colonocytes. Conflicting findings of normal and low levels of luminal SCFAs in UC have been reported by others. 106,107 SCFA levels may be related to severity of UC because butyrate was increased in quiescent UC but not in more severe disease.!" The trophic and anti-inflammatory effects of SCFAs reported in animals supported the investigation of SCFAs as an adjunctive topical therapy for inflammatory bowel disease, such as distal UC. SCFA enemas offer a treatment option that is inexpensive and associated with few adverse side effects. Initial clinical studies of SCFA or butyrate irrigations for UC suggested efficacy, but their methods were not well controlled or rigorous. These studies were open label and did not include a placebo group, included small numbers of patients whose UC was refractory to standard therapy, and allowed use of concomitant antiinflammatory medications. Randomized clinical trials show equivocal outcomes for symptomatic, endoscopic, and histologic measurements. The methods of the controlled studies varied in the formulations and timing of the SCFAs administered, the severity of disease of the enrolled subjects, and the continued use of concomitant anti-inflammatory medications." The trends in outcomes of these studies encourage additional research, but routine clinical use of colonic SCFA irrigations as adjunctive or initial therapy cannot be recommended at this time. The fibers, Plantago ovata and germinated barley foodstuff, have been examined for their potential use as a therapy for Uc. P. ovata seeds (20 g/day) were as effective as the anti-inflammatory medication mesalamine or mesalamine plus P. ovataseeds in maintaining remission of UC after 12 months. lOB In an open-label pilot study, patients with UC were observed to have improvements
165
in their clinical status and in an endoscopically determined index of mucosal inflammation after taking 30 glday of germinated barley foodstuff. Clinical symptoms relapsed after the fiber was discontlnued.l'"
Therapy to Stimulate Intestinal Adaptation and Strengthen the Gut Barrier The enterotropic effects of fermentable dietary fiber and SCFAs reported in numerous animal studies suggest that there may be a potential benefit from their use in patients with short bowel syndrome or those receiving long-term TPN, which is characterized by intestinal atrophy. Short bowel syndrome (SBS) results from extensive surgical resection of the intestines and is characterized by malabsorption, diarrhea, protein depletion, and weight loss. Intestinal adaptation is the process describing the morphologic and functional changes in the remaining bowel, which eventually increase nutrient, electrolyte, and fluid absorption. Few clinical studies of stimulation of the adaptive proliferation of the intestine with diet or dietary fiber have been conducted. Patients with SBS and their colon in continuity were found to ferment a greater amount of lactulose, have higher l3-galactosidase activity and fecal bacterial mass, and excrete a lower amount of fecal SCFAs than normal persons. 110 Resultssuggest that colonic bacteria in SBS salvage unabsorbed carbohydrates that may provide additional energy in the form of SCFAs for cells undergoing adaptation. Elderly patients receiving long-term TPN who were intragastricallyfed a semidigested diet supplemented with 7 g of galactomannan per day, a liquid-soluble fiber, showed signs of intestinal mucosal trophism. Serum diamine oxidase activity, which is an index of morphologic change in the small intestinal mucosa, increased between 2 and 4 weeks after administration of galactomannan and decreased after the fiber was discontinued.!" The improvements in stool consistency, frequency, and water content seen with galactomannan were reversed when the fiber was discontinued. Based on the theory of gut failure and bacterial translocation, a few studies have investigated whether enteral feedings containing dietary fiber reduce the incidence of systemic infections. Lower infection rates were reported in patients who underwent major abdominal surgery and received an enteral diet supplemented with a mixture of soluble and insoluble dietary fiber (15 giL) and live Lactobacillus organisms compared with those receiving a diet with heat-killed Lactobacillus or a fiberfree enteral or parenteral diet.!" Similarly, reduced infection rates were found in liver transplantation patients receiving the fiber and Lactobacillus supplernents.!"
Protection Against Cancer Some epidemiologic studies suggest that high-fiber diets prevent colon cancer whereas others do not support this
166
14. Non-Nutritive Supplements: Dietary Fiber
association. 114,115 Both dietary fiber and SCFAs are thought to protect against intestinal cancer but through different effects. Fiber that resists fermentation increases stool water content and thereby can dilute carcinogens and tumor promoters, such as bile acids and ammonia, reducing their potency. Acceleration of intestinal transit by fiber, such as wheat bran, potentially reduces the time for carcinogenic substances to be in contact with the colonic epithelium. The SCFA, butyrate, generated from fiber fermentation has anticarcinogenic effects on cell differentiation, apoptosis, and tumor cell growth. A clinical trial of the incidence of adenomatous polyps as a marker of cancer risk in subjects consuming a low-fat, high-fiber diet did not support a protective effect of diet.116 More studies are clearly needed to determine whether the hypothesized antineoplastic effects of dietary fiber and SCFAs and those demonstrated in vitro and in animals provide protection against colon cancer in humans.
Relief of Constipation Dietary fiber has become a standard component of clinical recommendations to prevent and treat chronic constipation. Constipation is commonly defined in terms of a low frequency of defecation and/or hard stool consistency with excessive straining. Constipation is a problem in patients who have limited ambulation and are exclusively fed fiber-free liquid enteral diets long term: The basis of the clinical recommendations relate to the ability of dietary fiber to increase intestinal transit, hold water, and increase stool bulk to stimulate voluntary defecation. The desired effects of fiber intake are to maintain a normal bowel elimination pattern without laxatives and, if necessary, to stimulate more frequent defecation, soften stools, and reduce discomfort associated with constipation. A reduction in laxative use is another outcome in clinical studies. Clinical studies for treating constipation have included fibers such as wheat bran, com bran, psyllium, ispaghula, glucomannan, calcium polycarbophil, and soy polysaccharide to supplement enteral liquid formulas. Colonic transit in response to fiber supplementation has been varied. The average colonic transit time in a group of community-living elderly people who were constipated was faster after a daily supplement of 24 g of psyllium.!" Smaller amounts of feces were excreted more often. In patients with spinal cord injuries in whom
colorectal transit was slowed, bran cereal, which increased the mean dietary fiber intake by 6 g/day for a total of 31 g/day, was ineffective as a treatment for constipation and actually prolonged transit through the colon and rectum. us The soluble dietary fiber, glucomannan (200 mg/kg), increased stool frequency without having any effect on the colonic transit in neurologically impaired children compared with their typical semiliquid diet of pureed food and formula. I 19 The conclusions of recent systematic reviews of controlled clinical studies of the effectiveness of dietary fiber to manage constipation in adults and older institutionalized persons was that the evidence is contradictory, and no definitive recommendations are possible.120,121
Reduction of Diarrhea Dietary fiber has been studied for its antidiarrheal effects during tube feeding, oral rehydration, inflammatory bowel disease, and fecal incontinence. One of the antidiarrheal effects of dietary fiber appears to be a firming of loose or liquid stool consistency. There may be several mechanisms underlying improvements in stool consistency and diarrhea, depending on the type of fiber consumed (Fig. 14-4). Soluble dietary fiber that resists complete fermentation may form a more gelatinous stool by holding water in a matrix of fiber and feces. Fermentation of dietary fiber yields SCFAs whose absorption stimulates sodium and water absorption. The absorptive capability of the colonic epithelium may be enhanced by metabolism of SCFAs. Bacteria sequester stool water and their proliferation is supported by SCFA metabolism. A variety of dietary fibers including pectin, banana flakes that contain pectin, psyllium, partially hydrolyzed guar gum, ispaghula husk, liquid galactomannan, soy polysaccharide, and oat fiber have been investigated for their effects on stool consistency and diarrhea in normal subjects and patients receiving liquid enteral diets. Nine randomized, controlled studies were conducted in tubefed patients to compare the effects of a fiber-free liquid enteral formula and an enteral formula with supplemental fiber (Table 14-4) in which diarrhea was measured as an outcome. In two studies, dietary fiber was administered separate from the enteral formula. 122,123 Dietary fiber was used to treat diarrhea in one stud yl23 and to prevent it in the others. Patients in an intensive care unit comprised all or the majority of subjects in five of the studies. 97,122-125
FIGURE 14-4. Effects of dietary fiber and shortchain fatty acids (SCFAs) that promote firmer stool consistency and may reduce diarrhea.
28
491CU and hospitalized patients
100 hospitalized patients
80 patients after head and neck surgery
311CU patients receiving full strength, fiber-free tube feeding formulas
16 postsurgery patients
251CU patients
Shankardass et al, 1990126
Heather et ai, 1991122
Homann et al, 199415
Reese et ai, 1996127
Emery et ai, 1997123
Khalil et ai, 1998128
Spapen et aI, 2001 16
Randomized
Randomized
Randomized double-blinded
Randomized double-blinded
Randomized
Randomized double-blinded cross-over
Randomized double-blinded
911CU patients
Dobb and Towler, 1990124
hospitalized patients
Randomized double-blinded cross-over
91CU patients
Frankenfield and Beyer, 198997
Study
Design
Partially hydrolyzed guar in Benefiber 22 gil
Soy polysaccharide in Ultracal" 1.44 g/100 mL
Banana flakes 3-24 tbsp/day containing 0.5 g flber/tbsp of which 0.2 g/tbsp is pectin as a treatment for diarrhea
Soy polysaccharide 14 gil in Jevity" or soy polysaccharide 7 gjL in one-half Jevity" and one-half Osmolite HN®l
Partially hydrolyzed guar gum in Sunfiber 20 gfL
Psyllium in Hydrocil 15 mL/day; amount of psyllium per mL was not reported
Soy polysaccharide 19.2 gil in Enrich"
Soy polysaccharide 21 gil in Enrich"
Soy polysaccharide 14 gil in Enrich"
Flber Source
Fiber-free isonitrogenous liquid formula (unspecified brand)
Isocal"
10 days
3-7 days
Not specified
Osmolite HNTM
Antidiarrheal medications and changes in tube feeding rate
5-10 days
26-week periods in cross-over design At least 6 days
Up to 15 days
4-6 days
Duration
Nutrodrip Standard
Osmollte", lsocal", lsocal" HCN
Ensure"
Ensure"
Ensure"
Comparison
Randomized. Controlled Clinical Studies of Fiber Supplementation in Tube-Fed Patients
N
·"aM'1I
Stool frequency ~3 times/day and stool consistency that was pasty, semiwatery, or watery Diarrhea score ~12 using frequency, consistency, and volume scales
Diarrhea scores >12 using stool frequency, consistency, and volume scales
liquid stools/day totaling ~500 mL
~3
No diarrhea definition; a mean stool consistency score and frequency score were calculated >3 liquid stools in 12 hours
Stool weight >300 g/day or watery stool consistency (score >12) or stool frequency >3 times/day Diarrhea score >12 using stool frequency, consistency, and volume scales ~3 liquid stools/day
Definition of Diarrhea
Fewer diarrhea days and lower diarrhea scores with fiber formula
No difference in mean stool frequency or consistency scores
Diarrhea incidence was similar between fiber formulas; multiple logistic regression showed diarrhea was more likely to occur in males receiving a fiber-free formula Incidence of diarrhea was lower on day 7, last study day, in patients treated with fiber
Lower incidence of diarrhea with fiber formula
Firmer stool consistency (i.e.. higher consistency scores) with fiber
Lower incidence of diarrhea with fiber formula
No difference in diarrhea incidence or 9{, of diarrhea days
No difference in diarrhea incidence or stool consistency score
Flndings
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-
3
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2-
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III
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168
14 • Non-Nutritive Supplements: Dietary Fiber
Sample sizes ranged from 9 to 100 patients. Soy polysaccharide was the fiber source in five of the studies.97,124,126-128 There were seven definitions of diarrhea among the nine studies, and one study did not provide a definition of diarrhea. 122 The findings that fiber prevented diarrhea in tube-fed patients were not consistent. There was a lower incidence of diarrhea after 1 week in patients who received banana flakes compared to those receiving antidiarrheal medications in the one treatment study. 123 An oral rehydration solution (ORS) is commonly used for children and adults with acute, profuse diarrhea that can result in dehydration. Acute diarrhea may be the result of infectious diseases such as cholera. ORSs containing glucose and other solutes stimulate the absorption of water from the small intestine and correct fluid losses but do not always reduce diarrhea. Improvements of oral rehydration solutions that reduce diarrhea through colonic salvage of water and electrolytes have been sought to promote greater acceptance of this therapy. A meta-analysis of studies of ORSs containing rice cereal showed that the volume of liquid fecal output was reduced by approximately 30% in patients with cholera.!" Recent randomized clinical trials have reported reductions in diarrhea from cholera and other causes using an oral rehydration solution containing partially hydrolyzed guar gum, green banana or pectin, or amylase resistant starch. Compared with a standard ORS, an ORS containing partially hydrolyzed guar gum (20 giL) administered to children with acute, non-cholerarelated diarrhea shortened the duration of diarrhea.P" Both pectin (4 g/kg) and green banana (250 gIL) mixed in an isocaloric rice-based diet reduced stool volume, shortened the duration of diarrhea, decreased the amount of intravenous fluid needed, and improved stool consistency in children hospitalized for rehydration therapy compared with the effects of the rice diet alone.!" Similar improvements were seen in adolescents and adults with cholera treated with resistant starch (50 gIL) in an ORS than in those treated with a standard ORS or an ORScontaining rice-flour (50 g/L).132
and administration through feeding tubes may lessen its effectiveness.
ADMINISTERING FIBER-CONTAINING FORMULAS VIA FEEDING TUBES Feeding tube patency is a practical concern when fibersupplemented liquid formulas are administered. The use of feeding tubes with an internal diameter of 10 F or greater is recommended. Many patients requiring fibersupplemented liquid formulas are fed with the aid of a feeding pump, but these formulas can be delivered successfully by drip feeding. If fiber supplements are delivered by a feeding catheter separately from liquid formulas, the catheter should be flushed with 60 mL of water after each dose. Flushing the catheter with 120 to 240 mL of water three times daily will provide additional fluid when it is indicated and also be helpful for maintaining tube patency. Additional complications of fiber-supplemented liquid formulas are bloating, flatulence, bezoar formation, and fecal impaction. Although some patients may experience bloating and flatulence with fiber-supplemented formulas, reduced doses should be tried before fiber-free diets are administered. Significant abdominal distension is a contraindication to receiving fiber-supplemented liquid formulas. Ileus, obstruction, or other serious GI problems should be treated before feeding is reinstituted. Bezoar formation is extremely rare and, like impaction, is associated with inadequate fluid intake and immobility. Careful monitoring for stool output, a gradual increase in fiber dose, adequate fluid intake, and periodic flushing of feeding catheters should reduce the likelihood of complications. If a standard feeding protocol is followed and regular GI assessment is performed, fibersupplemented enteral formulas can be safely administered to hospitalized patients.
CONCLUSION LIMITATIONS OF SOME CLINICAL STUDIES Clinical studies of the effects of dietary fiber often have methodologic limitations that warrant caution in interpreting and generalizing their findings. Several of the studies have been conducted in small groups of patients. Whether certain subgroups of patients are more likely to show a favorable response to dietary fiber has not been determined. Male tube-fed patients were observed to have lower rates of diarrhea when they received fibercontaining formulas than female patients. 127 With crossover designs there is a risk of cumulative or carryover effects. Because the definition of diarrhea influences outcomes, conclusions need to be interpreted in light of the stringency of the definition used.!" In shortterm studies, the full physiologic effects of fiber may not become apparent during the brief study period. The formulation of dietary fiber for inclusion in liquid formulas
The therapeutic applications of dietary fiber for health problems continue to be developed and investigated. Preliminary findings are encouraging in some areas. There seems to be a physiologic rationale to include dietary fiber as a component of dietary intake. In vitro and animal research has increased our knowledge of the properties, safety, and potential health benefits of dietary fiber. Clinical studies suggest that the human response to dietary fiber is complex and varied. Evidence from rigorous clinical investigations is still needed to support many clinical practices in which dietary fiber is used. REFERENCES 1. Cho S, DeVries JW. Prosky L: Dietary Fiber Analysis and Applications, Gaithersburg, MD, AOAC International, 1997. 2. Van Soest PJ: Symposium on nutrition and forage and pastures: New chemical procedures for evaluating forages. J Anim Sci 1964;23:838-845.
SECTION III • Nutrient Metabolism 3. Trowell H, Southgate DA, Wolever TM, et al: Letter: Dietary fibre redefined. Lancet 1976;1:967. 4. Bacic A, Harris PJ, Stone BA: Structure and function of plant cell walls. In PreissJ (ed): Biochemistry of Plants: Carbohydrates, San Diego, CA, Academic Press, 1988,Vol. 14, p 529. 5. Boudet AM, Lapierre C, Grima-Pettenati J: Biochemistry and molecular biology of lignification. New Phytol 1995;129:203-236. 6. Casler MD, Jung HG: Selection and evaluation of smooth bromegras clones with divergent lignin and etherified ferulic acid concentration. Crop Sci 1999;39:1866-1873. 7. Jung HG, Deetz DA: Cell wall lignification and degradability. In Jung HG, et al (eds): Forage Cell Wall Structure and Digestibility. Madison, WI, American Society of Agronomy, 1993,pp 315-346. 8. Prosky L, Asp NG, Schweizer TF, et al: Determination of insoluble, soluble, and total dietary fiber in foods and food products: Interlaboratory study. J Assoc Offic Anal Chemists 1988;71: 1017-1023. 9. Theander 0, Aman P, Westerlund E, et al: Total dietary fiber determined as neutral sugar residues, uronic acid residues, and Klason lignin (the Uppsala method): Collaborative study. J AOAC fnt 1995; 78:1030-1044. 10. Ranhotra GS, Gelroth JA, Astroth K: Total and soluble fiber in selected bakery and other cereal products. Cereal Chern 1990; 67:499-501. 11. Marlett JA: Content and composition of dietary fiber in 117 frequently consumed foods. J Am Oil Assoc 1992;92: 175-186. 12. Marlett JA, Vollendorll NW: Dietary fiber content and composition of vegetables determined by two methods of analysis. J Agric Food Chern 1993;41:1608-1612. 13. Fredstrom SB, Baglien KS, Lampe JW, et al: Determination of the fiber content of enteral feedings. JPEN J Parenter Enteral Nutr 1991; 15:450-453. 14. Bourquin LD, Titgemeyer EC, Fahey GC Jr, et al: Fermentation of dietary fibre by human colonic bacteria: Disappearance of, shortchain fatty acid production from, and potential water-holding capacity of, various substrates. Scand J Gastroenterol 1993;28:249-255. 15. Homann HH, Kernen M, Fuessenich C, et al: Reduction in diarrhea incidence by soluble fiber in patients receiving total or supplemental enteral nutrition. JPEN J Parenter Enteral Nutr 1994;18: 486-490. 16. Spapen H, Diltoer M, Van Malderen C, et al: Soluble fiber reduces the incidence of diarrhea in septic patients receiving total enteral nutrition: A prospective, double-blind, randomized, and controlled trial. Clin Nutr 2001;20:301-305. 17. Slavin JL, Nelson NL, McNamara EA, et al: Bowel function of healthy men consuming liquid diets with and without dietary fiber. JPEN J Parenter Enteral Nutr 1985;9:317-321. 18. Behall KM, Howe JC: Contribution of fiber and resistant starch to metabolizable energy. Am J Clin Nutr 1995;62:11585-1160S. 19. Duncan SH, Scott KP, Ramsay AG, et al: Effects of alternative dietary substrates on competition between human colonic bacteria in an anaerobic fermentor system. Appl Environ Microbiol2003; 69:1136-1142. 20. White BA, Mackie RI, Doerner KC: Enzymatic hydrolysis offorate cell walls. In Jung HG, et al (eds): Forage Cell Wall Structure and Digestibility. Madison, WI, ASA-CSSA-SSSA, 1993, pp 455-484. 21. Kirk TK, Farrell RL: Enzymatic "combustion": The microbial degradation of lignin. Annu Rev Microbiol 1987;41:465-505. 22. Finegold SM, Sutter VL, Mathisen GE: Normal indigenous intestinal flora. In Hentges DJ (ed): Human Intestinal Microflora in Health and Disease. New York, Academic Press, 1983, pp 3-31. 23. Macfarlane GT, McBain AJ: The human colonic microbiota. In Gibson GR, Roberfroid MB (eds): Colonic Microbiota, Nutrition and Health. Dordrecht, The Netherlands, Kluwer Academic Press, 1999, pp 1-25. 24. Mertens DR: Kinetics of cell wall digestion and passage in ruminants. In Jung HG, et al (eds): Forage Cell Wall Structure and Digestibility. Madison, WI, ASA-eSSA-SSSA, 1993, pp 535-570. 25. Hatfield RD, Weimer PJ: Degradation characteristics of isolate and in situ cell wall Lucerne pectic polysaccharides by mixed ruminal microbes. J Sci Food Agric 1995;69:185-196. 26. Cummings JH: Consequences of the metabolism of fiber in the human large intestine. In Vahouny GV, Kritchevsky D (eds): Dietary Fiber in Health and Disease.New York, Plenum Press, 1982, pp 9-22.
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27. Lu ZX, Gibson PR, Muir JG, et al: Arabinoxylan fiber from a byproduct of wheat flour processing behaves physiologically like a soluble, fermentable fiber in the large bowel of rats. J Nutr 2000; 130:1984-1990. 28. Cook SI, Sellin JH: Review article: Short chain fatty acids in health and disease. Aliment Pharmacol Ther 1998;12:499-507. 29. Roediger WE, Rae DA: Trophic effect of short chain fatty acids on mucosal handling of ions by the defunctioned colon. Br J Surg 1982;69:23-25. 30. Roediger WE, Heyworth M, Willoughby P, et al: Luminal ions and short chain fatty acids as markers of functional activity of the mucosa in ulcerative colitis. J Clin Pathol 1982;35:323-326. 31. Morin CL, Ling V, Bourassa D: Small intestinal and colonic changes induced by a chemically defined diet. Dig Dis Sci 1980;25:123-128. 32. Koruda MJ, Rolandelli RH, Bliss DZ, et al: Parenteral nutrition supplemented with short-ehain fatty acids: Effect on the small-bowel mucosa in normal rats. Am J Clin Nutr 1990;51:685-689. 33. Andoh A, Fujiyama Y, Hata K, et al: Counter-regulatory effect of sodium butyrate on tumour necrosis factor-alpha (TNF-alpha)induced complement C3 and factor B biosynthesis in human intestinal epithelial cells. Clin Exp Immunol 1999;118:23-29. 34. Kanauchi 0, Agata K, Fushiki T: Mechanism for the increased defecation and jejunum mucosal protein content in rats by feeding germinated barley foodstuff. Biosci Biotechnol Biochem 1997;61: 443-448. 35. Koruda MJ, Rolandelli RH, Settle RG, et al: The effect of a pectinsupplemented elemental diet on intestinal adaptation to massive small bowel resection. JPEN J Parenter Enteral Nutr 1986;10: 343-350. 36. Friedel D, Levine GM: Effect of short-ehain fatty acids on colonic function and structure. JPENJ Parenter Enteral Nutr 1992;16:1-4. 37. Kripke SA, Fox AD, Berman JM, et al: Stimulation of intestinal mucosal growth with intracolonic infusion of short-ehain fatty acids. JPENJ Parenter Enteral Nutr 1989;13:109-116. 38. Topcu 0, Karaday K, Kuzu MA, et al: Enteral and intraluminal shortchain fatty acids improves ischemic left colonic anastomotic healing in the rat. 1ntJ Colorectal Dis 2002;17:171-176. 39. Rolandelli RH, Koruda MJ, Settle RG, et al: Effects of intraluminal infusion of short-ehain fatty acids on the healing of colonic anastomosis in the rat. Surgery 1986;100:198-204. 40. Kelberman I, Cheetham BC, Rosenthal J, et al: Effect of fiber and its fermentation on colonic adaptation after cecal resection in the rat. JPENJ Parenter Enteral Nutr 1995;19:100-106. 41. Andoh A, Bamba T, Sasaki M: Physiological and anti-inflammatory roles of dietary fiber and butyrate in intestinal functions. JPEN J Parenter Enteral Nutr 1999;23:S70-S73. 42. Koruda MJ, Rolandelli RH, Settle RG, et al: Effect of parenteral nutrition supplemented with short-ehain fatty acids on adaptation to massive small bowel resection. Gastroenterology 1988;95: 715-720. 43. Tappenden KA, Thomson AB, Wild GE, et al: Short-ehain fatty acidsupplemented total parenteral nutrition enhances functional adaptation to intestinal resection in rats. Gastroenterology 1997; 112: 792-802. 44. Mortensen FV, Hessov I, Birke H, et al: Microcirculatory and trophic effects of short chain fatty acids in the human rectum after Hartmann's procedure. Br J Surg 1991;78:1391-1394. 45. Goodlad RA, Lenton W, Ghatei MA, et al: Proliferative effects of "fibre" on the intestinal epithelium: Relationship to gastrin, enteroglucagon and PYV. Gut 1987;28:573-582. 46. Frankel WL, Zhang W, Singh A, et al: Mediation of the trophic effects of short-ehain fatty acids on the rat jejunum and colon. Gastroenterology 1994;106:375-380. 47. Kanauchi 0, Iwanaga T, Mitsuyama K, et al: Butyrate from bacterial fermentation of germinated barley foodstuff preserves intestinal barrier function in experimental colitis in the rat model. J Gastroenterol HepatoI1999;14:880-888. 48. Cummings JH: Short-ehain fatty acid enemas in the treatment of distal ulcerative colitis. Eur J Gastroenterol Hepatol 1997;9: 149-153. 49. Gibson P, Rosella 0: Interleukin 8 secretion by colonic crypt cells in vitro: Response to injury suppressed by butyrate and enhanced in inflammatory bowel disease. Gut 1995;37:536-543. 50. Avivi-Green C, Polak-Charcon S, Madar Z, et al: Apoptosis cascade proteins are regulated in vivo by high intracolonic butyrate
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74. Kanauchi 0, Mitsuyama K, Saiki T, et al: Preventive effects of germinated barley foodstuff on methotrexate-induced enteritis in rats. Int J Mol Med 1998;1:961-966. 75. Cherbut C, Aube AC, Blottiere HM, et al: Effects of short-ehain fatty acids on gastrointestinal motility. Scand J Gastroenterol Suppl 1997;222:58-61. 76. Bouin M, Savoye G, Maillot C, et al: How do fiber-supplemented formulas affect antroduodenal motility during enteral nutrition? A comparative study between mixed and insoluble fibers. Am J Clin Nutr 2000;72:1040-1046. 77. Ropert A, Cherbut C, Roze C, et al: Colonic fermentation and proximal gastric tone in humans. Gastroenterology 1996;111:289-296. 78. Mclntyre A, Vincent RM, Perkins AC, et al: Effect of bran, ispaghula, and inert plastic particles on gastric emptying and small bowel transit in humans: The role of physical factors. Gut 1997;40:223-227. 79. Schonfeld J, Evans DF, Wingate DL: Effect of viscous fiber (guar) on postprandial motor activity in human small bowel. Dig Dis Sci 1997;42:1613-1617. 80. Tomlin J, Brown N, EllisA, et al: The effect of liquid fibre on gastric emptying in the rat and humans and the distribution of small intestinal contents in the rat. Gut 1993;34:1177-1181. 81. van Nieuwenhoven MA, Kovacs EM, Brummer RJ, et al: The effect of different dosages of guar gum on gastric emptying and small intestinal transit of a consumed semisolid meal. J Am Coli Nutr 2001;20:87-91. 82. Meier R, Beglinger C, Schneider H, et al: Effect of a liquid diet with and without soluble fiber supplementation on intestinal transit and cholecystokinin release in volunteers. JPEN J Parenter Enteral Nutr 1993;17:231-235. 83. Blackburn NA, Redfern JS, Jarjis H, et al: The mechanism of action of guar gum in improving glucose tolerance in man. Clin Sci (Land) 1984;66:329-336. 84. Pasman WJ, Saris WH, Wauters MA, et al: Effect of one week of fibre supplementation on hunger and satiety ratings and energy intake. Appetite 1997;29:77-87. 85. Oufir LE, Barry JL, Flourie B, et a1: Relationships between transit time in man and in vitro fermentation of dietary fiber by fecal bacteria. Eur J Clin Nutr 2000;54:603-609. 86. Fich A, Phillips SF, Hakim NS,et al: Stimulation of ileal emptying by short-ehain fatty acids. Dig Dis Sci 1989;34:1516-1520. 87. Cherbut C, Aube AC,Blottiere HM, et al: In vitro contractile effects of short chain fatty acids in the rat terminal ileum. Gut 1996;38:53-58. 88. Edwards CA:Short chain fatty acids: Production and effects on gut motility. In Kritchevsky D, Bonfield C (eds): Dietary Fiber in Health and Disease, New York, Plenum Press, 1997. 89. Lupton JR, Turner ND: Potential protective mechanisms of wheat bran fiber. Am J Med 1999;106:245-27S. 90. Yajima T: Contractile effect of short-ehain fatty acids on the isolated colon of the rat. J Physiol (Land) 1985;368:667-678. 91. Squires PE, Rumsey RD, Edwards CA, et al: Effect of short-ehain fatty acids on contractile activity and fluid flow in rat colon in vitro. Am J PhysioI1992;262:G813-G817. 92. Flourie B, Phillips S, Richter H 3rd, et al: Cyclic motility in canine colon: Responses to feeding and perfusion. Dig Dis Sci 1989;34: 1185-1192. 93. Kapadia SA, Raimundo AH, Grimble GK, et al: Influence of three different fiber-supplemented enteral diets on bowel function and short-ehain fatty acid production. JPEN J Parenter Enteral Nutr 1995;19:63-68. 94. Eastwood MA, Smith AN, Brydon WG, et al: Comparison of bran, lspaghula, and lactulose on colon function in diverticular disease. Gut 1978;19:1144-1147. 95. Chen HL, Haack VS, Janecky CW, et al: Mechanisms by which wheat bran and oat bran increase stool weight in humans. Am J Clin Nutr 1998;68:711-719. 96. Edwards CA, Eastwood MA: Caecal and faecal short-ehain fatty acids and stool output in rats fed on diets containing non-starch polysaccharides. Br J Nutr 1995;73:773-781. 97. Frankenfield DC, Beyer PL: Soy-polysaccharide fiber: Effect on diarrhea in tube-fed, head-injured patients. Am J Clin Nutr 1989;50:533-538. 98. Tomlin J, Read NW:The relation between bacterial degradation of viscous polysaccharides and stool output in human beings. Br J Nutr 1988;60:467-475.
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99. Daly J, Tomlin J, Read NW: The effect of feeding xanthan gum on colonic function in man: Correlation with in vitro determinants of bacterial breakdown. Br J Nutr 1993;69:897-902. 100. Bliss DZ, Jung HG, Savik K, et al: Supplementation with dietary fiber improves fecal incontinence. Nurs Res 2001;50:203-213. 101. Wenzl HH, Fine KD, Schiller LR, et al: Determinants of decreased fecal consistency in patients with diarrhea. Gastroenterology
the combined analysis of 13 case-eontrol studies. J Nat! Cancer Inst 1992;84:1887-1896. 116. McKeown-EyssenGE,Bright-SeeE, Bruce WR, et al: A randomized trial of a low fat high fibre diet in the recurrence of colorectal polyps. Toronto Polyp Prevention Group. J Clin Epidemiol
1994;47:525-536. 117. Cheskin W, Kamal N, Crowell MD, et al: Mechanisms of constipa-
1995; 108: 1729--1738. 102. McBurney MI, Horvath PJ, Jeraci JL, et al: Effect of in vitro fermentation using human faecal inoculum on the water-holding capacity of dietary fibre. Br J Nutr 1985;53:17-24. 103. Forsum E, Eriksson C, Goranzon H, et al: Composition of faeces from human subjects consuming diets based on conventional foods containing different kinds and amounts of dietary fibre. Br J Nutr 1990;64:171-186. 104. Marlett JA, Kajs TM, Fischer MH: An unfermented gel component of psyllium seed husk promotes laxation asa lubricant in humans. Am J Clin Nutr 2000;72:784-789. 105. Marshall JK, Irvine EJ: Rectal corticosteroids versus alternative treatments in ulcerative colitis: A meta-analysis. Gut 1997;40:
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409--413. 123. Emery EA, Ahmad S, Koethe JD, et al: Banana flakes control diarrhea in enterally fed patients. Nutr Clin Prac 1997;12:72-75. 124. Dobb GJ, Towler SC:Diarrhoea during enteral feeding in the criti-
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754-759. 126. Shankardass K, Chuchmach S, Chelswick K, et al: Bowel function
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609-615. 113. Rayes N, Seehofer D, Hansen S, et al: Early enteral supply of
Lactobacillus and fiber versusselective bowel decontamination: A controlled trial in liver transplant recipients. Transplantation
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31:503-507. 131. Rabbani GH, Teka T, Zaman B, et al: Clinical studies in persistent diarrhea: Dietary management with green banana or pectin in Bangladesh children. Gastroenterology 2001;121:554-560. 132. Ramakrishna BS, Venkataraman S, Srinivasan P, et al: Amylaseresistant starch plus oral rehydration solution for cholera. N Engl J Med 2000;342:308-313. 133. Lebak KJ, Bliss DZ, Savik K, et al: What's new on defining diarrhea in tube-feeding studies? Clin Nurs Res 2003; 12:174-204.
Nutrition and Wound Healing Jeremy Z. Williams, MD Julie E. Park, MD Adrian Barbul, MD, FACS
CHAPTER OUTLINE Introduction Nutrition and Wound Healing Protein Amino Acids Carbohyd rates Fats Vitamins Micronutrients Other Factors Affecting Wound Healing Infection Feeding Conclusion
INTRODUCTION The role of nutrition in wound healing has been noted throughout history, beginning with Hippocrates, who warned against underestimating the role of nutrition in health and illness.I The metabolic changes occurring in disease were first investigated in the late 19th century/ and later were delineated by Cuthbertson between 1930 and 1960. Studying the biochemical response to injury in animal models and human patients with long bone fractures, he noted variations in electrolyte levels, increased nitrogen turnover, and stimulation of overall metabolism. Research has advanced from understanding the physiology of wound healing to modulating the process with pharmacologic dosages of various elements of nutrition. Wound healing is sensitive to external manipulation of metabolic and nutritional factors.
NUTRITION AND WOUND HEALING There are many effects of injury on metabolism, including increases in metabolic rate, catecholamine levels, and collagen and cellular turnover. This is accompanied 172
by a decrease in total body water.' These catabolic responses are proportional to the severity of injury.i-' The body appears to prioritize healing by metabolic activity. Levenson and co-workers'r" showed decreased cutaneous healing in burned and traumatized animals. However, hepatic regeneration increased in similarly burned animals. This suggests that vital organs, such as the liver, are preserved at the expense of other organs, such as the skin. Although these differences in healing of different organ systems after injury are not well understood, wound healing is clearly impaired. There are many studies that focus on deconstructing the exact role of nutrition and supplementation on wound healing. However, it should be noted that most wounds heal uneventfully. In many clinical situations, wounds heal despite malnutrition. For example, oncology patients undergoing surgery often present with malnutrition and weight loss preoperatively. However, their wounds generally heal without infection or wound dehiscence. Discrepancies between data seen in animal models and what is observed clinically can be reconciled by understanding that the body appears to prioritize wound healing. In the mid-1990s, Albina" reviewed the thencurrent medical literature and concluded that the biologic priority of the healing wound explained the fact that most wounds heal even with coexisting moderate pre- and postoperative malnutrition. However, he also noted that severe protein-ealorie malnutrition and specific nutrient deficiencies can delay the wound healing process. Wound healing is a complex series of cellular and biochemical events that are interdependent with available energy. It has been recommended that the calorie-tonitrogen ratio be 120 to 150:1 during the early weeks of wound healing after severe injury and then be raised to 200 to 225:1 as the body shifts to a period of positive nitrogen balance." The substrates for production of the energy required for wound healing are proteins, amino acids, carbohydrates, fats, and micronutrients. Proteins and carbohydrates provide approximately 4 kcal/g whereas fats give 9 kcal/g. 12 Decreasing caloric intake by 50% results in decreased collagen synthesis, matrix
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protein deposition, and granulation tissue formation in rodent studies.lv'" Even a brief preoperative illness or decreased intake in the prewound period affects collagen synthesis. This finding indicates that preoperative nutritional intake may be more important to wound healing than the patient's overall nutritional status. IS A brief intervention, either enteral or parenteral, can overcome these impairments.l'v'?
Protein The importance of the role of proteins in wound healing has been recognized and researched since the early 1930s. Protein synthesis at the wound site must be increased for collagen deposition and healing to occur. In animal models, rodents fed either 0% or 4% protein diets demonstrated impaired collagen deposition, decreased skin and fascial wound-breaking strength, and increased rates of wound infection." Acute protein fasting in rats impaired collagen synthesis with a concomitant decrease in procollagen messenger RNA. 14 Administration of individual sulfur-eontaining amino acids abrogates impaired healing in protein-deficient rats as demonstrated by increased fibroblastic proliferation and collagen accumulation. Pure protein deficiencies are rarely seen in the clinical setting. The majority of patients show combined proteinenergy malnutrition or protein-calorie malnutrition. Severe protein malnutrition is known as kwashiorkor. Only modest protein-calorie malnutrition is required to impair fibroplasia in humans." Patients with proteincalorie malnutrition showed diminished hydroxyproline accumulation, an index of reparative collagen deposition, in subcutaneously implanted polytetrafluoroethylene (PTFE) catheters versus normal nourished control subjects." Protein deficiencies result in decreases in wound tensile strength, T'cell function, phagocytic activity, and complement and antibody levels, leading to decreases in the ability of the body to defend against infection. This correlates with increased wound complication rates and failure rates for lower extremity amputations and bypass procedures.P'<' It is difficult to simply translate findings obtained in the context of pure protein deficiency into the setting of protein-ealorie malnutrition, which is more clinically prevalent.
Amino Acids Over the last several decades, interest in the role of individual nutrients to promote wound healing has increased.P The role of several amino acids has been investigated in studies in which amino acids in pharmacologic dosages exceeding normal daily requirements have been administered. Two separate studies in the late 1940s and early I950s showed partial resolution of healing defects in protein-deficient rats with administration of a single sulfur-containing amino acid such as methionine and cysteine. However, the clinical relevance of these findings has not been pursued. 24,2s
173
GlutRmine The most abundant amino acid in the body is glutamine, which comprises approximately 20% of the total circulating free amino acids and 60% of the free intracellular amino acids. 26.27 Glutamine, along with alanine, is a critical substrate for gluconeogenesis in the liver. After conversion to glucose, it can then be used peripherally to fuel certain aspects of wound healing. Glutamine also serves as an energy source for lymphocytes and is essential for lymphocyte proliferation.v-" It is an important precursor for synthesis of nucleotides in cells including fibroblasts and rnacrophages.v-" Glutamine also plays a critical role in stimulating the inflammatory immune response that occurs early in wound healing." Given the various roles that glutamine has in numerous cells involved in the wound, it is not surprising that there is a precipitous fall in plasma and muscle glutamine levels after injury. This decrease is greater than that seen for any other amino acid. 32,33 Although the efficacy of supplemental glutamine administration has been demonstrated in some clinical situations." there has been no significant proven effect on wound healing."
Arginine Arginine is one of two semiessential amino acids in mammalian metabolism." It is a dibasic amino acid endogenously synthesized from ornithine via citrulline. Arginine is a normal constituent of numerous proteins in the body and is associated with a variety of essential reactions of intermediary metabolism. Arginine is absorbed in the intestines with substrate specificity via an energy- and sodium-dependent transport system that is also shared with lysine, ornithine, and cysteine. This common uptake and transport system is also seen in fibroblast and leukocytes." Although arginine is synthesized in adequate amounts to sustain muscle and connective tissue mass, it is insufficient for optimal protein biosynthesis and healing. Therefore, during stress or injury, the synthesis of arginine is not enough to meet the increased demands of protein turnover. Thus, arginine becomes an indispensable amino acid in the process of wound healing and maintenance of positive nitrogen balance. 38,39 The role of arginine in wound healing was first described in the 1970s. It was hypothesized that the amino acid requirements of an adult organism during injury would revert to those of a growing infant. Therefore, the effect of arginine deficiency on wound healing in young adult rats was investigated. The animals were given an arginine-deficient diet for 4 to 6 weeks before wounding. After being subjected to a dorsal skin incision and closure, they showed increased postoperative weight loss, increased mortality to approximately 50%, and a significant decrease in wound-breaking strength and wound collagen deposition compared with animals fed a normal diet (Fig. 15-1). In experiments in which rats were fed diets supplemented by an additional I% arginine, wound-breaking strength and collagen synthesis were increased compared with values in regular
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FIGURE 15-2. Effect of arginine supplementation on hydroxyproline (OHP, nanomoles per centimeter, ± SEM) accumulation in subcutaneously implanted polytetrafluoroethylene catheters in young human volunteers. Each group of 12 volunteers received a placebo syrup (control), 30 g of arginine aspartate (Arg Asp), or 30 g of arginine HCI (Arg HC!) for 2 weeks.
FIGURE 15-1 . Effect of arginine-free (defined) diet, regular chow, and arginine supplementation on wound healing in rats: fresh breaking strength of scar (FBS, grams); formalinfixed breaking strength (FxBS, grams); hydroxyproline content of subcutaneously implanted polyvinyl alcohol sponges (OHP, micrograms per 100 milligrams sponge dry weight).
chow-fed controls" Rats receiving high-dose arginine (7.5 giL) parenterally demonstrated increased woundbreaking strength, collagen accumulation, and immune function." Mature or old rats fed diets enriched with a combination of arginine and glycine have enhanced rates of wound collagen deposition compared with those of controls." Goodson and Hunr" developed a micromodel that enabled study of the human fibroblastic response. Collagen deposition was analyzed by assessing accumulation in a 5-cm segment of PTFE tubing that had been subcutaneously implanted in subjects. There have been two studies using this model in healthy human volunteers to investigate the effect of arginine supplementation on wound healing. The first study involved 36 young (25- to 35-year-old) healthy human volunteers who were randomly assigned to three groups. Group 1 received 30 g of arginine HCl (24.8 g of free arginine), group 2 received 30 g of arginine aspartate (17 g of free arginine), and group 3 received a placebo. Each group took the supplements daily for 2 weeks. At that time, the catheters were removed, and the hydroxyproline content and total protein were assessed. Both doses of arginine significantly increased hydroxyproline content and total protein deposition at the wound site43 (Fig. 15-2).
The second study involved 30 elderly (>70 years old) human volunteers who received 30 g of arginine aspartate and 15 volunteers who received a placebo. Again, each group took the supplements daily for 2 weeks. In addition to evaluating the fibroblastic response in the PTFE catheter, a split-thickness wound was created on the upper thigh of each subject to assess epithelialization. The catheter was analyzed for a-aminonitrogen content (measurement of total protein accumulation), DNA accumulation (reflection of cellular infiltration), and hydroxyproline content. There was no increase in DNA accumulation in the wounds of the arginine group, suggesting that the effects of arginine on wound healing are not mediated by an inflammatory mode of action (Fig. 15-3). Arginine also did not affect the rate of epithelialization, indicating that the predominant effect of arginine is on wound collagen deposition." A variety of possible mechanisms could explain the effect of arginine on wound healing. One is that even though arginine comprises a very small amount of the collagen molecule «5%), supplemental arginine could possibly provide a necessary substrate for collagen synthesis in the wound. This could occur through the use of arginine as a substrate via the pathway arginine -+ ornithine -+ glutamic semialdehyde -+ proline. Arginine levels are virtually nondetectable within the wound during the later phases of wound healing when fibroplasia predorninates.f Although ornithine levels are greater in the wound than in plasma, studies by Albina and associates" demonstrated that the rate of conversion of ornithine to proline is actually quite low. Therefore, this mechanism of the effect of arginine on wound healing is unlikely. Another possible mechanism explaining the effect of arginine on wound healing is based on the observation that the effects of supplemental arginine on wound healing are similar to those of growth hormone in their enhancement of wound-breaking strength and collagen deposition.Fr" A study investigated this possible relationship by comparing hypophysectomized rats and rats with normal pituitary glands. These animals were divided in
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FIGURE 15-3. Effect of arginine on wound healing parameters in healthy elderly human volunteers: accumulation of hydroxyproline (OHP, nanomoles per centimeter, ± SEM), total a-aminonitrogen (alpha-amino N, microgram per centimeter, ± SEM), and DNA (nanomoles per centimeter, ± SEM) in subcutaneously implanted polytetratluoroethylene catheters was measured at the end of 2 weeks. Controls (n = 15) received a placebo syrup; the arginine group (n = 30) received 30 g of arginine aspartate in doubleblind fashion.
two groups, one receiving growth hormone and the other receiving placebo. One-half of each group also received 1% arginine supplementation. Allanimals received a dorsal incision and implantation of a subcutaneous polyvinyl alcohol sponge. The intact pituitary group that received arginine demonstrated an increase in wound-breaking strength and collagen deposition regardless of growth hormone intake. In the hypophysectomized animals, arginine had no affect on wound-breaking strength or collagen deposition, regardless of growth hormone intake. Thissuggests that the effects of arginine on wound healing depend on an intact hypothalamopituitary axis.5o In humans, arginine supplementation in dosages that enhance wound healing also increase plasma insulin-like growth factor, the peripheral mediator of growth hormone. Another possible mechanism of the effect of arginine on wound healing focuses on its unique effect on T-cell function. Arginine stimulates T-cell responses and reduces the inhibitory effect of injury and wounding on T-cell function. 51- 54 T lymphocytes are essential for normal wound healing. T cells can be found immunohistochemically throughout various phases of wound healing. Recent studies demonstrate that each specific cell type modulates different phases of cutaneous healing necessary for normal repair of the wound. Animals treated with monoclonal antibodies against all T lymphocytes demonstrated decreased wound-breaking strength.P Although the exact mechanism has not been fully elucidated, it is thought that arginine may enhance wound healing by stimulating the host and wound T-cell responses, leading to increased fibroplasia. 56- 58 A final possible mechanism for the effect of arginine on wound healing is based on the fact that arginine is a unique substrate for nitric oxide (NO). NO is a highly reactive radical that has been shown to have a critical role in wound healing. Inhibitors of NO impair cutaneous incisional wounds and colonic anastomosis in rodents. 59,6o In vitro studies demonstrated increased collagen synthesis with administration of exogenous NO in cultured dermal fibroblasts." Arginine is catabolized in the wound via two different pathways. One involves the family of isoenzyme nitric oxide synthases (NOSs) and the other the enzyme arginase. Catabolism of arginine-producing NO via NOS isoenzymes has the end product of citrulline. The inducible form of NOS (iNOS) is activated in response to inflammatory stimuli such as wounding. In animal
models, supranormallevels of collagen deposition were observed after transfection of iNOS DNA into wounds.P Furthermore, mice lacking the iNOS gene (iNOS knockout mice) demonstrated delayed closure of excisional wounds, which was remedied by adenoviral transfection of the iNOSgene to the wound bed. 63 Additionally, these knockout mice did not show enhancement of wound healing when fed arginine supplementation was added to their diets whereas in wild-type mice fed argininesupplemented diets incisional wound healing improved by the parameters of wound-breaking strength and collagen deposition. This indicates that the iNOS pathway is as least partially responsible for the beneficial effects of arginine on wound healing."
Branched-Chain Amino Acids Branched-ehain amino acids include valine, leucine, and isoleucine. They have been used to treat liver disease and have an additional role in retaining nitrogen in the setting of sepsis, trauma, and bums. 6!HJ7 Branchedchain amino acids support protein synthesis and decrease muscle proteolysis after injury. Because they can be used as caloric substrates, branched-ehain amino acids can be metabolized as an energy source independent of liver function.~71 Despite these beneficial properties, supplementation of branched-ehain amino acids have not proven to be of any significant benefit in wound healing."
Carbohydrates Together with fats, carbohydrates are the primary source of energy in the body and therefore in the wound-healing process. The energy requirements of wound healing consist mostly of the energy needed to synthesize wound collagen. Estimation of caloric requirements for a wound can be determined by understanding that protein synthesis entails 0.9 kcal/g and that a 3 em? by 1 mm section of granulation tissue has 10 mg of collagen. Although simple wounds have little energy impact on overall metabolism, large, complicated wounds, or bum injuries may require a lot of energy to heal. 23 Glucose is the major fuel source to derive adenosine triphosphate (ATP), which powers the healing process. Although carbohydrates play an important role in providing energy for optimal healing, not much is
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understood about the function that different sources of carbohydrates play in this process. Glucose is thought to be a relatively inefficient means to generate ATP, yet it is essential to prevent depletion of other amino acids and protein substrates. The liver uses amino acids from degraded muscle proteins to fuel gluconeogenesis. This can be triggered by the catecholamine and cortisol surge after wounding. If unchecked and in the presence of inadequate carbohydrate and fat stores, it can lead to protein-ealorie malnutrition. Gluconeogenesis is an inefficient pathway for glucose production and may result in excess glucose levels that can complicate wound healing, especial in diabetic patients with poor glycemic control. Diabetic patients often suffer impairments in wound healing and increased complications due to multifactorial yet poorly understood reasons. Diabetes leads to microvascular and atherosclerotic changes that adversely affect wound healing. Furthermore, the disease process appears to exert an effect on the early inflammatory response and directly inhibits fibroblast and endothelial cell activity. This was established by Goodson and Hunt" in an animal model of streptozotocin-induced diabetes. In this model of type II diabetes a delay in epithelialization of open wounds and a decrease in collagen accumulation deep in wounds were also seen. Hyperglycemia interferes with the cellular transport of ascorbic acid into fibroblasts and leukocytes and causes decreased leukocyte chemotaxis. Mann74.75 suggested that the mechanism for altered ascorbic acid transport may be related to competitive inhibition due to structural similarities between glucose and ascorbic acid. It is possible that the effects of hyperglycemia on leukocytes may explain the decreased early inflammatory response and impairment of wound healing in diabetic patients. Large doses of ascorbic acid given to streptozotocininduced diabetic rats can reverse these effects and increase collagen production in skin via the reversal of underhydroxylation and degradation of collagen as well as improve intracellular ribosomal collagen production." Barr and Joyce" noted decreased reendothelialization of microarterial anastomoses in streptozotocin-induced diabetic rats. This delay was not alleviated with insulin therapy initiated at the time of surgery and extended into the postoperative period. The relationship between insulin and hyperglycemia was further elucidated by Weringer and associates. 78-80 Mice with dermal ear wounds were divided into three groups. Group 1 was treated with an antiserum to insulin, group 2 was rendered hyperglycemic with 2-deoxyglucose, and group 3 was subjected to starvation-induced hypoglycemia. Their data indicated that in addition to the deleterious effects of hyperglycemia, the lack of insulin itself appears to impair wound healing. Topical insulin applied to infected skin wounds of diabetic mice or systemic administration can improve wound healing, regardless of the route of administration." However, to achieve normal healing, insulin must be given early after wounding.P It is important to control serum glucose levels in diabetic patients at the time of injury, during operations and through the process of wound healing. Alterations in
glucose metabolism after injury and elective surgery can significantly affect wound healing through many of the aforementioned mechanism. Diabetic patients are also more susceptible to infection because of decreased host resistance. Therefore, it is important for physicians to both recognize and anticipate the needs of diabetic patients early, before complications arise.
Fats The role of fats in wound healing has not been as widely investigated as that of carbohydrates. In 1929, Burr and Burr83·84 identified the importance of fats by investigating the effects of a fat-free diet in animals and thereby offered the first clinical description of dietary lipid deficiency. Several unsaturated fatty acids must be supplied in the diet. These essential fatty acids include linoleic and arachidonic acid, which is a product of linoleic acid. Although linolenic and arachidonic acids can be synthesized in humans from linoleic acids, the rates of synthesis are inadequate for inherent metabolic needs. These fatty acids are components or precursors of phospholipids and prostaglandins. Therefore, deficiencies in these fatty acids can lead to impaired wound healing in animals and humans due to the important role that phospholipids play as constituents of the basement membrane of the cell and the participation of prostaglandins in cellular metabolism and inflammation. B5-88 Injury increases the demands for essential fatty acids. B9•90 Deficiencies of dietary essential fatty acids were not often encountered clinically until after introduction of prolonged parenteral feedings that did not contain fat. Biochemical changes with essential fatty acids deficiency can manifest themselves within 10 days of consumption of an entirely fat-free diet." Total parenteral nutrition (TPN) is the most common cause of essential fatty acid deficiency. A rapid onset of essential fatty acid deficiency in the setting of TPN therapy is due to the continuous infusion of a high concentration of glucose. This leads to elevated insulin levels that block lipolysis and essential fatty acid release." One specific lipid type that has been studied is the 003 fatty acids," which have anti-inflammatory properties mediated via inhibition of eicosanoid production'vf" and other mediators such as platelet-activating factor, interleukin-l, and tumor necrosis factor-a.. 97•98 Animals fed diets enriched in 00-3 fatty acids had weaker wounds than controls 30 days after injury. The weaker wounds did not have less collagen, indicating that the 00-3 fatty acid supplementation may interfere with the quality, cross-linking, or spatial orientation of collagen fibrils.
Vitamins Water-soluble vitamin C and fat-soluble vitamin A are the predominant vitamins involved in the wound healing process. Other water-soluble vitamins, such as vitamin B complexes, appear to have a small direct role in wound healing. However, they do exert an indirect influence on
SECTION III • Nutrient Metabolism
wound healing through their effects of host resistance. The remaining fat-soluble vitamins, such as D, E, and K, also have a small direct role in wound healing. They do have some supporting roles, such as their role as antioxidants or in controlling hemorrhage.
Vitamin C The importance of vitamin C, or ascorbic acid, in wound healing is well illustrated in the historical significance of scurvy (scorbutus), a disease caused by vitamin C deficiency. Scurvy is the result of a failure in collagen synthesis and cross-linking'" that results in impaired synthesis of collagen in connective tissues. Symptoms include bleeding into the gingiva, skin, joints, peritoneum, pericardium, and adrenal glands. Generalized symptoms include weakness, fatigue, and depression. The earliest accounts of scurvy were in sailors at sea and field armies who consumed diets lacking fresh fruits and vegetables. In the late 1800s, Sir William Osler'I" described this condition, noting that it had virtually disappeared as a clinical entity, due to the work of Lind. When Osler categorized the symptoms, the underlying collagen defect was not understood. In 1940, Crandon and co-workers'?' first highlighted the temporal aspects of vitamin C deficiency and the significance of an "intracellular substance," which turned out to be collagen. While working as a surgical resident, Crandon consumed a diet lacking in vitamin C. After 3 months, a skin incision healed normally and results of a biopsy at 10 days were also normal. However, after a 6-month interval, a second skin incision healed poorly and a biopsy at 10 days showed an absence of this intracellular substance. After a diet supplemented with Ig of ascorbic acid per day, healing improved and a final biopsy showed an increase in collagen and capillary formation. These early histologic descriptions reflect the adverse effects of vitamin C deficiency on wound healing, which include minimal collagen, decreased angiogenesis, and significant hemorrhage. Ascorbic acid believed to be a specific cosubstrate for the enzymes 4-hydroxylase and lysyl hydroxylase. It is a reducing agent and is required for the conversion of proline and lysine to hydroxyproline and hydroxylysine.Pi Electron microscopic examination of fibroblasts from patients with scurvy demonstrates a dilated and disordered rough endoplasmic reticulum with diminished polysome content. 103,104 Vitamin C deficiency has also been associated with increased susceptibility to wound infection. If wound infection does occur in the setting of vitamin C deficiency, it is apt to be more severe. This is thought to be due to the impairment of collagen synthesis interfering with wallingoff of bacteria and localizing infection and to impairment of neutrophil function and complement activity.P The recommended dietary allowance for vitamin C is 60 mg/day. However, the clinical spectrum for its administration varies widely. Burn victims may have requirements as high as 1 to 2 g/day. In human studies, administration of up to 2 g/day was required to restore urine and tissue levels to normal after major burn
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injuries. lOS In animal models, burned guinea pigs had histologic similarities to scorbutic, unburned animals. If supplemental vitamin C was given, the changes were prevented. Although doses in different settings may vary, there is no evidence to suggest that massive doses of ascorbic acid have any substantial benefit in wound healing. There is also no evidence that excess vitamin C is toxic. 106
Vitamin A Vitamin A was discovered in the early 1900s by McCollum and Davis. Later studies in 1941 by Brandaleone and Papper'!" showed that vitamin A deficiency impaired wound healing. In the 19605and 1970s, Ehrlich and Hunt'P' described the beneficial effects of vitamin A supplementation on wound healing in nondeficient humans and animals. They revealed that vitamin A can reverse the anti-inflammatory effects of corticosteroids on wound healing. Vitamin A, given either topically or systemically, can also improve wound healing of patients receiving chronic steroid therapy.109,11O Vitamin A has been shown to improve wound healing impaired by diabetes, tumor formation, cyclophosphamide, or radiation. II 1-114 Vitamin A increases the inflammatory response in wounds. This is thought to be due to enhanced lysosomal membrane lability, increased macrophage influx and activation, and stimulation of collagen synthesis. In vitro studies demonstrate that vitamin A increases epidermal growth factor receptors as well as collagen synthesis of fibroblast cell cultures.l'
Vitamin E Vitamin E maintains and stabilizes cellular membrane integrity, primarily by protection against destruction by oxidation.P? It has anti-inflammatory properties similar to those of steroids, as demonstrated by reversal of the wound healing impairment caused by vitamin E after administration of vitamin A in the first days after wounding. 121 Vitamin E also affects various host immune functions. As an antioxidant, vitamin E has been proposed to reduce injury to wounds caused by excessive amounts of free radicals. I 10 Liberation of free radicals from inflammatory cascades in necrotic tissue, tissue colonized with microbial flora, ischemic tissue, and chronic wounds
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can result in depletion of free radical scavengers such as vitamin E.122,123 This process is believed to underlie the complications seen in patients with chronic lower extremity wounds. In these patients, it is not known if the relative lack of vitamin E is due to consumption of the vitamin in its antioxidant capacity or to an overall vitamin E deficiency. Either cause would impair healing. Some authors suggest that after healing is firmly established in patients with chronic lower extremity wounds, vitamin E may decrease excess scar formation known to occur in these types of wounds."
Vitllmin K Vitamin K is known as the antihemorrhage vitamin. It is required for the carboxylation of glutamate in clotting factors II, VII, IX, and X. Although vitamin K contributes little directly to wound healing, its absence or deficiency leads to decreased coagulation, which consequently affects the initial phases of healing. Formation of hematomas within the wound can impair healing and predispose the wound to infection.' Vitamins A and E antagonize the hemostatic properties of vitamin K.
Micronutrients Micronutrients are essential components of cellular functions. They can be divided into organic compounds, such as the vitamins already discussed, and inorganic compounds or trace elements. The term micronutrients refers to the extremely small quantities of these compounds found in the body.!" Most minerals and trace elements do not directly influence wound healing but are cofactors or parts of an enzyme that are essential to healing and homeostasis. Although they comprise only a small portion of the overall nutritional needs of the body, they play an important role in the complex cellular machinery that carries out wound healing. Of the numerous trace elements in the body, zinc, iron, and copper have the closest relationship to wound healing, as does the macromineral magnesium. It is difficult to associate a deficit in specific minerals and trace elements with impairments in wound healing because micronutrient deficiencies are almost always accompanied by coexisting metabolic or other nutritional disturbances. Clinicians became more aware of deficiencies of these elements after introduction of longterm parenteral nutritional solutions, which did not include supplemental minerals and trace elements. It is often easier to prevent these deficiencies than to diagnose them clinically.P
Zinc Zinc has been used empirically in dermatologic conditions for centuries. Evidence that zinc is essential to wound healing was first described in rat model in the 1930sand later in humans in the 1950s.119.124-126 Asa cofactor for RNA and DNA polymerase, zinc is involved in DNA synthesis, protein synthesis, and cellular proliferation.
Zinc deficiency can impair the critical roles each of these processes play in wound healing. Zinc levels less than 100 Jlg/100 mL have been associated with impairments in wound healing." In zinc deficiency, fibroblast proliferation and collagen synthesis are decreased, leading to decreased wound strength and delayed epithelialization. These defects are readily reversed with repletion of zinc to normal levels." Immune function is also impaired in zinc deficiency. Both cellular and humoral elements are adversely affected, resulting in increased susceptibility to wound infection and an increased possibility of delayed healing. Zinc levels can be depleted in settings of severe stress as well as in patients receiving long-termsteroid therapy.127 In these settings, it is recommended that patients receive both vitamin A and zinc supplements to improve wound healing. I 10 The current recommended daily allowance for zinc is 15 mg/day. No studies have demonstrated any improvement in wound healing after supplementation of zinc to patients who do not have a zinc deflciency.P'
Iron Iron is required for hydroxylation of proline and lysine. Severe iron deficiency can result in impaired collagen production. As part of the oxygen transport system, iron can affect wound healing, but again, only in settings of severe iron deficiency anemia. In the clinical setting, iron deficiency is quite common and may result from blood loss, infections, malnutrition, or an underlying hematopoietic disorder. Unlike other trace elements, iron deficiency can be easily detected and treated.'
Copper Copper is a required cofactor of cytochrome oxidase and the cytosolic antioxidant superoxide dismutase. Lysyl oxidase is an essential copper enzyme used in the development of connective tissue, catalyzing the crosslinking of collagen and strengthening the collagen framework!" Experimentally, impaired healing is noted because of the decreased copper stores in patients with Wilson disease and in animal models after administration of penicillamine.129,130
MlIgnesium Magnesium is as a cofactor for many enzymes involved in protein synthesis.' Its primary role is to provide structural stability to adenosine triphosphate, which powers many of the processes used in collagen synthesis, making it a factor essential to wound repair. 120,109
OTHER FACTORS AFFECTING WOUND HEALING
Infection The body's response to tissue injury results in a complex cascade of events designed to restore cutaneous
SECTION III • Nutrient Metabolism
integrity and occurs in the presence of various environmental factors. Anyof these factors can impair the wound healing process ifnot effectively managed or prevented. Sepsis, either as a local bacterial colonization of a wound site or a systemic inflammatory response, poses one of the most formidable "environmental" obstacles to successful wound healing. Experimentally, the critical inoculum of microorganism that willsignificantly inhibit healing is 10-5 colony forming units/ern" of wound surface or gram of tissue.131,132 In addition to appropriate antibiotic therapy, an intact, functioning immune system is vital to preventing and eliminating wound infection. The immune system is clearly tied to overall host nutrition as well as to specific nutritional entities such as arginine and its related metabolic pathways. In critically ill patients, it is important that nutritional status be optimized to provide increased substrate availability to meet the demands of tissue repair and immune function and prevent infection and delayed wound healing.F'
Feeding Malnourished patients before wounding have increased rates of wound infection and delayed wound healing. Nutritional repletion before planned elective operations significantly reduces these complications. The route of administration of nutrition, be it enteral or parenteral, may be important, but the data are contradictory. TPN has been shown to reduce postoperative complications when administered to severely malnourished
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patients for at least 7 days preoperatively.134,135 However, TPN is not without its drawbacks, such as increased risk of infection. Although total enteral nutrition (fEN) also has associated risks, there is experimental evidence that TEN may be superior to TPN as a nutritional option. In a rodent study, rats administered TEN for 5 days after wounding demonstrated an increase in collagen deposition and wound breaking strength compared with rats that received TPN (Fig. 15-4). This effect appears to disappear during a period of maximal fibroplasia, which occurs between 5 to 10 days after injury (see Fig. 15-4). TEN appears to exert a greater influence over the early cellular, inflammatory phase of wounds than does TPN. The cellular phase of wound healing is exquisitelysensitive to nutrient availability. The influence TEN exerts on systemic immune function contributes to function and the number of inflammatory cells present during earlyhealing, ultimately affecting wound repair.P" TEN also appears to maintain local and system immune responses, preserves gut integrity, which decreases bacterial translocation, and improves protein metabolism and surviva1.137-140 The exact feeding regimen should be tailored to each individual patient. Malnourished patients should receive preoperative repletion by the route that exposes the patient to the least risk and, if possible, elective operations should be delayed until the patient is adequately supplemented. In patients who are unlikely to tolerate nutrition orally, TPN should be initiated early. Nutritional supplements should be as specific as possible for the patient's perceived nutritional deficiency and should include substrates that are rapidly turned over.
FIGURE 15-4. Top: Wound breaking strength (WBS, grams) in the enterally (TEN) and parenterally (TPN) fed groups. Bottom: Hydroxyproline content (OHP, micrograms per 100 mg of sponge) of subcutaneously implanted polyvinyl alcohol sponge in the enterally (TEN) and parenterally (TPN) groups.
Days post-wounding
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CONCLUSION The relationship between nutrition and wound healing has been the subject of study and experimentation for centuries. Despite many years of study and the substantial knowledge base of the specific processes and factors involved, wound healing remains somewhat enigmatic. There is still much to be learned about wound-specific nutritional interventions that are available to improve wound healing. It is clear that nutrition profoundly influences the process of wound healing. Nutritional depletion exerts an inhibitory effect on healing whereas nutritional supplementation with positive effectors such as arginine can stimulate wound healing. It is important that nutritional deficiencies are recognized early and that repletion be initiated early, because even brief periods of malnutrition can have significant negative effects on wound healing. Within this paradigm, the physician should be able to recognize those patients who may be expected to have wound healing difficulties and offer early intervention to avoid wound healing failure. REFERENCES 1. Hippocrates: The Genuine Works of Hippocrates (translated from the Greek by Francis Adams). Baltimore, Williams & Wilkins, 1939. 2. DuBois EF: Metabolism in Fever and in Certain Infections. In Barker LF(ed): Endocrinology and Metabolism. New York,Appleton, 1922, pp 95-151, Vol. IV, D. 3. Fischer JE: Nutrition in wound healing. In Nutrition and Metabolism in the Surgical Patient. Boston, Little, Brown, 1996. 4. Cuthbertson DP: Nutrition in relation to trauma and surgery. Prog Nutr Sci 1975;1:263-387. 5. Bessey PQ: Metabolic response to critical illness. In: Wilmore DW, Cheung LY, Harken AH, et al (eds): Scientific American Surgery: Care of the Surgical Patient. New York, WebMD, 1999, pp 1-26. 6. Levenson SM, Pirani CL, Braasch JW, et al: The effect of thermal bums on wound healing. Surg Gynecol Obstet 1954;99:74-82. 7. Levenson SM, Upjohn HL, Preston JA: Effect of thermal bums on wound healing. Ann Surg 1957;146:357-367. 8. Crowley LV, Seifter E, Kriss P, et al: Effects of environmental temperature and femoral fracture on wound healing in rats. J Trauma 1977;17:436--445. 9. Levenson SM, Crowley LV, Oates JF, et al: Effect of severe burn on liver regeneration. Surg Forum 1959;9:493. 10. Albina JE: Nutrition and wound healing. JPEN J Parenter Enteral Nutr 1994;18:367-376. 11. Levenson SM, Seifter E, Walton VW: Fundamentals of Wound Management in Surgery. South Plainfield, NJ, Chirurgecom, 1977. 12. Schwartz SI: Principles of Surgery. New York, McGraw-Hill, 1994. 13. Yue DK, Mclennan S, Marsh M, et al: Abnormalities of granulation tissue and collagen formation in experimental diabetes, uremia and malnutrition. Diabetic Med 1986;3:221-225. 14. Spanheimer RG, Peterkofsky B: A specific decrease in collagen synthesis in acutely fasted, vitamin C-supplemented, guinea pigs. J Bioi Chern 1985;260:3955-3962. 15. Windsor JA, Knight GS, Hill GL: Wound healing response in surgical patients: Recent food intake is more important than nutritional status. Br J Surg 1988;75:135-137. 16. Haydock DA, Hill GL: Improved wound healing response in surgical patients receiving intravenous nutrition. Br J Surg 1987;74: 320-323. 17. Schroeder D, Gillanders L, Mahr K, et al: Effects of immediate postoperative nutrition in body composition, muscle function and wound healing. JPEN J Parenter Enteral Nutr 1991;15:376-383. 18. Irvin 11: Effects of malnutrition and hyperalimentation on wound healing. Surg Gynecol Obstet 1978;146:33-37.
19. Goodson WH 3rd, Lopez-Sarmiento A, Jensen JA: The influences of a brief preoperative illness on postoperative healing. Ann Surg 1987;205:250-255. 20. Kay SP, Moreland JR, Schmitter E: Nutritional status and wound healing in lower extremity amputations. Clin Orthop 1987;217: 253-256. 21. Dickhaut SC, Delee JC, Page CP: Nutritional status: Importance in predicting wound healing after amputation. J Bone Joint Surg Am 1984;66:71-74. 22. Casey J, Flinn WR, Yao JS: Correlation of immune and nutritional status with wound complications in patients undergoing vascular operations. Surgery 1983;93:822-827. 22. Barbul A, Purtill WA: Nutrition in wound healing. Clin Dermatol 1994;12:133-140. 24. Williamson MB, Fromm HJ: The incorporation of sulfur amino acids into protein of regenerating wound tissue. J Bioi Chem 1955;212:705-712. 25. Localio SA, Morgan ME, Hintown JW: The biological chemistry of wound healing. The effect of di-methionine on the healing of wounds in protein depleted animals. Surg Gynecol Obstet 1948;86:582. 26. Demling RH, DeSanti L:Involuntary weight loss and the nonhealing wound: The role of anabolic agents. Adv Wound Care 1999;12(suppl): 1-14. 27. Bergstrom J, Furst P, Noree LO, et al: Intracellular free amino acid concentration in human muscle tissue. J Appl Physiol 1974;36:693-697. 28. Ardawi MSM, Newsholme P, et al: Glutamine metabolism in lymphocytes of the rat. Biochemistry 1983;212:835. 29. Newsholme EA, Newsholme P: A role for muscle in the immune system and its importance in surgery, trauma, sepsis and burns. Nutrition 1988;4:261. 30. Zetterberg A, Engstrom W: Glutamine and the regulation of DNA replication and cell multiplication in fibroblasts. J Cell Physiol 1981;108:365-373. 31. Zielke HR, Ozand PT, Tildon IT, et al: Growth of human diploid fibroblasts in the absence of glucose utilization, Proc Natl Acad Sci USA1976;73:411Q-4114. 32. Askanazi J, Carpentier YA, Michelsen CB, et al: Muscle and plasma amino acids following injury: Influence of intercurrent infection. Ann Surg 1980;192:78-85. 33. Roth E, Funovics J: Metabolic disorders in severe abdominal sepsis: Glutamine deficiency in skeletal muscle. Clin Nutr 1982;1:25. 34. Ziegler TR, Young LS, Benfell K, et al: Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplant. A randomized, double-blind controlled study. Ann Intern Med 1992;116:821-828. 35. McCauley R, Plate II C, Hall J, et al: Effects of glutamine on colonic strength anastomosis in the rat. JPEN J Parenter Enteral Nutr 1991; 15:437-439. 36. Rose WC:The nutritive significance of the amino acids and certain related compounds. Science 1937;86:298. 37. Barbul A: Biochemistry, physiology and therapeutic implications. JPEN J Parenter Enteral Nutr 1986;10:227-238. 38. Rose WC: Amino acid requirements of man. Fed Proc 1949;8: 546. 39. Seifter E, Rettura G, Barbul A, et al: Arginine: An essential amino acid for injured rats. Surgery 1978;84:224-230. 40. Barbul A, Fishel RS: Intravenous hyperalimentation with high arginine levels improves wound healing and immune function. J Surg Res 1985;39:328-334. 41. Chyun J, Griminger P: Improvement of nitrogen retention by arginine and glycine supplementation and its relation to collagen synthesis. J Nutr 1984;114:1697-1704. 42. Goodson WH, Hunt TK: Development of a new miniature method for the study of wound healing in human subjects. J Surg Res 1982;33:394-401. 43. Barbul A, Lazarou S: Arginine enhances wound healing in humans. Surgery 1983;108:331. 44. Kirk SJ, Hurston M, Regan MC, et al: Arginine stimulates wound healing and immune function in elderly humans. Surgery 1994;114:155. 45. Albina JE, Mills CD, Barbul A, et al: Arginine metabolism in wounds. Am J Phys 1988;254:E459-E467.
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46. Albina lE, Abate lA, Mastrofrancesco B: Role of ornithine as proline precursor in healing wounds. 1Surg Res 1993;55:97-102. 47. Kowalewski K, Yong S: Effect of growthhormone and an anabolic steroid on hydroxyproline in healing dermal wounds in rats. Acta Endocrinol 1968;59:53-66. 48. Jorgensen PH, Andreassen IT: Influence of biosynthetic human growth hormone on biochemical properties of rat skin incisional wounds. ActaChirScand 1988;154:623-626. 49. Herndon DN, Barrow RE, Kunkel KR, et al: Effects of recombinant human growth hormone on donor site healing in severely burned children. Ann Surg 1990;212:424-429. 50. Barbul A, Rettura G, Levenson SM, et al: Wound healing and thymotropiceffects of arginine: A pituitary mechanism of action. Am 1 Clin Nutr1983;37:786-794. 51. Barbul A, Wasserkrug HL, Seifter E, et al: Immunostimulatory effectsof arginine in normal and injured rats.1 Surg Res 1980;29: 228-235. 52. Barbul A, Wasserkrug HL, Sisto DA, et al: Thymic stimulatory actions of arginine.lPEN 1 Parenter EnteralNutr 1980;4:446-449. 53. Barbul A, Wasserkrug HL, Yoshimura N, et al: Higharginine levels in intravenoushyperalimentation abrogate post-traumatic immune suppression. 1SurgRes 1984;36:620-624. 54. Barbul A, Fishel RS, Shimazu S, et al: Intravenous hyperalimentation with high arginine levels improves wound healing and immune function. 1 SurgRes 1985;39:328-334. 55. Agaiby AD, Dyson M: Immuno-inflammatory cell dynamics during cutaneous wound healing. 1. Anat 1999;195:531-542. 56. Fishel RS, Barbul A, Beschorner WF, et al: Lymphocyte participation in wound healing: Morphologic assessmentusing monoclonal antibodies.Ann Surg 1987;206:25-29. 57. Peterson1M, Barbul A, Breslin RJ, et al: Significance of T lymphocytes in wound healing.Surgery 1987;102:300-305. 58. Barbul A: Role of T cell-dependent immune system in wound healing. In Growth Factors and Other Aspectsof Wound Healing: Biologic and Clinical Implications. NewYork, Alan R. Liss, 1988. 59. Schaffer MR, TantryU, Thornton Fl, et al: Inhibitionof nitric oxide synthesis in wounds: Pharmacologyand effecton accumulation of collagen in wounds in mice. Eur1 Surg 1999;165:262-267. 60. Efron DT, Thornton Fl, Steulten C, et al: Expression and function of inducible nitric oxide synthase during rat colon anastomotic healing. 1 Gastrointest Surg 1999;3:592-601. 61. Schaffer MR, Efron PA, ThorntonFl, et al: Nitric oxide, an autocrine regulator of wound fibroblast synthetic function. 1 Immunol 1997;158:2375-2381. 62. Thornton Fl, Schaffer MR, Witte MB, et al: Enhanced collagen accumulation following direct transfection of the inducible nitric oxide synthase gene in cutaneous wounds. Biochem Biophys Res Commun 1998;246:654-659. 63. Yamasaki K, Edington HD, McClosky C, et al: Reversal of impaired wounds repair in iNOS deficient mice by topical adenoviralmediated iNOS gene transfer. 1 ClinInvest 1998;101:967-971. 64. Shi HP, Efron DT, Most D, et al: Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice. Surgery 2000;128:374-378. 65. Cerra FB, Upson D, Angelico R, et al: Branched chains support postoperativeprotein synthesis. Surgery 1982;92:192-199. 66. Cerra FB, Shronts EP, Konstantinides NN, et al: Enteral feeding in sepsis: Aprospective, randomized double blind trial.Surgery 1985; 98:632-639. 67. Sax HC, Talamini MA, Fischer lE: Clinical use of branched chain amino acids in liver disease, trauma, sepsis and burns. Arch Surg 1987; 121 :358-366. 68. Cerra FB, Siegel lH, Coleman B, et al: Septic autocannibalism: A failure of exogenous nutritional support. Ann Surg 1980;192: 570-580. 69. Hedden MP, Buse MG: General stimulation of muscle protein synthesis by branched chain amino acids in vitro. Proc Soc Exp Bioi Med 1979;160:410-415. 70. BuseMG, ReidSS: Leucine. Apossible regulatorof protein turnover in muscles. 1 Clin Invest 1975;56:1250-1261. 71. Freund HR, LapidotA, FischerlE, et al:The use of branched chain amino acids in the injuredseptic patient. In WalserM, Williamson lE (eds): Metabolism and Clinical Implications of Branch Chain Amino and Ketoacids. NewYork, Elsevier, 1981.
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72. McCauley R, Platell C, Hall 1, et al: Influence of branched chain amino acid infusions on wound healing. Aust NZ 1 Surg 1990; 60:471-473. 73. Goodson WH 3rd, Hunt TK: Wound collagen accumulation in obese hyperglycemic mice. Diabetes 1986;35:491-495. 74. MannGV: The impairment of transport of amino acid by monosaccharides [abstract]. Fed Proc 1974;33:251. 75. MannGV: The membrane transportof ascorbic acid. Ann NY Acad Sci 1974;258:243. 76. Schneir M, Rettura G, et al: Dietary ascorbic acid increases collagen production in skin of stretozotocin induced diabetic rats by normalizing ribosomal efficiency. Ann NY Acad Sci 1987; 194:42. 77. Barr LC, Joyce AD: Microvascular anastamoses in diabetes: An experimental study. Br1 Plast Surg 1989;42:50-53. 78. Weringer £1, Kelso 1M, Tarnai IY, et al: Effects of insulin in wound healing in diabetic mice. Acta Endocrinol (Copenh) 1982;99: 101-108. 79. Weringer £1, Arquilla E: Wound healing in normal and diabetic Chinese hamsters.Diabetologia 1981;4:394-401. 80. Weringer £1, Kelso 1M, Tarnai IY, et al: The effect of antisera to insulin, 2-deoxyglucose-induced hyperglycemia and starvation on wound healing in normal mice. Diabetes 1981;30:407-410. 81. Hanam SR, Singleton CE, Rudek W, et al: The effect of topical insulin on infected cutaneous ulcerations in diabetic and nondiabetic mice. 1 FootSurg 1983;22:298-301. 82. Goodson WH 3rd, Hunt TK: Studies of wound healing in experimental diabetes mellitus. 1 SurgRes 1977;22:221-227. 83. BurrGO, BurrMM: A new deficiency disease produced by the rigid exclusion of fat from the diet. 1 Bioi Chern 1929;82:345. 84. BurrGO, BurrMM: On the nature and role of the fatty acids essential in nutrition.1 Bioi Chern 1930;86:587. 85. Hulsey TK, O'Neill lA, NeblettWR, et al: Experimental wound healing in essential fatty acid deficiency. 1 Pediatr Surg 1980;15: 505-508. 86. Caffrey BB, Jonsson HTJr: Role of essential fatty acids in wound healing in rats. Prog Lipid Res 1981;20:641--647. 87. Caldwell MD, Jonsson HT, Othersen HB Jr: Essential fatty acid deficiency in an infant receiving prolonged parenteral alimentation. 1 Pediatr 1972;81:894-898. 88. Burney DP, Goodwin C, Caldwell MD, et al: Essential fatty acid deficiency and apparent wound healing in an infant with gastroschisis. AmSurg 1979;45:542. 89. Nordenstrom 1, Carpentier YA, Askenazi 1, et al: Free fatty acid mobilization and oxidation during total parenteral nutrition in trauma and infection.Ann Surg 1983;198:725-735. 90. Wolfram G, Eckart 1, Walther B, Zollner N: Factors influencing essential fatty acid requirements in total parenteral nutrition.lPEN 1 Parenter Enteral Nutr 1978;2:634-639. 91. Wene 10, Connor WE, DenBesten L: The development of essential fatty acid deficiency in men fed fat free diets intravenously and orally.1 Clin Invest1975;56:127-134. 92. Greig PD, Baker lP, leejeebhoy KN: Metabolic effects of total parenteral nutrition.Annu RevNutr 1982;2:179-199. 93. AlbinalE, Gladden P, WalshWR: Detrimental effectsof an omega3 fatty acid-enriched diet on wound healing. lPEN 1 Parenteral EnteralNutr 1993;17:519-521. 94. Simopoulos AL: Omega-S fatty acids in health and disease and in growthand development. Am1 Clin Nutr 1991;54:438-463. 95. Prickett 10, Robinson DR, Steinberg AD: Effects of dietary enrichment with eicosapentaenoic acid upon autoimmune nephritis in female NZB X NZW/F1 mice. Arthritis Rheum 1983;26:133-139. 96. KremerJM, Jubiz W, Michalek A, et al: Fish-oil fatty acid supplementation in active rheumatoid arthritis: A double-blind, controlled, crossoverstudy. Ann Intern Med 1987;106:497-503. 97. SperlingR1, Robin Jl., KylanderKA, et al: The effectsof N-3 polyunsaturated fatty acids on the generation of platelet-activating factoracether by human monocytes. 1 Immunol 1987;139:4186-4191. 98. EndresS, Ghorbani R, Kelley VE, et al: The effect of dietarysupplementation with N-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl 1 Med 1989;320:265-271. 99. Englard S, Seifter E: The biochemical functions of ascorbic acid. Annu Rev Nutr 1986;6:365-406.
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100. Osler W: The Principles and Practice of Medicine. New York, D. Appleton, 1892. 101. Crandon lH, Lund CC, Oil DB: Experimental human scurvy. N Engl 1 Med 1940;223:353. 102. Kivirikko KI, Helaakoski T, Tasanen K, et al: Molecularbiologyof prolyl4-hydroxylase. Ann NY Acad Sci 1990;580:132-142. 103. LanmanTH, Ingalls TH: Vitamin C deficiencyand wound healing (experimental and clinical study). Ann Surg 1937;105:516. 104. Bourne GH: Effect of vitamin C deficiency on experimental wounds. Tensilestrength and histology. Lancet 1944;1:688. 105. LundCC, Levenson SM, Green RW, et al: Ascorbicacid, thiamine, riboflavin and nicotinic acid in relation to acute burns in man. ArchSurg 1947;55:557. 106. Rivers 1M: Safety of high-level vitamin C injection. Ann NY Acad Sci 1987;498:445-454. 107. Brandaleone H, Papper E: The effectof the local and oral administration of cod liveroil on the rate of wound healing in vitaminA deficient and normal animals. Ann Surg 1941;114:791. 108. Ehrlich HP,HuntTK: Effects of cortisone and vitaminAon wound healing. Ann Surg 1968;167:324-328. 109. Levenson SM, Seilter E, VanWinkle W: Nutrition. In Hunt TK, Dunphy lE (eds): Fundamentals of Wound Management in Surgery. NewYork, Appleton-Century-Crofts, 1979, pp 286-363. 110. Goodson WH 3rd,HuntTK: Woundhealingand nutrition. InKinney 1M, leejeebhoy KN, Hill GL, et al (eds): Nutrition and Metabolism in PatientCare. Philadelphia, WB Saunders, 1988, pp. 635-642. 111. SeifterE, Rettura G, Padawer 1, et al: Impaired wound healing in streptozotocin diabetes: Prevention by supplemental vitamin A: Ann Surg 1981;194:42-50. 112. Weinzweig 1,Levenson SM, Rettura G,et al: Supplemental vitamin A preventsthe tumor induced defect in wound healing. AnnSurg 1990;211 :269-276. 113. Stratford F, Seilter E: Impaired wound healing by cyclophosphamide: Alleviation by supplemental vitamin A. Surg Forum 1980;31:224. 114. Levenson SM, Gruber CA, Rettura G, et al: Supplemental vitamin A prevents the acute radiation-induced defect in wound healing. AnnSurg 1984;200:494-512. 115. Demetriou AA, Levenson SM, Rettura G, et al: Vitamin A and retinoic acid: Induced fibroblast differentiation in vitro. Surgery 1985;98:931-934. 116. Jetten AM: Modulation of cell growth by retinoidsand their possible mechanisms of action. Fed Proc 1984;43:134-139. 117. Moody 81: Changes in the serum concentrations of thyroxinebinding prealbumin and retinol binding protein following bum injury. ClinChimActa 1982;118:87-92. 118. Rai K, Courtemanche AJ: Vitamin A assay in burned patients. 1 Trauma 1975;15:419-424. 119. Ramsden DB, Prince HP, BurrWA, et al: The inter-relationship of thyroid hormones, vitamin A and the binding proteins following stress. ClinEndocrinol 1978;8;109-122. 120. Demling RH, DeBiasse M: Micronutrients in critical illness. Crit Care Clin 1995;11:651-673.
121. Hunt TK: Vitamin A and wound healing. 1 Am Acad Dermatol 1986;15:817-821. 122. BaxterCR: Immunologicreactions in chronic wounds. Am1 Surg 1994;167:125-14S. 123. Shukla A, Rasik AM, Patnaik GK: Depletion of reduced glutathione, ascorbic acid, and vitamin E and antioxidant defense enzymes in a healing cutaneous wound. Free Radic Res 1997;26: 93-101. 124. Todd WR, Elvehjem CA, Hart EB: Zinc in nutrition of the rat. Am1 Physiol 1934;107:146. 125. Vallee BL: Metabolicrole of zinc. Report of Council of Foods and Nutrition. lAMA 1956;162:1053-1057. 126. Prasad AS, Miale A Jr, Farid Z, et al: Biochemical studies on dwarfism, hypogonadism and anemia. Arch Intern Med 1963; 111:407-428. 127. Prasad AS: Acquired zinc deficiency and immune dysfunction in sickle cell anemia. In Cunningham-Rundles S (ed): Nutrient Modulation of the Immune Response. NewYork, Marcel Decker, 1993, pp. 393-410. 128. Hallbook T, Lanner E: Serum zinc and healing of leg ulcers. Lancet 1972;2:780-782. 129. Nimni ME: Mechanism of collagen crosslinking by penicillamine. Proc R Soc. Med 1977;70(suppl 3):65-72. 130. Geever EF, Youssef SA, Seilter E, et al: Penicillamine and wound healing in young guinea pigs.1 Surg Res 1967;6:160. 131. Raahave D, Friis-Moller A, Bierre-lepsen K, et al: The infective dose of aerobic and anaerobic bacteria in postoperative wound sepsis. Arch Surg 1986;121:924-929. 132. Robson MC, Shaw RC, Heggers lP: The reclosure of postoperative incisional abcesses based on bacterial quantification of the wound. Ann Surg 1970;171:279-282. 133. Thornton Fl, SchafferMR, BarbulA: Wound healing in sepsis and trauma. Shock 1997;8:391-401. 134. Mullen Jl., BuzbyGP, Matthews DC, et al: Reduction of operative morbidityand mortalityby combined preoperative and postoperative nutritional support. Ann Surg 1980;192:604-613. 135. Williams RH, Heatley RV, Lewis MH: Proceedings:A randomized control trial of preoperative intravenous nutrition in patients with stomach cancer. Br1 Surg 1976;6:667. 136. Kiyama T, WitteMP, Thornton El,et al: The route of nutritionsupport affects the early phase of wound healing. lPEN 1 Parenter Enteral Nutr 1998;22:276. 137. Zaloga GP, Knowles R, Black KW, et al: TPN increases mortality alter hemorrhage. CritCare Med 1991;19:54-59. 138. Kudsk KA, Stone 1M, Carpenter G, et al: Enteral and parenteral nutrition influences mortalityalter hemoglobin-E. coli peritonitis in normal rats.1 Trauma 1984;23:605-609. 139. Delany HM, John 1, Teh EL, et al: Contrastingeffects of identical nutrients given parenterally or enterally after 70% hepatectomy. Am1 Surg 1994;167:135-143. 140. Lin MT, Saito H, Fukushima R, et al: Route of nutritional supply influences local, systemic and remote organ responses to intraperitoneal bacterial challenge. Ann Surg 1996;223:84-93.
Nutrition-Focused History and Physical Examination Linda Lord, NP, MSN, CNSN Robert Schaffner, NP, DPH, MSN
CHAPTER OUTLINE Introduction PsychosocialcuItu ral Review Current Health Status Clinical History Medical Diagnoses Surgical Procedures Anthropometric Data Diet Oral Fortified Foods Complete Medical Foods Enteral Access Device Total Parenteral Nutrition Parenteral Access Device Medications (Prescription and Over-the-Counter) Alternative Therapies Medication Allergies/Intolerances Food Allergies/Intolerances Bowel Pattern Habits Pain Assessment
Review of Systems Related to Nutrition/Hydration General Visual
INTRODUCTION An evaluation of nutrition status should be a part of any history and physical examination because inadequate nutrition increases the overall risk for morbidity and mortality. Morbidities include delayed wound healing and increased risk for infection and abscess formation that translate to prolonged hospital stays and higher mortality rates.":'? In addition, abnormal physical signs or symptoms discovered during the history and physical examination may be due to a deficiency or excess of
Auditory Gustatory Gastrointestinal Function Renal Function Genital Neurologic Function
Nutrition-Focused Physical Examination General Survey Vital Signs Temperature Pulse Rate Respiratory Rate Blood Pressure Skin Nails Hair, Head and Neck, Eyes, and Mouth and Throat Chest and Heart Abdomen Musculoskeletal and Neurologic Systems
Laboratory Findings Assignment of Nutritional Risk Based on Subjective Global Assessment Nutrition Support and Medical Ethics
macro- or micronutrients. No one clinical nutrition marker or laboratory finding can determine a patient's nutrition status because none is all inclusive and all need to be interpreted in relation to the patient's history and current health status. An evaluation of current health status, a nutrition-focused history and physical examination, and laboratory testing should be performed in all patients, especially those who are acutely ill, to identify preexisting malnutrition or those at risk of becoming malnourished. Periodic nutrition assessments are crucial, especially in malnourished patients or patients 185
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determined to have a risk for malnutrition. Malnutrition can develop quickly or worsen during hospitalization or outpatient treatments. Follow-up is also necessary to reevaluate the nutrition plan.
PSYCHOSOCIALCULTURAL REVIEW One of the most notable process changes in modem medical care has been the change from paternalist practice to the modem participatory doctor-patient relationship. The same is true for the allied professions of pharmacy, nursing, and dietetics. When a patient consults with any health professional, a contractual relationship is established. The patient provides the clinician with personal, intimate information for assessment and planning. Although the disciplines of medical care are generally transcultural, moral values and ethics depend on historical, religious, social, and cultural experiences. Thus, for a clinician to provide competent care he or she must consider the total person and look beyond the diagnosis to learn "who" is the person experiencing the condition. The clinician must understand clearly what is important to the patient (e.g., safety, control, or religious convictions toward medical interventions). Without a clear understanding of the psychosocialcultural ontology of the patient, treatments may be proposed that the patient cannot accept. One excellent model for making such an assessment is that of Block,11,12 who has developed one of the foremost cancer treatment programs in the United States. He described its core component as « ••. addressing who the patient is,how they live,how they take care of themselves, who their immediate others are, basically looking at the internal and external microenvironment of the patient."!" His assessment of a patient's psychosocial profiles builds on Maslow's Hierarchy of Needs, and includes an attitudinal, stress, and learning profile to determine the manner in which patients process information. Such a model can also be used to incorporate cultural values and be instructive for patient approaches and care. Lerner'! provided an in-depth analysis of Block's work, and, the reader may find the Case Western Reserve University link for cultural competencies available at http://cme.cwru.edu/cae/ resource.htm helpful for developing a personal psychosocialcultural assessment approach. Before an interview and physical examination, the clinician should understand that patients (whether in the hospital or clinic) will have at least some anxiety about their physical condition that requires nutritional care and examination by touch from a person they do not know. For this reason, it is important to establish a comfortable atmosphere for assessment as outlined in the next paragraph. Greet the patient with a handshake if it is appropriate, and introduce yourself. Ask the patient to make himself or herself comfortable, and project a confident attitude. If the patient has come to see you, ask how you can help. If you have been referred to consult with the patient, identify the reason you were asked to see him or her. Tell the patient that your interview will be confidential
and that you will be making notes. As the patient gives information, validate what you have heard. Important areas of the nutrition-focused assessment include current health status, clinical history, including anthropometric data, diet, nutritional support, medications, bowel function, and habits, and laboratory findings. Next the standard approach to physical assessment includes a review of systems to identify symptoms and a nutrition-focused physical examination. Nutritional risk can then be determined.
CURRENT HEALTH STATUS Current clinical conditions that affect clinical nutrition markers and laboratory findings include the presence of illness or disease and fluid balance. Illness or disease conditions tend to affect clinical nutrition markers and laboratory findings by influencing food intake, changing the metabolic rate, interfering with nutrient digestion/absorption, or changing fluid balance. Food intake is affected by many factors including energy level, mental health status, eating disorders, appetite, early satiety, taste changes, nausea, discomfort and pain, dysphagia, and dental condition. Conditions known to significantlyincrease metabolic rate and caloric requirement include multiple trauma, closed-head injuries,severe bums, large draining wounds or abscesses, sepsis, and protracted fever. These conditions can increase caloric needs up to twofold. Conditions that prevent nutrients from being adequately digested and/or absorbed include exacerbation of inflammatory bowel disease, pancreatitis, radiation enteritis, carcinoid, short bowel syndrome, vomiting, diarrhea, and high-output fistulas or ostomies. Potential macro- or micronutrient deficiencies can be predicted in these malabsorptive states before clinical manifestations are apparent. Fluid status affects almost all clinical nutrition markers and laboratory findings. Fluid retention results in non-nutritional weight gain, potentially masking an emaciated appearance. Vasodilatation, which leads to thirdspace fluid retention in interstitial spaces, allows leakage of plasma proteins, resulting in lowered plasma protein levels. Plasma proteins are commonly used to evaluate visceral protein status. In addition, intravenous fluid therapy may have a dilutional effect on plasma proteins. Alternately, dehydration results in non-nutritional weight loss and falsely elevated plasma protein levels.
CLINICAL HISTORY A complete clinical history is needed to determine what factors are significant in the nutrition assessment and plan. In critically iII patients, food records are not generally available, so information about the patient's health status before the illness or trauma will help determine the nutritional state. Patients with a history of oncologic diseases, musculoskeletal diseases, swallowing disorders, eating disorders, malabsorptive states, alcoholism, and recreational drug use have an increased risk of
SECTION IV. Principles of Enteral Nutrition
malnutrition. If the patient's condition on referral appears complex, requiring a detailed assessment, plan to have a dietitian see the patient with you or refer the patient to a dietitian. Data to include in the nutrition assessment are as follows.
Medical Diagnoses Include dates of diagnosis, treatments, and hospitalizations.
Surgical Procedures Include dates of procedures, indications, and complications. For significant bowel resections and reconstructions, the current bowel anatomy and the length of remaining bowel are recorded.
Anthropometric Data Data on height, current weight, usual weight, and weight changes are recorded, if available. If the patient is fluid overloaded, a dry weight should be estimated and is usually based on the preillness weight. From these measurements, ideal body weight (IBW) and body mass index (BMI) can be calculated. IBW for the individual can be determined from the height (for males: 106pounds for the first 5 feet and 6 pounds for each additional inch; for females: 100 pounds for the first 5 feet and 5 pounds for each additional inch). Individuals are considered cachectic if their actual weight is less than or equal to 80% of IBW, and the nutrition goal is usually weight gain. Obesity adjustments are calculated when actual weight is greater than or equal to 125% of IBW, unless the gain is due to muscle weight gain. If the weight gain is due to fat deposition, one fourth of the difference between the actual weight and the IBW is added back to the actual weight and yields the obesity adjusted weight. Caloric and protein needs are then based on this adjusted weight. The BMI is weight in kilograms divided by the square of height in meters. People with BMls between 19 and 22 live longest. Mortality rates are higher for people with BMls of 25 and greater. The U.S. government in 2001 changed the normal range to a minimum of 20 and a maximum of 24 (seehttp://usgovinfo.about.com/ Iibrary/ weekly/aa010803a.htm#bmi). BMls, however, must be judged against the physical habitus of the patient. A weight builder with a BMI of 26 is vel}' different from an obviously obese individual with the same BM!. These data will help to guide the nutrition intake history as described later.
Diet Special diets and food preferences are noted. If possible, 2 to 3 days of food records should be obtained to
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determine the usual pattern of food choices and estimate total caloric, macronutrient, vitamin/mineral, and fluid intake. A 24-hour recall can be done initially if food records are not available." Careful attention to portion sizes and ingredients will make the analysis more accurate. Rough estimates of portion sizes can be used, such as equating 3 oz of meat to a deck of cards, 1 oz of cheese to 4 dice, 1 medium potato to a standard computer mouse, 1 medium piece of fruit to a tennis ball, and 1 cup of anything to a baseball. Nutrition intake history questions provide a sense of the patient's eating habits and also help identify factors that may be affecting health or a disease state." The patient should be asked about the following: How many times a week are red meat, chicken, turkey, pork, and fish eaten? How many meals and snacks are eaten each day and are they eaten while watching TV? How many meals each week are eaten away from home and at what types of places (e.g., restaurant or fast food place)? How many times a week are desserts and sweets eaten? How many servings of vegetables and fruits and fiber cereal are eaten each day? Which types of beverages are drunk each day (ask particularly about water, sodas, and beer and other alcoholic beverages)? The answers to these questions will reveal the regularity of eating patterns (place and times) and snacking habits and risk factors for many systems. For example, when the majority of food intake occurs in front of the TVand or at night, there is a high risk for obesity. Lack of consumption of fiber, fruit, or vegetables or frequent intake of alcohol or red meat reveals other risks to the nutritionist. The patient may be using supplements to or substitutions for the oral diet that may include manufactured nutrition foods (liquid or powdered enteral products) and parenteral formulas.
Oral Fortified Foods Oral intake of nutrient-fortified liquid, powder, and bar supplements is documented to determine the contribution of these foods to the total caloric, protein, and micronutrient intake.
Complete Medical Foods Complete medical foods are supplied in liquid or powder form and can be administered as the sole source of nutrition, provided that enough water is supplied to meet fluid needs. These products can be administered orally or by enteral tube feeding. Flavoring agents are added to products designed for oral use. The product type, strength, volume per day, and infusion schedule should be noted as well as tolerance to the product and the calories, protein, and fluid provided. If the product is being delivered as a tube feeding, the feeding schedule and volume of water flushes should be noted.
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Enteral Access Device Tube feedings are delivered by an enteral access device. Data that should be collected include the following: • Brand (manufacturer) • Type (i.e., nasogastric, nasoenteric, gastrostomy, or jejunostomy) • French size • Balloon volume (if applicable) • Tube/shaft length (if applicable) • Placement date • Inserter • Appearance of insertion site
Total Parenteral Nutrition The formula components, volume per day, infusion schedule, and calories, protein, and fluid provided should be noted.
Parenteral Access Device If the patient is receiving total parenteral nutrition, data
that should be collected include the following: • Brand (manufacturer) • Type (i.e., tunneled central venous catheter, implantable vascular access device, or peripheral intravenous central catheter) • Tip location • Placement date • Inserter • Appearance of insertion site
Medications (Prescription and Over-the-Cou nter) A list of medications, dose, and frequency of use is recorded. Medications are drugs approved by the Federal and Drug Administration (FDA) for sale in the United States. Through rigorous scientific testing and procedures, they are determined to be safe and effective. FDA labels include the indication for use; who should take the medication; potential adverse side effects; instruction for uses in pregnant women, children, and other populations; and safety information. The strength of the product is determined by the amount of active ingredient and purity is determined by medical analysis. A list of medications is important in a nutrition assessment because all medications alter the body's function in some way. Examples of medicinal alterations in body function that affect the nutrition plan include changes in metabolic rate, glucose utilization, appetite, level of consciousness, gastrointestinal motility and digestive and absorptive capability, and fluid status. Medications that have catabolic properties and call for an increase in nutrient need include steroids, immunosuppressive
agents, and antitumor agents. Some medications such as neuromuscular blocking agents decrease energy expenditure and therefore lower caloric need. Standarddose multivitamins, minerals, and trace elements are also considered medications and need to be included in the listing. Medications may also interact with other medications, food, or tube feeding products. Known interactions are listed on the package insert that is included with the medication.
Alternative Therapies It is important that the clinician purposely ask patients if they use alternative therapies because Eisenberg and associates discovered in 199716 that approximately 15 million adults in the United States do so. These therapies included ingestion of herbal products and megavitamins along with massage, membership in self-help groups, and energy healing. Eisenberg and associates also reported that fewer than 40% of patients informed their medical doctors that they were using alternative therapies. Many patients fail to inform clinicians that they are using alternative therapies because they are not asked about them. These patients generally are not dissatisfied with conventional medicine and are seeking treatment options that fit in with their personal values and cultural beliefs about health care.F Many times, patients are not aware of the potential harm that ingestion of herbal products and megavitamins can cause. The clinician needs to be proactive during the nutrition assessment in determining alternative therapy use. The goal is to attain a mutually agreed upon nutrition plan of care that is considered safe and is based on sound scientific principles while integrating the patient's personal and cultural beliefs.
Unproven Herbal Products Unproven herbal products are botanical (plant-based) drugs that can legally be produced and distributed in the United States but are not regulated by the FDA. There is no obligation for manufacturers of herbal products to provide information on their strength, purity, or potential adverse side effects; on who should or should not take them; or on their safety. These products may interact with or potentiate the effects of medications. Predicting potential interactions of herbal products and medications is difficult because scientific information on herbal products varies widely and simply does not exist for some of them. Hence, serious illness and death have resulted from use of these so-called "natural" herbal remedies.
Nonplant-Based Products Some examples of nonplant-based supplements are hormones, enzymes, probiotics, cartilage, and ozone therapies.
SECTION IV • Principles of Enteral Nutrition
High-Dose Vitamin, Mineral, and Trace Element Supplements The clinician must ask for the dose and frequency of ingested vitamins and trace elements because these can be taken in safe doses to meet the Recommended Dietary Intake (RDI) or in megadoses that can potentially be harmful.
Medication Allergies/1ntolerances Note the medication and the reaction to it.
Food Allergies/Intolerances Note the food and the reaction to it.
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form, quantity, frequency, and duration of use. Note any drug treatment programs the patient has participated in and the successfulness of therapy.
Pain Assessment In 2000 the Joint Commission on Accreditation of Healthcare Organization (JCAHO) developed formal standards of care for the assessment and management of pain." One of these standards states that "All healthcare organizations must assess the existence, and, if present, the nature and intensity of pain in all patients, residents and clients." It is important to note the presence of pain during a nutrition assessment, not only to meet JCAHO standards, but also because pain and its treatment can interfere with oral intake and appetite and can affect metabolic rate, learning ability, and sense of overall physical, psychologic, and spiritual well-being.
Bowel Pattern Information on frequency, color, consistency, shape, and estimation of size or volume of bowel movements is obtained. Note any reported difficulties with moving bowels and what treatments are being used, changes in bowel habits, and any reports of hematochezia, mucus, oiliness, or pus in stool.
Habits Tobacco Use Note the form of tobacco used (inhaled verses chewing) and the frequency and duration of use. If the patient has quit, record the time period.
REVIEW OF SYSTEMS RELATED TO NUTRITION/HYDRATION In the review of systems, the patient is asked about the presence of common nutrition-related symptoms in each body system to be sure that an important symptom is not overlooked. Possible nutrition- or fluid status-related etiologies of the symptoms are listed. Note that there will also be possible etiologies of these symptoms that are not related to nutrition or hydration and need to be ruled out. Generally, the review of symptoms either precedes or is done in conjunction with the physical examination and includes the following.
General Alcohol Consumption Significant alcohol intake contributes to the calorie load and may interfere with the bioavailability of vitamins, particularly thiamine and folic acid, leading to symptoms of vitamin deficiency. If a patient is a potential candidate for home nutrition support therapy, alcohol consumption can interfere with the his or her ability to safely administer this therapy and care for the access device. Note whether the patient has had or currently has a drinking problem and the type, quantity, frequency, and duration of alcohol use. If the patient has quit, record the time period. Note any alcohol rehabilitation programs that the patient has participated in and the successfulness of the program.
Recreational Drug Use Like alcohol, illegal drug use can have an impact on a patient's health, directly relate to a patient's symptoms, and interfere with the safe administration of the nutrition support plan. In a nonjudgmental manner, question the patient about recreational drug use and note the type,
• Activity/energy level: Note usual daily activities, frequency of exercise, and sleeping pattern help determine calorie and protein need. A decreased energy level may be due to unmet calorie and/or protein needs or to iron, folic acid, or iodine deficiency. • Lethargy, irritability, disorientation: Mental status changes may be due to hyperglycemia, hypoglycemia, infection, metabolic acidosis, thiamine deficiency, or folic acid deficiency or excess or deficiency of sodium, potassium, calcium, phosphorus or magnesium. • Chills: Possible fever. In a patient with a parenteral access device, a fever may be a sign of an access line-related infection. If a line-related infection is suspected, blood cultures are obtained as soon as possible, and broad-spectrum antibiotic therapy is initiated, if indicated. • Dizziness or Iightheadedness: Possible dehydration • Shortness of breath: Possible hypophosphatemia, metabolic acidosis, fluid overload or air embolus (central line-related) • Bleeding tendencies, petechiae, ecchymosis: Possible vitamin C or K deficiency
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16 • Nutrition-Focused History and Physical Examination
• Poor wound healing: Possible protein, vitamin C, zinc, or essential fatty acid deficiency
Visual
Neurologic Function • Peripheral neuropathies (numbness or tingling of "pins and needles" in fingers or toes) leading to weakness and paralysis: Possible thiamine, vitamin 8 12, or selenium deficiency
• Nightblindness: Possible vitamin A or zinc deficiency. Note date of last eye examination.
Auditory • Hearing loss: Possible iron deficiency. Note date of last hearing examination.
Gustatory • Hypogeusia (impaired taste): Possible vitamin A or zinc deficiency • Anorexia (decreased appetite): Possible zinc deficiency, hypercalcemia, hypomagnesemia • Dysphagia (difficulty swallowing) • Odynophagia (painful swallowing) • Increased hunger: Possible hypoglycemia • Increased thirst: Possible dehydration, hyperglycemia • Dental problems: Note date of last dental examination.
Gastrointestinal Function • Diarrhea: Possible folic acid, niacin, vitamin 8 12, or zinc deficiency • Nausea/emesis: Possible folic acid deficiency, hypercalcemia, or hyper/hypomagnesemia • Early satiety • Heartburn • Excessive belching or passing of gas
NUTRITION-FOCUSED PHYSICAL EXAMINATION As stated earlier, clinicians should validate information from patients. When the nutritionist and patient agree that the problem or reason for consultation is understood, the physical examination should begin. Patients should be told that the clinician will be inspecting, feeling, listening, and tapping for sound (inspection, palpation, auscultation, and percussion) during the examination and that if anything makes them uncomfortable that portion of the examination will be stopped. It is also important to ask whether patients have pain, where it is located and its timing, quality, intensity, and history so that precautions can be taken in examination of the area. All procedures should be explained, and it is important for the patient's comfort that the clinician maintain a calm, relaxed demeanor despite a finding that may be alarming or distasteful. Equipment useful for the examination includes the following: • Penlightlflashlight • Ophthalmoscope • Tongue depressor • Stethoscope • Gowns or towels for draping as necessary • Tape measure
General Survey Renal Function • Urination: Frequency, timing; color of urine • Decreased urine output, darker yellow color: Possible dehydration • Polyuria: Possible hyperglycemia, fluid overload
Genital Male • Decreased sexual interest/function: Possible testosterone deficiency due to malnutrition
Female • Last menstrual period • Dysmenorrhea: Possible malnutrition, essential fatty acid deficiency
This portion of the examination is ongoing from the moment the clinician first sees the patient. If in a clinic, how is the patient dressed? Is the clothing appropriate to the weather and clean, and what message does it give (e.g., does the patient appear to be a member of a subculture or different culture and does he or she care about appearance)? As the patient walks, how does he or she ambulate (e.g., is it easy or does the patient appear to be weak or have a limp)? If the patient is in a hospital, how is he or she positioned in the bed (e.g., is the patient slumped over, is the gown appropriately draped, or how does the patient move)? For all patients, examine the facial expression, note whether they are breathing easily or not, and observe for any signs of distress. Ifthe patient has a recent history of malnutrition and the clinician observes a new disorientation, a deficiency in vitamin 8 12, thiamine, niacin, or magnesium may be suspected. Make mental notes to validate this suspicion later during the interview and examination.
SECTION IV • Principles of Enteral Nutrition
Vital Signs In either the clinic or the hospital, most patients will have their vital signs measured by a registered nurse or clinical technician before the patient is seen by the nutritionist. This includes measurement of temperature, pulse rate, respiratory rate, and blood pressure. The patient should be allowed to rest at least 5 minutes before vital sign measurements, so findings are not affected by exertion. Because there is a potential for measurement error, repeat measurement should be done by the clinician when values are outside of the normal range or do not seem to be consistent with the general survey. In all cases, hands should be washed and gloves used if indicated and the patient should be seated. Ifvalues for any vital sign are markedly outside of the normal range, the physician should be notified at once.
Temperature Temperature can be measured by glass thermometer, paper, or electronic tongue/ear machine. Fever is defined as temperature greater than 38.5°C or 101.5°F. In patients with prolonged fever (e.g., hospitalized patients), a need for increased calories and fluids is indicated.
191
rate is between 60 and 100 pulsations/min. Tachycardia (regular rate >100) in patients without a history may indicate anemia or dehydration and should be validated by history and exam. If the pulse is irregular, it should be counted for a full minute. If the pulse is not countable (very irregular or thready), atrial fibrillation should be suspected and reported to the physician immediately.
Respiratory Rate Because most people become self-conscious about their breathing if attention is brought to it, many clinicians will observe the patient's chest for a full inspiration-exhalation cycle after counting the pulse (continuing to hold the patient's wrist as if continuing the pulse check) to watch the number of cycles in 30 seconds and then multiply by two. Normal respiratory rate is between 12 and 20 cycles/min. In general, respiratory rate provides information for the clinician when pulmonary or cardiovascular disease is present. For example, patients with chronic obstructive pulmonary disease exhibit shortness of breath and often are cachectic because it is difficult for them to eat and breathe at the same time.
Blood Pressure Pulse Rate The pulse can be felt and counted at any place where a large artery is close to the skin (e.g., the temporal bone, carotid artery, or brachial artery) or by auscultating the heart. Usually the pulse rate is palpated with the index and middle finger where the thumb base meets the wrist (Fig. 16-1). The wrist is supported and the touch is light at first so as not to occlude the vessel. Press more firmly if the patient is obese or the pulse cannot be felt. A common method is to count the pulsations for 30 seconds and multiply by 2 if the pulse is regular. 19 A normal pulse
Blood pressure is measured using a sphygmomanometer (arterial blood pressure manometer) (Fig. 16-2) and stethoscope. The mercury manometer is an upright tube that measures arterial blood pressure in millimeters of mercury. The aneroid (portable) manometer has a glass enclosed circular gauge containing a needle that registers millimeter calibrations. Clinics should have pediatric (helpful for the cachectic patients), normal adult, and obese cuff sizes. For a correct fit the inflatable bladder (felt through the vinyl covering of the cuff) should reach roughly 80% around the circumference of the arm while its width should cover roughly 40%.
Figure 16-1. Measuring pulse rate.
Figure 16-2. Blood pressure cuff.
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16 • Nutrition-Focused History and Physical Examination
systems'", In this chapter, examination of the skin and its related structures: hair and nails; the head, eyes, and mouth; and systems considered to be related to nutrition by interview or clinical findings will be reviewed.
Skin
Figure 16-3. Finding the artery and inflating the cuff.
The procedure is as follows. Hold the arm up at heart height. Wrap the cuff so that the line marked "artery" is over the brachial artery, which is palpated in the crook of the elbow. Place the stethoscope diaphragm over that spot and insert the binaurals (the two listening tubes) into the ears; then inflate the cuff until the pulse can no longer be felt. Release for 5 minutes; then inflate to 30 mm above the first inflation pressure. Release at a rate of 2 mm at a time and listen for the first (systolic) and last (diastolic) sounds (Fig. 16-3). Normal blood pressure is between 100/60 and 140/90 mm Hg. Hypertension is thus defined as either systolic blood pressure greater then 140 mm Hg or diastolic blood pressure greater than 90 mm Hg and may indicate a need for calorie, fluid, and/or sodium restriction. Hypotension (defined as systolic blood pressure less than 80 mm Hg or diastolic blood pressure less than 60 mm Hg) with symptoms of dizziness when the patient is standing may indicate dehydration. After vital signs are assessed, the physical examination follows. The clinician focuses on at least three body areas: skin, oral area, and related structures and
Figure 16-4. The Skin.
Inspection of the skin begins when the patient is first seen and continues throughout the examination. The first step of the physical examination is to determine what protective precautions are indicated. If the skin is not intact or there is another need for caution, observe the universal precautions of hand washing and use of gloves, masking, and any other protective measure as indicated. If the skin is intact, wash and warm the hands. As the examination is conducted, note the color, texture, vascularity, and temperature of the skin (Fig. 16-4). Many clinicians feel the skin with the back of their fingers to best assess temperature. A fold of the skin should be lifted to note the ease of movement and speed of return to a relaxed position (mobility and turgor). Also feel the nails for smoothness and shape. Note any lesions. Example of some lesions are the following: • Macule: A small flat skin discoloration (Fig. 16-5) • Papule: A raised solid area (to 0.5 cm); nodules are up to 2 ern, tumors are larger than 2 ern (Fig. 16-6). • Vesicle: A serous fluid-filled elevation (up to 0.5 ern). Bullae are larger, and the lesion is called a pustule when pus is present (Fig. 16-7). Nutritional findings related to the skin are listed in Table 16-1. A dermatologic textbook is best referred to for diagnosis. Also available are helpful Web sites such as Archives of Dermatology (http://archderm. ama-assn.org) .
Nails Nails can reflect hygiene, psychologic status (bitten edges), state of nutrition, and occupation. The normal
Figure 16-5. Macule.
SECTION IV • Principles of Enteral Nutrition
193
Figure 16-6. Papule.
Figure 16-7. Vesicle.
nail is smooth, transparent, and convex with a nail bed angle of 160 degrees. Palpate nails for shape, thickness, and texture, and observe for color and condition of the folds around the nail bed. Nutritional findings related to the nails are listed in Table 16-2 and illustrated in Figures 16-8 and 16-9.
sequence. Different portions are included, depending on the situation and the examiner.
Hair, Head and Neck, Eyes, and Mouth and Throat Assessment of the head, hair, eyes, mouth, and throat begins with the general survey and is not a single, fixed
Examination
of the
Hair
Before actual palpation of the head, explain to the patient that inspection of the hair and scalp requires parting sections of the hair. Ask if the patient is wearing a wig (request that it be removed) or has had any recent trauma or sores. Wear gloves if lice or lesions are expected. Have the patient flex the chin to the neck and part the hair in several places. Inspect for color, thickness, distribution, texture, and elasticity
_ _ Nutritional Findings Related to the Skin Skin
Findings
Face
Dark skin under the eyes and over the cheeks Pallor
Face, trunk, arms, hands
Yellow jaundice Yellow palms
Exposed areas Pressure points, legs, general skin General
Spider angioma (a red macule shaped like a spider) on face, arms, upper body Flaking skin and ruborous hands Grayish tan or bronze Pressure sores, edema, delayed wound healing Dry, scaly skin Desquamating dermatitis Rash Symmetric pattern rash worsened by sun/heat (pellagra) Large desquamating, hyperpigmented patches and plaques resembling enamel paint on the extensor surfaces of the arms and legs and on the lower back, leaving a raw, erythematous surface Follicular hyperkeratosis (goose bumps that do not rub away) Petechiae, purpura Edema
Potential Nutritional Deficiency or Other Condition Niacin or other B vitamins Iron, copper, folate, vitamin B6 , vitamin B I2 , vitamin E Liver disease Caused by a diet high in carrots and yellow vegetables Vitamin B, liver disease, sometimes normal
Essential fatty acids Hemochromatosis Protein and calorie, zinc, vitamin C Dehydration, vitamin A, riboflavin, essential fatty acids Essential fatty acids Zinc Niacin Kwashiorkor-extreme protein deficiency, niacin, riboflavin
Vitamin A, vitamin C Vitamin C, vitamin K Protein, severe thiamine deficiency, fluid overload
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16 • Nutrition-Focused History and Physical Examination
_ _ Nutritional Findings Related to the Nails Flndings
Potential Nutritional Deficiency
Dry and brittle
Essential fatty acids Copper (excess) Iron Protein and calorie
Blue lunula Spooning (Fig. 16-8) Transverse lines, ridging (Fig. 16-9)
(Fig. 16-10). Nutritional findings related to the hair are listed in Table 16-3.
Examination of the Head and Neck Have the patient bring the chin upright and look at his or her face for symmetry, bone prominence, temporal fullness, and involuntary movements (Fig. 16-11). Note color, scars, rashes, lumps, or other lesions. Next feel the underside of the mandible and on either side of the neck, along the sternocleidomastoid muscles from the angle of the jaw to the top of the clavicle for lymph node enlargement, which may indicate infection. Because these muscles allow the head to turn, they can be examined by asking the patient to turn the head right and left (Fig. 16-12). Submental lymph nodes drain the teeth and oral cavity, and those along the underside of the jaw drain structures of the mouth floor. The sternocleidomastoid lymph nodes drain internal parts of the pharynx, tonsils, and thyroid. The nodes along the clavicle drain part of the thoracic cavity and abdomen. Infected lymph nodes tend to be warm, firm, tender, and enlarged. Inflammation can cause the overlying skin to appear reddened. At the same time as the patient's neck is turned, the external jugular vein, which drains most of the blood from the scalp and face, can be seen. It runs backward and downward across the sternocleidomastoid muscle.
Figure 16-8. Spooning of nail.
Figure 16-9. Transverse lines or ridging of nail.
Next, examine the neck for symmetry and the thyroid gland for enlargement. The normal thyroid may not be visible. To palpate the thyroid, look for the thyroid cartilage. This is the midline bulge seen prominently in some men and known as the Adam's apple. It is best seen by having the patient tilt the head backward. The gland lies approximately 2 to 3 em below this cartilage ring, on either side of the trachea. Then stand behind the patient and explain the procedure. Place the middle three fingers of either hand along the midline of the neck. Using gentle pressure, palpate down the midline until you reach the thyroid cartilage. Walk your fingers down the thyroid cartilage to the next well-defined tracheal ring, and then slide the three fingers of both hands to either side of the rings. Two main lobes may be palpated. If the thyroid is enlarged, estimate the size and shape. Nutritional findings related to the head and neck are listed in Table 16-4.
Examination of the Eyes For the nutritionist the examination for visual acuity is not necessary because the structures will reflect any nutritional deficiencies. Observe for symmetry during the overall head assessment. Then examine the sclera, which is normally white and surrounds the iris. Next gently apply pressure and pull down the lower lid to examine the conjunctival reflection for normal red color (Fig. 16-13).
Figure 16-10. Examination of the hair.
SECTION IV • Principles of Enteral Nutrition
195
_ _ Nutritional Findings Related to the Hair Halr
Andings
Scalp and general
Recent hair loss, thinning easily plucked from scalp Slanting loss of hair Corkscrew hair Petechiae and ecchymoses on hair-bearing parts Lanugo body hair/trunk
Potential Nutritional Deficiency Protein, zinc, biotin, vitamin A, essential fatty acids Protein, copper Vitamin C Vitamin C Anorexia
Observing the pupillary response to light gives information about cranial nerves; however, the funduscopic examination yields more information. To do this, set the ophthalmoscope to O. This should result in a white, medium-sized cone of light. Have the patient look to a corner of the ceiling and wall and darken the room. Start about 15 em from the patient, approaching from about 15 degrees (Fig. 16-4). Note the size and shape of each pupil (Fig. 16-15). Then assess whether each pupil constricts equally in response to the light. Dial to the lens identified by a green 4 or 6 to better examine the sclera, conjunctiva, pupil, cornea, and iris. To observe the fundus, adjust the lens to O. Look with your right eye into the patient's right eye, moving in closely. When the retina is in view, change the lens one or two turns to scan for blood vessels and follow one to the optic disc. Inspect outward from the optic disc to four quadrants. Note any abnormalities because these may reflect hypertension, diabetes, or atherosclerosis, which will lead to asking more questions about the patient's diet. Nutritional findings related to the eyes are listed in Table 16-5. Virtual details of the eye are available at
Figure 16-12. Examination for lymph node enlargement.
http://www.redatlas.org/main.htm.adigital eye atlas sponsored by Johns Hopkins. Detailed views of pathologic conditions of the eye are available from the DigitalJournal of Ophthalmology at http://www.djo.harvard.edu.
Examination
Mouth and Throat
Examination of the mouth should be done in good lighting with a flashlight and tongue depressor to see the interior. Have the patient stick out his or her tongue and say a prolonged "Ah" to examine the back of the throat (Fig. 16-16). The normal pharynx is dull red in color. The tonsils lie in an alcove created by arches on either side of the mouth. Normal tonsils range from being barely apparent to being quite prominent. This maneuver also lifts the soft palate. Illuminate with the flashlight. If it is difficult to examine, use the tongue depressor to press down half way on the tongue, so the patient will not gag. Midline from the roof of the mouth is the uvula, which should rise when the patient says "Ah." Examine the upper and lower gum lines and the mucosa. The flashlight will help in examination of the tooth crowns. The ducts that drain the parotid glands enter in line with the lower molars and are readily visible. If any areas appear abnormal or have been reported to be painful, wear gloves and palpate for size, hardness, and location.
_
Figure 16-11. Examination of the head and neck.
of the
Nutrit ional Findings Related to the Head and Neck
Body Area
Potential Nutritional Andings
Deficiency
Head Neck
Temporal muscle wasting Jugular distention Enlarged thyroid Parotid gland enlargement
Protein Excess fluid Iodine deficiency Bulimia
196
16 • Nutrition-Focused History and Physical Examination _ _ Nutritional Findings Related to the Eyes Potential Nutritional Deficiency
Findings Triangular, shiny gray spots on the conjunctiva (Bltot spots) (Fig. 16-15) Conjunctival Inflammation, corneal vascularization, redness and fissuring of the eyelid corners (angular blepharitis) Yellowsclera Brownish green rings seen In the periphery of the cornea (Kayser-Fleischer rings)
Vitamin A Riboflavin
Liver disease Copper excess
For the nutritionist, the examination of the chest and heart can be brief. The patient must be in a gown for this examination, and the room must be quiet for auscultation with the stethoscope. Position the patient supine with the head of the table slightly elevated. To examine the chest of a male, bring the gown down and fold it across the abdomen. For a female, the gown may be folded to above the nipple line, with a folded towel placed across the nipples and the gown folded to the waist if she is uncomfortable with the examination. Observe the thorax for muscle mass and shape. The contour of the chest is normally symmetric, and respirations
are passive. Note whether the patient is using accessory muscles to breathe. Are there bony prominences? Examine from the right side for the point of maximal impulse. It is normally located in the fourth or fifth intercostal space just medial to an imaginary line drawn from midclavicular shoulder to lower chest. Next auscultate for rate and sound of the heart. Ask the patient not to speak. Listen with the stethoscope first at the right second intercostal space near the sternum (aortic valve) and then the at the second intercostal space on the left (Fig. 16-17). As stated earlier for the pulse, a common method is to count the pulsations for 30 seconds and multiply by two, if the beat is regular. Normal heart rate is between 60 and 100. Listen for skipped beats or extra sounds and note their location, timing, and pitch. The presence of tachycardia in clients without a history of cardiac problems may indicate anemia or dehydration and should be validated by history and examination. Nutritional findings related to the chest and heart are listed in Table 16-7. For further details on cardiac conditions, the nutritionist is advised to consult a textbook; however, helpful Web sites such as http://www. studentbmj.com/back_issues/0200/education/19.html are also available.
Figure 16-14. Ophthalmoscopic examination.
Figure 16-1 5. Examination of the pupil.
Figure 16-13. Examination of the lower lids of the eyes.
Nutritional findings related to the mouth and throat are listed in Table 16-6. Additional information on pathologic findings in the oral cavity is available at http://www.pathguy.com/lectures/oralcav.htm.
Chest and Heart
SECTION IV • Principles of Enteral Nutrition
197
Figure 16-1 7. Examination of the chest and heart. Figure 16-16. Examination of the mouth.
Abdomen Disorders in the chest will often manifest with abdominal symptoms. For this reason examination of the abdomen naturally follows examination of the chest. The patient is already supine and draped. Now fold the gown to just above the pubis. It is best that the patient have an empty bladder before the examination, and each step of the procedure should be explained to help the patient relax. The abdomen is divided into four quadrants by imagining a line vertical from sternum to pubis and another line horizontal at the midline (umbilicus): right upper quadrant, right lower quadrant, left upper quadrant, and left lower quadrant. Above the quadrants is the epigastric area and below the quadrants is the suprapubic area (Fig. 16-18). Inspect the abdomen for shape. Note if it is protuberant, flat, or scaphoid. Look for peristaltic movement or
-
pulsations. Note lesions, rashes, and vascular patterns. To auscultate, place the diaphragm of the stethoscope lightly on each quadrant for at least 15 seconds to listen for bowel sounds. Note if they are hypoactive, hyperactive, or normal. Normal sounds occur at an estimated rate of 5 to 34/min and can be clicks and gurgles." Listen for bruits over the aorta, renal, and iliac arteries, which have a murmur-like sound. Nutritional findings related to the abdomen are listed in Table 16-8.
Palpation Because the patient may be ticklish or tender, explain that this procedure is to examine for masses or tenderness. Begin with light palpation first, using the palm and pads of the fingertips in a smooth rubbing movement to the depth of 1 ern. After surveying the abdomen, lightly proceed to deeper palpation to identify masses or deeper pain.
Nutritional Findings Related to the Mouth and Throat
Flndlngs
Nasolabial seborrhea Gingival changes from hemorrhages to hyperplastic gingivitis Reddened mouth, lips, or tongue Inflamed tongue Magenta tongue Atrophy of the papilla Tongue fissuring Cracking at the corners of the mouth and lips (cheilosis) Mottled teeth Dental erosions Loose teeth Dry mucus
Potential Nutritional Deficiency Niacin, riboflavin, pyridoxine Vitamin C Niacin Niacin, iron, riboflavin, folate, vitamin BI2 Riboflavin Niacin, iron, riboflavin, folate, vitamin B12 Riboflavin, niacin Riboflavin, niacin Fluoride excess Bulimia Vitamin C Dehydration
_
• .
Nutritional Findings Related to the Chest and Heart
Body Part Flndlngs Chest
Heart
Thoracic rosary PMlleft of maximal impulse left of the midclavicular line Visible use of accessory muscle Tachycardia (regular pulse rate> 100) High-output failure signs: laterally displaced apex beat, elevated jugular venous pressure, third heart sound
Potential Nutritional Deficiency or Other Condition Vitamin D Cardiac enlargement COPD, protein and calorie deficiency Dehydration, thiamine Thiamine
COPD,chronic obstructive pulmonary disease; PMI, point of maximal impulse.
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16 • Nutrition-Focused History and Physical Examination
\(
•
• <.:»
Epigastric • I I I
AUQ
I
LUQ
I
----~---• I • RLQ
I
LLQ
~supra~UbiC
;;
Figure 16-18. Examination of the abdomen. RUQ, right upper quadrant; RLQ, right lower quadrant; LUQ. left upper quadrant; LLQ, left lower quadrant.
Percussion Percuss in all four quadrants by hyperextending the middle finger of the dominant hand so the distal finger joint is firmlyagainst the area, and tap with middle finger of the other hand. Starting at the right midclavicular line for the span of liver dullness, on the same line percuss upward toward the liver to identify the upper border of liver dullness (normally 6 to 12 em from the fourth intercostal space to just below the rib cage). Sounds are categorized as tympanic or dull. Tympany is normally present over most of the abdomen when the patient is in the supine position. Dullness may be a clue to an underlying abdominal mass. Many Web sites such as http://www.avera.org/adam/ency/article/003137.htm are available for further information on these examinations, and audiotapes are available in medical libraries to help identify these sounds.
up to this point. Simply noting orientation, ambulation, coordination of movement (e.g., tongue, body positioning, and orientation to time and place), and bone or muscle tenderness during the examination may suffice. For patients with illnesses that put them at risk for developing nerve dysfunction, more specific procedures may be indicated. For example, patients with short bowel syndrome or diabetes may develop peripheral neuropathies. For these patients the nutritionist may want to test sensation to pain, temperature, and soft and sharp touch. Nutritional findings related to the musculoskeletal and neurologic systems are listed in Table 16-9. Detailed instructions for testing the neurologic system are available in standard textbooks." Videos of detailed procedures are also available at http://imc.gsm.com/ scripts/mainframeset.asp?url=http://www.imc.gsm.com/ integrated/bcs/index.html.
LABORATORY FINDINGS A review of laboratory findings can give the clinician a general feel for the stability of a patient's condition. If there are significant alterations in serum protein or electrolyte levels, acid base balance, and/or mineral status that reflect the severity of the patient's current clinical condition, immediate interventions may be necessary. The principles of fluid and electrolyte balance and vitamin and mineral status are addressed in other chapters in this book.
•
Nutritional Findings Related to the Musculoskeletal and Neuromuscular Systems
System
Findings
Musculoskeletal
Bowlegs Muscle tenderness, muscle pain Muscle wasting and weakness
Musculoskeletal and Neurologic Systems
Softening of bone
For the nonhospitalized patient this examination can be cursory, and data can be obtained by observing the patient from the general survey through the examination
..
Bone tenderness
Neurologic
Nutritional Findings Related to the Abdomen
Findings
Potential Nutritional Deficiency or Other Condition
Concave shape Distention Hepatosplenomegaly High-pitched tinkling sounds Bruits
Calorie Protein and calorie Protein and calorie Possible obstruction Arterial stenosis
Bone ache, joint pain Edema Dementia, disorientation Confabulation Ataxia, loss of vibratory and position sense Tetany, carpopedal spasm Hyporeflexia, wrist and foot drop Parestheslas
Potential Nutritional Deficiency Vitamin D Thiamine, vitamin C Protein, calories, thiamine, vitamin B I2, selenium Calcium, vitamin D, phosphorus Vitamin C, vitamin D, calcium, phosphorus Vitamin C Protein, thiamine Niacin, magnesium, manganese (excess) Thiamine Thiamine, vitamin B I2 Magnesium, calcium Thiamine Vitamin B 12 , thiamine, niacin
SECTION IV • Principles of Enteral Nutrition
The serum proteins used most commonly to assess visceral protein status are albumin, transferrin, thyroxinebinding prealbumin, and retinol-binding protein. Visceral proteins comprise the internal organs, the hematopoietic system, immunoglobulins, enzymes, and plasma. However, both nutritional and non-nutritional conditions can affect these serum proteins. In general, serum protein levels can reflect visceral protein status in the absence of severe illness or inflammation, liver disease, fluid overload, or dehydration. In severe illness and inflammation, serum protein levels are usually markedly low because they are negative acute-phase reactants and are catabolized to synthesize acute-phase proteins. Their levels generally will not improve, despite adequate protein-calorie intake, until the illness resolves. All of these proteins are synthesized by hepatocytes, so in liver disease, synthesis rates may be slowed. Serum protein levels tend to be dilutionally low with overhydration and abnormally elevated in dehydration. Serum albumin level is the most easily obtained serum protein measurement because it is included in most comprehensive chemistry panels. Albumin is a large molecule and maintains plasma oncotic pressure. It is also a carrier for calcium, magnesium, and zinc. Therefore, in hypoalbuminemia the total plasma levels for these minerals will be lowered, reflecting the lowered portion that is bound to albumin. In this case, amounts of the unbound portion of these minerals, which is the physiologically active value, may still be normal. Albumin has a half-lifeand synthesis rate of 20 days, and therefore changes in albumin levels will not immediately reflect protein-calorie malnutrition. In severe illness, the severity of hypoalbuminemia is used as a predictor of clinical outcome rather than visceral protein status. Serum albumin levels may rise with use of anabolic steroids and insulin therapy and decrease with renal insufficiency, nephrotic syndrome, and protein-losing enteropathy. Serum transferrin has a half-life and synthesis rate of 8 to 10 days, making it more sensitive to changes in visceral protein status than albumin. Transferrin levels increase with pregnancy, hypoxic states, and estrogen therapy. Transferrin also binds plasma iron, and, thus levels can rise in iron deficiency and with chronic blood loss. Alternatively, transferrin levels decrease with iron overdose. Nephrotic syndrome, cortisone, and testosterone will also decrease levels. Serum prealbumin or transthyretin, a rapidly changing protein, has a half-life and synthesis rate of 2 to 3 days, making it a useful indicator of recent changes in visceral protein status. Levels will rise with renal insufficiency. It binds triiodothyronine and thyroxine, and levels can decrease with hyperthyroidism. Levels can also decrease in cystic fibrosis. Retinol-binding protein, a very rapidly changing protein, has a half-life and synthesis rate of 12 hours, making it a highly sensitive indicator of visceral protein status. It transports vitamin A in plasma, so values will rise with aggressive vitamin A supplementation and decrease with vitamin A deficiency. Retinol-binding protein also binds noncovalently to prealbumin. Levels can rise with
199
renal insufficiency and decrease with hyperthyroidism and cystic fibrosis. Total lymphocyte count is a measure of immune function and decreases with protein malnutrition. Creatinine-height index is calculated from a 24-hour collection for urinary excretion of creatinine and is used to measure skeletal muscle catabolism. Providing that renal function is normal, a decrease in creatinine excretion reflects a decrease in skeletal muscle mass. Urinary urea nitrogen (UUN) is a widely used measurement to estimate the relative change in lean body mass. A comparison is made between a known nitrogen intake and urine levels of urea nitrogen over a 24-hour collection period. UUN represents the end products of protein metabolism. Non-UUN losses are generally estimated to be 2 to 4 g. However, non-UUN losses increase with catabolic illness and draining wounds, fistulas, ostomies, and diarrhea. When nitrogen intake exceeds nitrogen loss from all sources, a positive nitrogen balance occurs, reflecting tissue anabolism. Similarly, when nitrogen intake is less than the calculated nitrogen loss from all sources, a negative nitrogen balance ensues, reflecting tissue catabolism. Each 1-g change in nitrogen equates to a change of 6.25 g of protein: Nitrogen balance = protein intake (in g)/6.25 - (24-hour UUN in g + estimated non-UUN losses in g)
ASSIGNMENT OF NUTRITIONAL RISK BASED ON SUBJECTIVE GLOBAL ASSESSMENT Subjective global assessment (SGA) is a widely accepted method for nutrition assessment because it has been validated in a variety of patient populations. It utilizes easily obtainable measures to determine nutritional risk, making it user friendly for a variety of clinicians and costeffective. It relies on both objective data and the clinician's subjective expertise. Detsky and associates," initially developed this practical method for nutrition assessment, and it includes both a nutrition-focused history and physical examination. The clinician then relies on his or her subjective clinical judgment to classify patients in one of three categories: (A) well nourished, (8) moderately (or suspected of being) malnourished, or (C) severely malnourished. The history includes documentation of recent weight changes, recent dietary intake relative to usual intake, persistent gastrointestinal symptoms (nausea, vomiting, diarrhea, or anorexia), functional capacity (ambulatory, working suboptimally, or bedridden), and the degree of stress from the comorbid conditions (stress rated as none, low, moderate, or high). Physical data collection includes notation of any loss of subcutaneous fat in the triceps and chest, muscle wasting in the quadriceps and deltoids, ankle/sacral edema, and ascites. The clinician is to place the heaviest weighting on weight loss, poor dietary intake, loss of subcutaneous tissue, and muscle wasting. The other variables are used to support the patient's self-report of weight changes and dietary intake. If the patient has
200
16 • Nutrition-Focused History and Physical Examination
significant edema, ascites, or tumor mass, the clinician is instructed to view the weight change as less significant. Patients may be classified in the A rank even if they had weight loss of 5% to 10% with mild subcutaneous tissue loss but have recently begun to gain good weight with an improvement in dietary intake. A B rank shows at least 5% continued weight loss in the last few weeks with a definite reduction in dietary intake and mild subcutaneous tissue loss. Nutrition assessments need to be ongoing, because not only should overt malnutrition be noted but also patients at risk for developing malnutrition need to be identified.
NUTRITION SUPPORT AND MEDICAL ETHICS The opportunities for ethical dilemmas for a nutritionist in choosing support are rife in the cost-eontainment atmosphere of today's health care environment. On the one hand, the rising costs of technically expensive medical interventions and decreasing availability of resources have raised difficult questions about priorities and fairness in allocation of therapies, whereas, on the other hand, there are institutional pressures to decrease length of hospital stay. For this reason, many hospital care and discharge plans include total parenteral nutrition (fPN). Although clinically the use of the gut is optimal, time and effort are required to educate patients about and encourage them to try tube feedings. This is especially true when they are already receiving intravenous therapies. The right of the individual to be fully informed and consulted on medical decisions that relate to his or her health has been firmly established and is expressed in the Patients' Bill of Rights and Responsibilities; however, the ease of using TPN may explain the frequency of use in discharge plans and the lack of seeking or providing information on alternative therapies. One of the most difficult ethical dilemmas is when such plans are underway for terminally ill patients without hope of recovery. TPNwas introduced as an aggressive rescue therapy in the 19805, enabling the survival of many patient populations, such as premature infants, infants with necrotizing enterocolitis, patients with short bowel syndrome, and cancer patients undergoing therapy, who previously would have died. Soon after the development of TPN, the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) was established to protect patients and set standards for provision of nutritional therapy. These include optimizing the use of the gut whenever possible by aggressive strategies for using enteral formulas, if an oral diet is not possible. 23-25 Knowledgeable nutritionists are aware that patients with at least a partial working alimentary canal should have feedings (oral or enteral). Ignoring or not advising patients of the risks of and alternatives to TPN violates the professional obligation of veracity (truth-telling) and legal patient rights. Prolonged TPN is not a benign therapy because morbidity and costs can be significant. Bypassing normal intestinal stimulation in these patients will cause intestinal atrophy, frequent catheter sepsis, o-lactate
acidosis, nephrolithiasis, liver complications, and ultimately hepatic failure." Enteral or oral diet intervention through interdisciplinary care planning and monitoring simplifies and optimizes outcomes for patients; however, many members of the health care team are too busy and do not have enough education to understand the big picture. For terminally ill patients without hope of recovery, TPNoffers little benefit. The latest human trials for cancer patients in particular confirm that TPN stimulates tumor cell growth and therefore advances the disease state." Canada-" argued that reduced calorie intake may prolong life in cancer patients. Evidence shows that withholding artificial nutrition and providing mouth care and requested foods and liquids for patients with terminal conditions does not lead to suffering but rather keeps them comfortable.P:" This evidence is consistent with the general impression among hospice clinicians that starvation and dehydration do not contribute to suffering among dying patients and might actually contribute to comfortable passage from life. Most cultures, however, equate provision of food and water with nurturing and caring, and therefore the discussion of withholding these substances is very difficult to broach on either side of the medical relationship. The availability of an intravenous access site and the opportunity to move the patient out of the hospital without serious discussions of end-life issues or complications may ease the issue in the short term. Strong positions, however, have been taken that the ethical principles of beneficence and nonmaleficence are violated when artificial nutrition and hydration delay the natural process of death." To deal with a patient with a complicated case, there are two ways to start the process of getting an ethical dilemma addressed. First, the nutritionist can go to his or her director with ethical concerns. Often the dilemma can be easily resolved at this level. The second option is to go directly to a member of an ethics consultation team. Hospitals in many states are required to have such teams. The nutritionist can relate the issue of concern and ask: "What should I do at this point?" Of primary importance for the nutritionist is to remember that as any health care provider, his or her role is to duly inform patients of treatment options including associated risks and benefits. Further information is available at http://www.hospicepatients.org/hospic28.html. REFERENCES 1. Alexander JW, Macmillan BG, Stinnett JD, et al: Beneficial effects of aggressive protein feeding in severely burned children. Ann Surg 1980;192:505-517. 2. Beier-Holgerson R, Boesby S: Influence of postoperative enteral nutrition on postsurgical infections. Gut 1996;39:833-835. 3. Grahm 1W, Zadrozny DB, Harrington T: The benefits of early jejunal hyperalimentation in the head-injured patient. Neurosurgery 1989;25:729-735. 4. Heyland DK: Enteral and parenteral nutrition in the seriously ill, hospitalized patient: A critical review of the evidence. J Nutr Health Aging 2000;1:31-41. 5. Moore EE, Jones TN: Benefits of immediate jejunostomy feeding after major abdominal trauma-A prospective, randomized study. J Trauma 1986;26:874--881.
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6. PollerJ, Langhorne P, Roberts M: Routine protein energy supplementationin adults:Systematic review. BMJ 1998;317:495-501. 7. Rapp RP, Young B,Twyman D, et al: The favorable effect of early parenteralfeeding on survival in head-injured patients.J Neurosurg 1983;58:906-912. 8. Sandstrom R, Drott C,Hyltander A,et al:The effectof postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg 1993;217: 185-195. 9. Singh G, Ram RP, KhannaSK: Early postoperative enteral feeding in patientswith nontraumaticintestinal perforation and peritonitis. J Am Coil Surg1998;187:142-146. 10. Carney D, Meguid M: Current concepts in nutritional assessment. ArchSurg2002;137:42-45. 11. Block K: Integrative oncology: One physician's effort to combine the best complementary medicine and conventional care [plenary, June 11, 1999]. Available at hllp://www.cmbm.org/conferences/ccc99/transcripts99/block.html. 12. Office of Technology Assessment: Unconventional cancer treatments. OTA-H405, no. 9, p 44,1990. 13. LernerM: Choicesin Healing: Integrating the Bestof Conventional and Complementary Approaches to Cancer. Cambridge, MA, MIT Press, 1994. 14. Centers for Disease Control: Daily dietary fat and total food-energy intakes-Third National Healthand Nutrition Examination Survey, Phase I, 19~91. MMWR Morb Mortal Wkly Rep 1994;43:116-117, 123-125. 15. HarkL, Deen D: Taking a nutrition history: Apracticalapproach for family physicians. AmFam Physician 1999;3:1521-1530. 16. Eisenberg DM, Davis RB, Ellner SL, et al: Trends in alternative medicine use in the United States. JAMA 1998;280:1569-1575. 17. Astin JA: Why patients use alternative medicine. JAMA 1998;279:1548-1553. 18. Joint Commission on Accreditation of HealthcareOrganizations. (2000). Pain assessment and management: an organizational approach. JCAHO Publication: Terrace, IL. 19. Hollerbach A, Sneed N: Accuracy of radial pulse assessment by length of counting interval. Heart Lung J Acute Crit Care 1990;19:258-264.
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20. Knight MA, Kelly MP, Castillo S, et al.: Conductingphysicalexamination rounds for manifestations of nutrient deficiency or excess: An essentialcomponent of JCAHO assessmentperformance. JPEN J ParenterEnteral Nutr1999;14:93-98. 21. BatesB: AGuideto Physical Examination and History Taking, 7thed. Philadelphia, JBLippincott, 1999. 22. Detsky AS, McLaughlin JR,BakerJP,et al: Whatissubjectiveglobal assessment of nutritional status? JPEN J Parenter Enteral Nutr 1987;11:8-13. 23. American Society of Parenteral and Enteral Nutrition: A.S.P.E.N. standards forhome nutritionsupport. NutrClinPract 1992;7: 65-69. 24. American Society of Parenteral and Enteral Nutrition Board of Directors: Guidelinesforthe use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 1993;17(suppl):1SA-52SA. 25. American Society of Parenteral and Enteral Nutrition Committee on Standards: Standardsforhome nutrition support. NutrClinPract 1999;14:151-162. 26. SchaffnerR: Demonstrating outcomes in APN specialty practice: Nutrition support. In Outcome Assessment in Advanced Practice Nursing. NewYork, Springer-Verlag, 2001. 27. Jin D, Phillips M, Byles JE: Effects of parenteral nutrition support and chemotherapy on the phasic composition of tumor cells in gastrointestinal cancer. JPEN J Parenter Enteral Nutr 1999; 23:237-241. 28. Canada T: Clinical dilemma in cancer: Is tumor growth during nutritionsupport significant? NutrClinPract 2002;17:246-248. 29. McCann RM, HallWJ, Groth-Junker A: Comfort care for terminally ill patients.JAMA, 1994;272:1263-1266. 30. Burge F: Dehydration symptomsof palliative care cancer patients. J Pain Symptom Manage1993;8:454-464. 31. Sullivan RJ: Accepting death withoutartificial nutrition or hydration. J Gen InternMed 1993;8:220-224. 32. BernatJL, Gert B, Mogielnicki RP: Patient refusal of hydrationand nutrition: An alternative to physician-assisted suicide or voluntary active euthanasia. Arch Intern Med,1993;153:2723-2728.
Access to the Gastrointestinal Tract Robin Bankhead, eRNP, RN Rolando Rolandelli, MD
CHAPTER OUTLINE Introduction Considerations in the Selection of Enteral Access Patient Considerations Route of Feeding Considerations Materials for Enteral Access
Methods of Obtaining Access to the Gastrointestinal Tract Nasally Placed Tubes Tube Enterostomies
Postprocedure Initiation of Enteral Feeding Managing Complications of Enteral Access Devices Nasal Tubes Tube Enterostomies
Catheter Removal/Exchange Summary
in weighing the potential benefits against the potential for morbidity. The selection of the appropriate type of access port is just as crucial as the timing of placement of a feeding tube. An intragastric access port is of little value in a patient with a high risk of aspiration or a patient with acute pancreatitis. We believe that the overuse of parenteral nutrition in some acute care hospitals is largely due to unawareness of the importance of timely placement of appropriate feeding tubes.
CONSIDERATIONS IN THE SELECTION OF ENTERAL ACCESS Elements to consider when selecting an enteral access port are the patient's underlying medical condition and any comorbidities, the length of time tube feedings will be necessary, and the setting in which these feedings will be administered. The specific combination of these elements in a certain patient determines the list of possible materials and methods for placement of a feeding tube. These possibilities are then weighed in the context of all other therapies planned for a particular patient.
INTRODUCTION
Patient Considerations One of the key elements in the successful implementation of enteral nutrition is the timely placement of an appropriate access port to the gastrointestinal tract for delivery of tube feedings. The timing of placement of an access port to the gastrointestinal tract determines the feasibilityof using enteral nutrition in many patients. For instance, patients who undergo a laparotomy are not likely to tolerate intragastric feedings in the early postoperative period. Therefore, unless the surgeon makes the decision to create a feeding jejunostomy, in addition to the planned surgical procedure, the opportunity to use the gastrointestinal tract for feedings may be lost for as long as the patient is unable to eat. However, creating a feeding jejunostomy adds potential morbidity to the operation, and the surgeon has to apply clinical judgment
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Certain pathologic conditions in individual patients create technical difficulties for some methods of tube placement. These conditions include patency of the nasopharynx and esophagus, esophageal varices, coagulopathy, ascites, obesity, and previous abdominal surgery. An obstruction of the nasopharynx eliminates the possibility of nasally placed tubes. An obstruction of the esophagus eliminates the possibility of nasally, endoscopically, or fluoroscopically placed tubes, which necessitates placement of a nasogastric tube into the stomach for air insufflation. The presence of esophageal varices is a relative contraindication to the placement of nasogastric, nasoduodenal, or nasojejunal tubes. The presence of coagulopathy precludes the use of open surgical methods.
SECTION IV • Principles of Enteral Nutrition
The presence of ascites is a relative contraindication for percutaneous placement of tubes because of the risk of peritonitis and leakage of ascitic fluid around the tube. Obesity and previous abdominal surgery are both relative contraindications for tube enterostomies placed by percutaneous methods. Aside from technical impediments, other pathologic conditions influence the ability of the gastrointestinal tract to safely assimilate tube feedings. These include delayed gastric emptying and gastroesophageal reflux, paralytic ileus, colonic pseudoobstruction (Ogilvie syndrome), pancreatitis, and malabsorption due to prior resection or intrinsic disease (i.e., radiation enteritis or Crohn disease). The overall clinical condition of the patient also plays a role in the decision process for gaining access to the gastrointestinal tract for feedings. A patient who requires strict bed rest in a recumbent position has a high risk of aspiration pneumonia if feedings are delivered intragastrically. Some patients may be too unstable for them to be moved out of the intensive care unit to undergo placement of any form of enteral access port. The predicted length of time a patient will need tube feedings determines invasiveness the placement method can be. Although a patient's nutritional status may still be adequate after surgery for head and neck cancer, the knowledge that the patient will require adjuvant chemotherapy and radiation therapy leads to an expeditious decision fora surgical gastrostomy. In patients who require long-term tube feedings, the potential benefits of a feeding jejunostomy need to be weighed against the need for continuous or cyclic feedings with an electronic pump for infusion of tube feedings and the ease and portability of bolus feedings via a gastrostomy tube in the more independent and stable tube-fed person.
Route of Feeding Considerations Intragastric feedings are clearly more physiological because the stomach is the natural reservoir for ingested nutrients, holding volumes as high as 1 L and being capable of diluting hyperosmolar foodstuffs. The small bowel serves more as a conduit than a reservoir and is sensitive to sudden increases in volume and to the infusion of hyperosmolar substances. Therefore, the gastric route allows for intermittent or bolus feedings whereas the duodenal or jejunal route forces the use of continuous infusion of nutrients. Intermittent feedings produce cyclic elevations and descents in blood insulin levels, promoting protein synthesis and lipolysis, respectively. The purported advantage of continuous feedings is that they allow for greater nutrient intake in patients with marginal digestive and absorptive capacity. The main potential problem with the gastric route is eliciting gastroesophageal reflux and aspiration of the feeding formula into the tracheobronchial tree. However, the use of the duodenal or jejunal route does not eliminate the risk of aspiration pneumonia. One advantage of the gastric route is that the infusate is exposed to hydrochloric acid. Hydrochloric acid is a potent bactericidal agent that also
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produces the acidification of some nutrients for proper absorption. Therefore, the risk of infection from infusion of formula contaminated with an infectious agent (e.g., Clostridium difficile) is lower when it is infused into the stomach than when it is infused into the small bowel. Transgastric jejunal feedings allow for gastric decompression in patients with delayed gastric emptying after injury or gastric atony. Indications for gastric versus small bowel placement of enteral access tubes and contraindication of these tubes are outlined in Table 17-1.
Materials for Enteral Access Tubes for enteral nutrition are classified as nasoenteric or enterostomy tubes. These tubes are made of either silicone rubber or polyurethane, and each material offers some advantages and disadvantages. Silicone rubber is the most inert soft material for indwelling catheter use. The softness of silicone rubber makes it more comfortable for the ambulatory patient. However, in the hospitalized patient who receives multiple medications in addition to the feeding formula, silicone tubes are more likely to clog than are polyurethane tubes. In chronically ill patients who need long-term feeding, the feeding tube may also be used for administration of medication. In this case, size makes a difference in the likelihood of tube clogging; therefore, larger sized tubes are preferred, i.e., 24 F for open gastrostomies, 22 F for percutaneous gastrostomies, and 16 F for jejunostomies. Another important feature of feeding tubes is the assembly of multiple lumens. Some tubes for transgastric placement are single tubes with an internal partition whereas others are coaxial systems in which tubes are inserted inside tubes. The transgastric jejunal tube for surgical or radiologic placement is a single tube with a partition whereas the systems for percutaneous endoscopic jejunostomies are coaxial systems. These tubes, which are used for combined gastric decompression and small bowel feedings, are more durable and effective in the single-tube form than in the coaxial form.
_
Enteral Access Device Placement Indications and Contraindications
Access Site
Indications
Contraindicatlons
Gastric
Patients with <600 mL/ 24 hr of gastric drainage, cancer of the head and neck; neurologic disorders such as cardiovascular accident, trauma; respiratory failure with prolonged intubation Prior gastrectomy, gastrocutaneous fistula, gastroparesis; pancreatitis
Documented gastroesophageal reflux, gastroparesis, distal fistula
Small bowel
Short bowel syndrome, inability to provide continuous/cyclic infusion
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17 • Access to the Gastrointestinal Tract
. . . Enteral Access Device Characteristics Nasal tubes
Enterostomy tubes
Weighted tip Stylet Length (inches)
pH Sensor Materials V-Connector French sizes Internal retention device: PEG/PEJ Gastrostomy/jejunostomy External retention device Materials French sizes: PEG, gastrostomy PEJ, jejunostomy Access ports
+/+/Gastric: 36 Duodenal: 40-45 Jejunal: 60 Gastric/jejunal: 67
+/Polyvinylchloride, silicone, polyurethane
+/6, 8, 10, 12, 16 (Gastric/Jejunal) Cap or cross bar Balloon Disc or cross bar Polyvinylchloride, silicone, polyurethane 20,22,24 8, 10, 12, 14, 16, 18 Single: feeding Double: Gastric (for suction) Jejunal (for feeds)
Balloon port: Gastrostomy: 10-20 mL Jejunostomy: 3-5 mL
Coaxial tubes tend to bend backwards and return to the stomach. Various characteristics of feeding tubes are presented in Table 17-2.
METHODS OF OBTAINING ACCESS TO THE GASTROINTESTINAL TRACT Feeding tubes can be placed into the stomach, duodenum, or jejunum by using bedside, endoscopic, fluoroscopic, or open surgical techniques. The least invasive methods involve the placement of tubes through the nares. The more invasive methods, gastrostomy or jejunostomy, involve open surgical procedures. Procedures of intermediate invasiveness are those in which percutaneous techniques are applied using endoscopic, fluoroscopic, or laparoscopic guidance. An algorithm illustrating the decision-making process for selecting the method for placing an enteral access device is presented in Figure 17-1. The degree of invasiveness is counterbalanced by the discomfort caused to the patient. In the alert patient, nasogastric tubes cause much more discomfort (and poor cosmetic appearance) than surgical or percutaneous tube enterostomies. Therefore, the decision to use nasal versus enterostomy tubes is based on the level of consciousness of the patient and the length of time that tube feedings will be required. Conventional wisdom indicates that most alert patients cannot tolerate nasal tubes for more than 6 weeks, and many patients cannot tolerate them for even more than 2 weeks. Each method of enteral access has both, pathologic implications, and potential complications (Table 17-3).
Nasally Placed Tubes
Nasogastric Tubes Nasogastric tube placement allows cost-effective, easy placement in the patient with a fully functional gastrointestinal tract. A nasogastric tube can be placed at the bedside without endoscopic or fluoroscopic guidance. Feeding through the gastric route should be done in the patient with a low risk of aspiration and normal gastric emptying. Boyer and Kruse! described four steps to tube placement: (1) the length of tube needed to be inserted is determined by measuring the nose-ear-xiphoid length (about 50 to 60 cm in the adult), (2) the lubricated tube is advanced into the esophagus to the designated length with the patient in an upright position, (3) the tube tip position is confirmed, and (4) the tube is secured in place.
Nasoenteric Tubes In the patient with delayed gastric emptying, nasoenteric tube placement can be useful. Placement into the small bowel is assisted through various procedures including proper positioning of the patient; use of prokinetic agents, air insufflation, or magnetic forces; intraoperative manipulation; and manipulation under fluoroscopic, sonographic, or endoscopic guidance.r" Deterrents to nasoenteric tube placement include the high rate of failure, lengthy insertion time, radiation exposure from the use of fluoroscopy, the need for multiple radiographs, and the risk of transporting and positioning critically ill patients. There are many procedures available to increase the likelihood that a nasal tube placed at the bedside will
SECTION IV • Principles of Enteral Nutrition
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Guidelines for Placing a Tube Enterostomy Assess patency of pharynx/esophagus
Previous gastric resection
Previous upper abdominal surgery
Laparoscopic gastrostomy
EGD (follow EGD path on right side of chart)
CT Scan Assess viscus between stomach and abdominal wall
FIGURE 17-1. Guidelines for placing tube enterostomy device. CT, computed tomography; EGD, esophagogastroduodenoscopy; PEG, percutaneous endoscopic gastrostomy; PFG, percutaneous fluoroscopic gastrostomy.
reach a postpyloric position have been described. Zaloga' and Thurlow- both reported success with the use of a hygrorner-coated, self-lubricated tube with a weighted tip and a 30° bend in the metal stylet. When the premarked tube reaches the stomach, a rotating or corkscrew process is used to pass the tube through the
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Comparison of Tube Enterostomy Site
Placement
Laparotomy Bore size Clogging/accidental removal Replacement Feeding method Complications
Gastrostomy
Jejunostomy
Endoscopic. surgical, fluoroscopic Mini 20 and up Uncommon
Surgical
Easy (delayed) Bolus or continuous "Granulation tissue," aspiration
Full 18 and down Common Difficult (immediate) Continuous Small bowel obstruction, diarrhea
pylorus. However, several authors also successfully used unweighted feeding tubes. Ahmed and associates" found a significant difference in pyloric passage between unweighted and weighted tubes. All unweighted tubes passed faster than weighted tubes (58% versus 29% at 48 hours and 62% versus 32% at 72 hours). In a study conducted by Lord and colleagues'? that compared unweighted versus weighted tubes, spontaneous transpyloric migration on insertion was superior with the unweighted tubes than with the weighted tubes (84% vs. 36% and 92% vs, 56% after 48 hours). The air insufflation technique as described by Salasidis and co-workers begins with a standard insertion technique followed by insufflation of 500 mL of air using a 6D-mL syringe. I I Asufficient length of feeding tube must be advanced in anticipation of passage into the small bowel. If a radiograph does not confirm that the tube is in the small bowel, the procedure is attempted again with use of a promotility agent. Attempts have been made to advance tubes by use of external magnetic forces." An external magnet is positioned over the right upper quadrant while the feeding tube is inserted using a standard insertion technique. Distal duodenal placement is achieved by moving the
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17 • Access to the Gastrointestinal Tract
external magnet to the suprapubic area. This method offers the benefit of bedside placement. One problem with this technique is that the magnetic force attracts the tip of the tube against the gastric folds and toward the anterior abdominal wall, which impedes the advancement of the tube. Tubes placed under fluoroscopic guidance are available for immediate feeding as opposed to a delay of 9 to 24 hours for bedside placement. This method is also more cost effective if bedside placement fails, and multiple radiographs are then required.Y With the fluoroscopic technique, the catheter and guidewire are placed into the stomach using standard intubation techniques, and the guidewire is then passed through the pylorus into the small bowel. When the guidewire is in position, the catheter is advanced over the guidewire. In sonographic image-guided nasoenteric tube placement, an insertion technique as described by Zaloga" is used with the added guidance of sonographic images only after the initial attempt has failed.' The benefits of this method are the portability of sonographic equipment and cost effectiveness compared with endoscopyand fluoroscopy-assisted insertions. Several endoscopic techniques have been described. In one technique a nasobiliary or colonic decompression tube is passed through the biopsy channel of the endoscope, and both are passed into the small bowel. Reed and co-workers" advised removal of the guidewire while the tube is still in the duodenum. After removal of the guidewire, the nasoenteric tube is advanced beyond the ligament of Treitz while the endoscope is simultaneously withdrawn. In another technique, the feeding tube is passed into the stomach, and then the tip of the tube is grasped with a biopsy forceps and positioned postpylorically. Another endoscopic method involves the use of a tube with a suture thread at its end. In this technique, a snare passed through the endoscope is used to grasp the suture and drag the feeding tube into position in the small bowel.
Combined Nasogastric-jejuna' Tubes
into the feeding tube, which will clear the tube and assist in releasing it from the gastric or intestinal wall, and then the syringe is pulled back. This procedure can be repeated as many times as needed." Nasoenteric tubes with pH sensors are also available; they can provide ongoing assessment of tip location without the need for repeat radiographs.l'r" However, because no single method or combination of methods is 100% reliable, a radiograph is the only definitive test to confirm the position of the tube. 15,19 Clearly the success of nasoenteric feeding tube placement depends on the commitment of specialized professionals who achieve and maintain competency in a particular insertion technique.
Tube Enterostomies The process of placing a tube enterostomy begins by assessing the patient for coagulation status and ongoing infection as part of a preprocedure workup. The need to administer platelets and to stop anticoagulation must be coordinated with the patient's primary care service. The type of anesthesia (local vs. local with conscious sedation vs. general) is determined by the technique used for tube placement and the patient's ability to withstand various forms of anesthesia. A preprocedure antibiotic is given intravenously, such as 1 g of cefazolin.
Percutaneous Endoscopic Gastrostomy Percutaneous endoscopic gastrostomy (PEG) can be performed by one of three different techniques: Ponsky or "pull," Sacks-Vine or "over the wire," and Russell or "push." All three forms involve performance of a complete esophagogastroduodenoscopy, insufflation of air into the stomach, transillumination of the stomach through the anterior abdominal wall (Fig. 17-2) to ensure that the colon has been displaced and that the stomach lies approximated against the abdominal wall, allowing visualization of stomach indentation using a finger (Fig. 17-3). Then a needle is placed through the left upper quadrant into the stomach, and a wire is advanced
These tubes provide gastric decompression with the benefit of simultaneous access to the small bowel for enteral feeding. Baskin and Johanson 13 described a combined bedside endoscopic and fluoroscopic procedure for tube placement. The tube is placed into the distal duodenum using endoscopic guidance followed by advancement of the tip of the tube beyond the ligament of Treitz using a guidewire under fluoroscopic guidance.
Confirming P'acement of Nasally P'aced Tubes Placement of a small-bore feeding tube is confirmed by a variety of methods. Air insufflation with auscultation is the most inaccurate method. Another method uses examination of the aspirate for color and pH to establish whether the tip is in the stomach (clear and acidic aspirate) or the duodenum (bilious and alkaline aspirate)." At times it may be difficult to aspirate fluids from a small-bore feeding tube. A large syringe can be used to insufflate 20 mL of air
FIGURE 17-2. Transillumination of the percutaneous endoscopic gastrostomy.
stomach
during
SECTION IV • Principles of Enteral Nutrition
207
Contraindications for PEG insertion include prior subtotal gastrectomy, uncorrectable coagulopathy, ascites, marked hepatomegaly, portal hypertension, esophageal obstruction, and any situation in which transillumination of the abdominal wall through the stomach is impossible.P'" Endoscopic ultrasound can be used when the stomach cannot be transllluminated."
Percutaneous Endoscopic Jejunostomy
FIGURE 17-3. Creating an indentation in the stomach to ensure that no interposition of liver or colon between stomach and anterior abdominal wall occurs.
into the stomach (Fig. 17-4). With the Ponsky and SacksVine techniques, the wire is then captured with a polypectomy snare and pulled up through the esophagus to exit the mouth of the patient (Fig. 17-5). The Ponsky technique involves tying the tube to the wire and pulling it down through the esophagus into the stomach to exit the abdomen at the point of puncture with the needle. The Sacks-Vine technique involves advancing the tube over the wire using a Seldinger technique similar to that used for placement of vascular catheters. The Russell technique involves the dilatation of the tract for insertion of a "peel away" introducer and direct placement of balloon catheter into the stomach. 2(}-22
In one method of placement the endoscope and biopsy forceps are advanced into the third portion of the duodenum along with the jejunal tube. Limitations of this procedure include difficulty in releasing the silk suture at the time of insertion, which dislodges the tube as the endoscope is withdrawn, and the inability to pass the endoscope beyond the third portion of the duodenum. To overcome these limitations a short plastic tip is added onto the jejunal tube for easy grasping and release of the tube and a pediatric colonoscope is used."
Percutaneous Endoscopic Gastrostomy-Jejunostomy For the patient who requires gastric decompression and small bowel feedings, the PEG-jejunostomy tube provides this dual function. Placement proceeds as for a standard PEG insertion using a 24-F catheter through which a guidewire is threaded and positioned in the small bowel with the endoscope. A 12-F jejunal tube is passed over this guidewire until it reaches the distal duodenum or proximal jejunum." Leichus and associates'" use a snare passed through a PEG. The endoscope, positioned in the stomach, is passed through the snare and both are advanced through the pylorus and positioned distal to the ligament of Treitz. A guidewire is passed through the biopsy channel and held in place by the snare as the endoscope is withdrawn; the jejunal tube is threaded over the guidewire. In another technique, a 28-F PEG tube and guidewire are positioned in the second portion of the duodenum with the endoscope." Next, to keep the guidewire from buckling, a 12-F biliary catheter is passed over the guidewire and both are advanced beyond the ligament of Treitz using a torque device in a clockwise motion. The biliary catheter is removed and replaced with a 12-F jejunal tube using a twisting motion as it passes over the guidewire.
Percutaneous Fluoroscopic Gastrostomy
FIGURE 17-4. Placement of needle and guidewire in the stomach.
Percutaneous fluoroscopic gastrostomy is similar to the Russell technique with the identification of the site by the presence of air insufflated into the stomach via a nasogastric tube. The stomach is then held up against the anterior abdominal wall by T fasteners. The stomach is then pierced with a needle and a guidewire is introduced into the lumen. Passing dilators over the guidewire enlarges the point of entry into the stomach so that a peel away introducer can be inserted for placement of a balloon or pigtail tube.
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FIGURE 17-5. Percutaneous endoscopic gastrostomy by the Ponsky ("pull") technique.
Percutaneous Fluoroscopic Gastrojejunostomy When the gastric tube is placed as described earlier, a stiff sheath passed over the guidewire is then passed through the pylorus, the guidewire is advanced into the small bowel, the sheath is withdrawn, and the gastrojejunal tube is threaded over the guidewire.
Laparoscopic Gastrostomy and Jejunostomy Laparoscopic methods have revolutionized gastrointestinal surgery. The principle of laparoscopic surgery is to work by visualizing the operative field through a camera introduced into the peritoneal cavity, i.e., the laparoscope. To create sufficient space to manipulate the camera and the necessary instruments, a pneumoperitoneum is created with carbon dioxide gas. The laparoscope is maneuvered through an access port placed at the umbilicus. A second port is placed in the left upper quadrant of the abdomen for grasping of the stomach. The gastrostomy tube is usually exteriorized through this
port site. 31.32 Peitgen and associates'" use a third port site in the right upper quadrant for placement of atraumatic graspers. For jejunostomy placement, ports are placed in the left upper quadrant and lower abdominal midline "run" of the bowel and identify the proper site just distal to the ligament of Treitz." Approximation of either the stomach or the jejunum to the abdominal wall is accomplished with T-fasteners, which are secured with metal crimps.31-34 Once the jejunum is approximated to the abdominal wall, an introducer needle is placed into the lumen, a guidewire is passed through the needle, and then a peel away introducer is used to advance the tube into the lumen. Intraoperative fluoroscopy is used to confirm placement."
Open Gastrostomy The gold standard of gastrostomy tube placement is still the open (Stamm) gastrostomy. This method has minimal morbidity and mortality. It does require a small laparotomy that creates discomfort and a minor ileus. However, because the stomach is directly visualized, the risk of complications is quite low. Percutaneous techniques
SECTION IV • Principles of Enteral Nutrition
209
FIGURE 17-6. Grasping of the stomach in the open technique.
involve steps in which instruments are used blindly; thus, the risk for serious complications (e.g., liver laceration or colonic perforation) is always a matter of concern. The Stamm technique involves entering the peritoneal cavity through an upper midline incision. The stomach is grasped near the greater curvature and gently lifted up (Fig. 17-6). Inadvertent grasping and lifting of the stomach from the lesser curvature can result in serious bleeding from tearing of the coronary vein, especially in patients with portal hypertension. With the stomach exposed through the laparotomy one, or two, purse-string sutures are placed to seal the entry to the stomach around the tube. The tube is brought into the peritoneal cavity through a counter incision in the left upper quadrant.
Transgastric Jejunal Tubes In patients with a risk for aspiration pneumonia, feeding into the jejunum does not eliminate the possibility of regurgitation of gastric contents. Rombeau and colleagues" introduced the concept of using dual lumen tubes for simultaneous gastric decompression and jejunal feedings. The placement of this type of tube requires a larger laparotomy for access to the duodenum on the right side and the duodenojejunal junction on the left side. The key in placement of transgastric jejunal tubes is the gentle advancement of the tube along the various angles of the duodenum and of the duodenojejunal junction (Fig. 17-7). All "slack" in the tube has to be eliminated to avoid a perforation of the jejunum by tension generated by an alpha loop in the duodenum. When properly placed the tip has to lie several inches beyond the ligament of Treitz (Fig. 17-8). Some tubes available commercially are too short to reach the jejunum and too
FIGURE 17-7. Steps in placing a transgastric jejunal tube.
stiff, creating a risk for duodenal perforation. If placed through a mature gastrostomy site, the tip of the tube is pulled through the stomach and positioned in the jejunum with the use of a guidewire and fluoroscopy.
Jejunostomy The gold standard for jejunostomy is the Witzel technique. As opposed to gastrostomies in which a tube can be placed directly into the lumen in a right angle from the abdominal wall, jejunostomies require some mechanism to prevent reflux and leakage. This is accomplished by "burying" the tube in a submucosal tunnel and main-
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17. Access to the Gastrointestinal Tract
FIGURE 17-10. Leakage around jejunostomy tube to undoing of Witzel tunnel.
FIGURE 17-8. Proper placement of a transgastric jejunal tube.
taining a parallel alignment of the tube to the bowel lumen (Fig. 17-9). Unfortunately, this configuration is often disrupted by the stiffness of the tube, resulting in very cumbersome leakage (Fig. 17-10). An access port to the jejunum enables early postoperative enteral nutrition. This is a consideration in patients who undergo abdominal surgery (e.g., major resectional procedures such as pancreaticoduodenectomy and esophagogastrectomy or for abdominal trauma) and are likely to require nutritional support. Unfortunately, with either type of surgery the surgeon is usually under a time constraint because the patient either has already spent too long in the operating room or is at risk of developing sequelae of hypovolemia (hypothermia, coagulopathy, and third spacing of fluid in the abdomen). To circumvent this problem, a simplified jejunostomy technique has been proposed, in which a small catheter is introduced across the bowel layers through a needle and guidewire using a Seldinger technique. This procedure is known as the "needle-catheter" jejunostomy. Although very easy and quick to perform, it has the drawback of using a very narrow catheter that tends to kink, clog, or break.
Skin Level or Low-Profile Device Gastrostomy The skin level, low-profilegastrostomy device, or gastrostomy "button," is a small device that provides access to the stomach, eliminating the bulk of a tube hanging by the side of the abdomen. These devices are particularly
FIGURE 17-9. Witzel jejunostomy.
convenient in children who otherwise tend to lose their feeding access by accidental extraction of the tube. In adults these devices can be less obtrusive and may be preferable as long as the patient has sufficient hand-eye coordination to assemble the extension tubing necessary to connect the formula container to the gastrostomy device. These devices can be placed as the initial feeding tube or more commonly are used as a replacement for a previously established gastrostomy tube. The advantage of using low-profile devices as replacements for established gastrostomies is that the thickness of the abdominal wall may be more stable than with initial placement in a patient who may be profoundly malnourished with a very thin abdominal wall. This distinction results from the fact that the length of these devices is fixed and selected at the time of placement from an assortment of different French sizes and lengths. Another convenient feature of these devices is an antireflux valve.
POSTPROCEDURE INITIATION OF ENTERAL FEEDING There is great variability in the literature, and in actual practice, as to when enteral feedings are initiated after placement of gastrostomy tubes. There is a consensus that before feeding is started the site should be inspected for signs of blood or fluid leaking from around the tube, erythema, and abdominal distention. Choudhry and coworkers" found no difference between initiation of full strength isotonic formula at 30 mUhr in 3 hours versus 24 hours after PEG placement in 41 patients. Tube feedings were held for 2 hours if gastric residual volumes were greater than 60 mL. Gastric residual volumes were checked every 4 hours, the tube site was inspected for leakage, bleeding, erythema and abdominal distention, and the presence or absence of bowel sounds and abdominal tenderness was noted. Kirby and associates" initiated jejunal feedings immediately after percutaneous endoscopic gastrojejunostomy insertion. In patients with a percutaneous endoscopic jejunostomy, Henderson and colleagues" began feedings 24 hours after placement. Our protocol for starting enteral feedings entails keeping the feeding tube positioned for gravity drainage for 16 to 24 hours. This has the dual purpose of decompressing the stomach or jejunum of liquid contents and also of gas instilled into the stomach during tube insertion. If the output is less than 200 mU8 hr and no abdominal distention
SECTION IV • Principles of Enteral Nutrition
211
_ _ Assessment of Enteral Access Complications
Problem
Cause
Intervention
Clogging
Pill fragments
Tube displacement with feeding into the tracheobronchial tree
Feeding tube positioned in the tracheobronchial tree or esophagus
Nasopharyngeal ulcers/necrosis, rhinitis, otitis media, hoarseness, and vocal cord paralysis Stomal leakage of gastric/intestinal fluid
Use of large-bore (Salem and Levin) feeding tubes and those made of polyvinylchloride Gastrostomy: migration of internal retention device away from gastric wall; full or partial deflation of balloon Jejunostomy: disruption of Witzel tunnel; overinflation of jejunal tube balloon, can result In ileus and leakage of bile onto surrounding jejunostomy site
Frequent flushing, adequate crushing of medications with water flushes between and after delivery Confirm initial placement by radiograph or fluoroscopy, aspirate for color and pH to reassess placement Use of small bore polyurethane feeding tubes
is present, then tube feedings are initiated the morning after the procedure."
MANAGING COMPLICATIONS OF ENTERAL ACCESS DEVICES All feeding tubes are subject to mechanical complications such as clogging, tube displacement, and aspiration (fable 17-4).1,39,40 Clogging is caused by pill fragments, formula residue, drug-drug interaction, and drug-nutrient interaction. Use of polyurethane tubes and frequent tube flushes before and after residual volumes are checked and after each medication is administered can prevent catheter clogging. Prevention of aspiration entails identification of high-risk patients, use of small-bore feeding tubes, transpyloric tube placement, elevation of the head of the bed, abdominal assessment, and if the patient is receiving gastric feedings, measurement of gastric residual volumes. Several studies have failed to show a difference in rate of occurrence of aspiration pneumonia in patients fed into the stomach compared with those fed into the small bowel. For instance, Mullan and co-workers" found that pulmonary aspiration occurred in 8 of 212 patients (3.8%) fed into the small bowel, 3 of 46 patients (6.5%) fed through a gastrostomy, and 1 of 18 patients (5.6%) fed through a jejunostomy (P = .51). In another study, Strong and colleagues'? found a 31% incidence of aspiration pneumonia in patients fed into the stomach versus 40% of those fed beyond the pylorus. Even the most critically ill patients can tolerate gastric feedings.'!
Assess balloon volume, if ruptured, replace tube, if underinflated, instill required amount Gastric tube: 10-15 mL Jejunal tube: 3 mL Ensure that the internal and external retention devices are correctly approximated; avoid placing a larger French size in an attempt to stop leakage
confirming feeding tube placement. Use of small-bore feeding tubes can help avoid complications of nasopharyngeal irritation and necrosis, rhinitis, and otitis media. Throat pain, hoarseness, and vocal cord paralysis have been identified in patients with prolonged placement of larger-bore Salem tubes. 4 ,43
Tube Enterostomies Complications of tube enterostomies include gastric perforation, hemorrhage, wound infections, stomal leak, and tube migration. Migration of catheters is primarily due to the use of urinary-type catheters for feeding tubes (Fig. 17-11). This can result in wound care issues because of erosion of the exit site and leakage of gastric or intestinal contents onto the surrounding skin. Leakage can also be precipitated by the improper sealing of the internal and external retention disk (Fig. 17-12). Several
Nasal Tubes Tube displacement and subsequent feeding into the tracheobronchial tree can result in pneumothorax, pneumonia, hydrothorax, and empyema. A postinsertion radiograph remains the most reliable method of
FIGURE 17-11. Leakage around a gastrostomy tube by migration of the tube internally due to the use of a uninary catheter for a feeding gastrostomy.
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17 • Access to the Gastrointestinal Tract
FIGURE 17-12. Leakage around a gastrostomy tube due to improper sealing by a loose retention disk.
FIGURE 17-14. Proper placement of percutaneous endoscopic gastrostomy tube.
case reports described retrograde jejunoduodenal intussusception caused by the use of Foley-type gastric catheters that have migrated beyond the pylorus into the small bowel. In an attempt to reposition the catheter, the tube is pulled back while the balloon is fully inflated." The result is telescoping of the distal small bowel into the proximal small bowel, leading to ischemia and necrosis of the bowel. Buried bumper syndrome is a result of migration of the internal bumper into the gastric wall (Fig. 17-13), and in some patients, the bumper becomes completely covered by gastric epithelium."
Partially covered tubes could be pulled out with a polypectomy snare. For totally covered tubes, an incision is made with a papillotomy needle knife to expose the bumper, which is then grasped with a snare." The internal and external bumpers must be closely approximated to seal the track between the stomach and the abdominal wall (Figs. 17-14 and 17-15). However, after the first 24 hours, the ability to rotate the catheter and maintain a space no more than 0.25 ern between the skin and external retention device can assist in preventing this syndrome. Complications of jejunal tubes include proximal migration of the tube into the stomach, distal migration, intraperitoneal leak, wound infection, and bowel obstruction. Several reports have associated the infusion of hyperosmolar formula and bacterial contamination with disturbances of mucosal integrity or local vasospasm resulting in small bowel necrosis."
CATH ETER REMOVAL/EXCHANGE
FIGURE 17-13. Migration of percutaneous gastrostomy tube outside of the stomach.
endoscopic
All enterostomy tubes, both gastric and jejunal, require periodic replacement due to balloon rupture, tube erosion (older tubes), or the need to remove the tube when it is no longer needed. Occasionally a tube may be removed at the request of the patient who desires a skin level device. Removal of a PEG tube using the traction method causes the least amount of patient distress if steps are taken to adequately prepare the patient. The patient should keep the abdominal muscles as relaxed as possible, through deep breathing and placement in a semi-Fowler position with the knees bent. The external retention disc is slid away from the exit site, and the tube is lubricated, using plain or lidocaine lubricant. The lubricant is dispersed into the tract by gently advancing the
SECTION IV • Principles of Enteral Nutrition
FIGURE 17-1 S. Proper placement of surgical gastrostomy tube.
tube 2 to 3 em back and forth into the stomach. A local anesthetic can be injected in the area surrounding the stoma. It is essential having an assistant to apply counter pressure to the abdominal wall surrounding the tube at the time of removal. The PEG tube is withdrawn by firmly grasping it with the dominant hand and using constant and continuous traction to pull it out of the stomach. Dressings should be available to apply over the site and to protect the skin from gastric drainage. Bleeding may occur if granulation tissue is present around the stoma; silver nitrate can be used to cauterize this tissue. If a feeding tube is not to be placed, patients are instructed to eat and drink as they would normally, to expect drainage from the exit site for the following 24 to 48 hours, and if drainage persists beyond 48 hours to inform their health care provider. A balloon type catheter is removed by using lubricant to the stoma with the same method as described in the preceding paragraph. Fluid is then withdrawn from the bal-
213
loon, unless it is known to have ruptured, and the catheter is then withdrawn. Feeding catheters inserted by radiologists usually have a coiling system at the end, which gives them the name pigtail catheters. The coiling is produced by traction on a wire that runs through the catheter all the way to the end. The tension is held by a locking mechanism on the proximal side, usually a plastic turning piece covered by a rubber cap. Before these catheters are extracted, this pigtail has to be undone. It is always preferable to refer the patient back to the radiologist who placed the catheter. If the radiologist is not available and the catheter has to be removed by another clinician, the proximal end has to be uncovered. Usually a rubber cap is folded over the locking mechanism. Then the locking plastic piece is unturned to release the tension on the wire. Sometimes the wire has become fused within the channel and does not slide freely. A drastic measure then is to cut off the entire proximal end. This maneuver will result in a higher likelihood of the wire becoming loose, although it is possible that the wire will remain stuck beyond the cut made on the catheter. The only possibility then is to instill some fluid through the wire channel to loosen the wire. If the catheter is extracted with a pigtail conformation at the end, the extraction will be more traumatic and may result in some bleeding; however, usually the tissue damage is minor and does not lead to any sequelae. Gastric tubes are replaced at a 90° angle with a welllubricated catheter. The balloon is inflated with 10 to 15 mL of water or saline, and then it is approximated against the gastric wall while the external retention device is positioned against the abdominal wall. The catheter should be gently rotated to ensure that there is no pressure against the gastric or abdominal wall that can cause skin erosion, gastric ulceration, or buried bumper syndrome. Jejunal tubes are replaced at a 45° angle with a well-lubricated catheter. If a tube with a balloon is used, the tube must be advanced through the Witzel tunnel before 2 to 3 mL of water or saline are instilled into the catheter. The catheter is then gently pulled back until tension is felt; at this point the external retention device is approximated against the abdominal wall. A larger volume of fluid injected into the balloon will obstruct the small bowel, resulting in leakage of bile and subsequent skin erosion and eventually peritonitis if not treated. Approximation of the internal and external retention devices must not be too tight to avoid traction on the Witzel tunnel. Urinary catheters should never be considered as replacement catheters, and their use should be limited to short-term replacement to maintain the integrity of the stoma until a proper feeding tube can be placed. The use of urinary catheters can result in numerous complications caused by migration of the catheter. Complications include obstructed pylorus, aspiration, intestinal obstruction, enlargement of the stoma site, leakage of gastric contents, and erosion of the skin. Patients and caretakers can be instructed to place the dislodged catheter back into the stomach; this maintains stoma integrity until the catheter can be replaced. This also avoids an untimely emergency room visit. Replacement tubes can be sent
214
17. Access to the Gastrointestinal Tract
home with those who can replace their own tubes or who can get assistance from a visiting nurse.
SUMMARY There are many options for establishing an access port to the gastrointestinal tract for feedings. At the same time there are many variables that make some forms of enteral access more suitable than others for a certain patient. Nutrition support practitioners can be of great service to patients and to physicians placing enteral access devices by properly selecting the right site, method, and type of access device for an individual patient. REFERENCES 1. Boyer RJ, Kruse JA: Nasogastric and nasoenteric intubation. Crit Care Clin 1992;8:865--878. 2. Thurlow PM: Beside enteral feeding tube placement into duodenum and jejunum. JPEN J Parenter Enteral Nutr 1986;10: 104-105. 3. Zaloga GP: Bedside method for placing small bowel feeding tubes in critically ill patients. Chest 1991;100:1643-1646. 4. Caulfield KA, Page CP, Pestana C: Technique for intraduodenal placement of transnasal enteral feeding catheters. Nutr Clin Pract 1991;6:23-26. 5. Chen MY, Ott OJ, Gifford OW: Nonfluoroscopic, postpyloric feeding tube placement: Number and cost of plain films for determining position. Nutr Clin Pract 15:40-44,2000. 6. Gabriel SA, Ackemann RJ, Castresana MR: A new technique for placement of nasoenteral feeding tubes using external magnetic guidance. Crit Care Med 1997;25:641-645. 7. Hernandez-Socorro CR, Martin J, Ruiz-Santana S, et al: Bedside sonographic-guided versus blind nasoenteric feeding tube placement in critically ill patients. Crit Care Med 1996;24:1690-1695. 8. Gutierrez ED, Balfe OM: Fluoroscopically guided nasoenteric feeding tube placement: Results of a 1 year study. Radiology 1991; 78:759-762. 9. Ahmed W, LevyH, Kudsk K,et al: The rates of spontaneous transpyloric passage ofthree enteral feeding tubes. Nutr Clin Pract 1999;14: 107-110. 10. Lord LM, Weiser-Maimone A, Pulhamus M, et al: Comparison of weighted vs. unweighted enteral feeding tubes for efficacy of transpyloric intubation. JPEN J Parenter Enter Nutr 1993; 17:271-273. 11. Salasidis R, Fleiszer T, Johnston R: Air insufflation technique of enteral tube insertion: A randomized, controlled trial. Crit Care Med 1998;26:1036-1039. 12. Reed RL, Eachempati SR, Russell MK, et al: Endoscopic placement of jejunal feeding catheters in critically ill patients by a technique. J Trauma 1998;45:388-393. 13. Baskin WN, Johanson JF: An improved approach to delivery of enteral nutrition in the intensive care unit. Gastrointest Endosc 1995;42:161-165. 14. Metheny NA, Clouse RE, Clarke JM, et al: pH testing of feedingtube aspirates to determine placement. Nutr Clin Prac 1994;9:185-190. 15. Metheny NA, Reed L, Worseck M, et al: How to aspirate fluid from small-bore feeding tubes. Am J Nurs 1993;May:86-88. 16. Berry S, Orr M, Schoettker P, et al: Intestinal placement of pHsensing nasointestinal feeding tubes. JPEN J Parenter Enter Nutr 1994;18:67-70. 17. Heiselman DE,Vidovich RR, Milkovich G, et al: Nasointestinal tube placement with a pH sensor feeding tube. JPEN J Parenter Enter Nutr 1993;17:562-565. 18. Botoman VA, Kirtland SH, Moss RL: A randomized study of a pH sensor feeding tube vs a standard feeding tube in patients requiring enteral nutrition. JPEN J Parenter Enter Nutr 1994;18:154-158.
19. Welch SK, Hanlon MD, Waits M, et al: Comparison of four bedside indicators used to predict duodenal feeding tube placement with radiography. JPEN J Parenter Enter Nutr 1994;18:525-530. 20. Ponsky JL, Gauderer WL, Stellato TA: Percutaneous endoscopic gastrostomy: Review of 150 cases. Arch Surg 11983;18:913-914. 21. Gauderer MWL, Ponsky JL, 1zant RJ: Gastrostomy without laparotomy: A percutaneous endoscopic technique. J Pediatr Surg 1980; 15:872-875. 22. Russell TR, Brotman M, Norris F: Percutaneous gastrostomy: A new simplified and cost-effective technique. Am J Surg 1985; 48:132-135. 23. Grant JP: Percutaneous endoscopic gastrostomy: Initial placement by single endoscopic technique and long-term follow-up. Ann Surg 1993;17:168-174. 24. Cosentini EP, Sautner T, Gnant M, et al: Outcomes of surgical, percutaneous endoscopic, and percutaneous radiologic gastrostomies. Arch Surg 1998;33:1076-1083. 25. Bergstrom LR, Larson DE, Zinsmeiserter AR, et al: Utilization and outcomes of surgical gastrostomies and jejunostomies in an era of percutaneous endoscopic gastrostomy: A population-based study. Mayo Clin Proc 1995;70:829-836. 26. Panzer S, Harris M, Berg W, et al: Endoscopic ultrasound in the placement of a percutaneous endoscopic gastrostomy tube in the non-transilluminated abdominal wall. Gastrointest Endosc 1995;42: 88-90. 27. Henderson JM, Strodel WE, Gilinsky NH: Limitations of percutaneous endoscopic jejunostomy. JPEN J Parenter Enter Nutr 1993; 17:546-550. 28. De Legge MH, Patrick P, Gibbs R: Percutaneous endoscopic gastrojejunostomy with a tapered tip, nonweighted jejunal feeding tube: Improved placement success. Am J Gastroenterol 1996;91: 1130-1134. 29. Leichus L, Patel R, Johlin F: Percutaneous endoscopic gastrostomy/jejunostomy (PEG/PEl) tube placement: A novel approach. Gastrointest Endosc 1997;45:79-81. 30. Parasher VK, Abramowicz CJ, Bell C, et al: Successful placement of percutaneous gastrojejunostomy using steerable glidewire-A modified controlled push technique. Gastrointest Endosc 1995;41:52-55. 31. Murayama KM, Johnson TJ, Thompson JS: Laparoscopic gastrostomy and jejunostomy are safe and effective for obtaining enteral access. Am J Surg 1996;172:591-595. 32. Lydiatt DO, Murayama KM, Hollins RR, et al: Laparoscopic gastrostomy versus open gastrostomy in head and neck cancer patients. Laryngoscope 1996;106:407-410. 33. Peitgen K, Walz MK, Krause U, Eigler FW: First results of laparoscopic gastrostomy. Surg Endosc 1997;11:658-662. 34. Modesto V, Harkins B, Carlton WC, Martindale RG: Laparoscopic gastrostomy using four-point fixation. Am J Surg 1994;167:273-276. 35. Rombeau JL,Twomey PL,Mclean GK,et al: Experience with a new gastrostomy-jejunal feeding tube. Surgery 1983;93:574-578. 36. Choudhry U, Barde C, Markert R, et al: Percutaneous endoscopic gastrostomy: A randomized prospective comparison of early and delayed feeding. Gastrointest Endosc 1996;44:164-167. 37. Kirby OF, Guy LC, Turner H, et al: Early enteral nutrition after brain injury by percutaneous endoscopic gastrojejunostomy. JPEN J Parenter Enter Nutr 1991;15:298-302. 38. Bankhead RR, Rolandelli RH, Fisher C, et al: Comparison of outcomes for gastrostomy placement methods. Abstract presented at the 25th Clinical Congress of the American Society of Parenteral and Enteral Nutrition, Chicago, 2002. 39. Bower S: Tubes: A nurse's guide to enteral feeding devices. MEDSURG 1996;5:313-326. 40. Kohn CL,Keithley JK:Enteral nutrition potential complications and patient monitoring. Nurs Clin North Am 1989;24:339-353. 41. Mullan H, Roubenoff RA, Roubenoff R: Risk of pulmonary aspiration among patients receiving enteral nutrition support. JPEN J Parenter Enter Nutr 1992;16:160-164. 42. Strong RM, Condon SC, Solinger MR, et al: Equal aspiration rates from postpylorus and intragastric-placed small-bore nasoenteric feeding tubes: A randomized, perspective study. JPEN J Parenter Enter Nutr 1992;16:59-63. 43. Sofferman RA, Haisch CE, Kirchner JA et al: The nasogastric tube syndrome. Laryngoscope 1990;100:962-968.
SECTION IV. Principles of Enteral Nutrition 44. Ciaccia 0, Quigley RL, Shami PJ, et al: A case of retrograde jejunoduodenal intussusception caused by a feeding gastrostomy tube. Nutr Clin Pract 9:18-21, 1994. 45. Bareham B, Ammori BJ:Laparoscopic percutaneous endoscopic gastrostomy removal in a patient with buried-bumper syndrome: A new approach. Surg Laparosc Endosc Percutan Tech 2002;12:356-358.
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46. Ma MM, Semlacher EA, Fedorak RN, et al: The buried gastrostomy bumper syndrome: Prevention and endoscopic approches to removal. Gastrointest Endosc 1995;41 :505-511. 47. Schunn COG, Daly JM: Small bowel necrosis associated with postoperative jejunal tube feeding. J Am Coli Surg 1985;180:41D-416.
II Enteral Formulations Pam Charney MS, ROlLO, CNSO Mary Russell MS, ROlLO, CNSO
CHAPTER OUTLINE Introduction Brief History of Enteral Formula Development Regulatory Status of Enteral Formulas Components of Enteral Formulas Water Carbohydrates Fiber Fat Protein Vitamins and Minerals Other Nonessential Nutrients Types of Formulas Homemade Formulas Standard Polymeric Formulas Chemically Defined and Elemental Formulas Special Formulas The Enteral Formulary
INTRODUCTION Rapid advances in enteral formula development have been made over the past 20 to 30 years. In the past, only two or three commercial enteral formulas were available for tube feeding of patients requiring enteral nutrition support. Homemade formulas, ground in a blender from table foods, were commonly used. Improvements in food technology as well as scientific knowledge of the requirements of sick patients have led to the development of the wide array of formulas now available. There are now more than 200 different enteral formulas for clinicians to choose from, which may lead to considerable confusion and increased cost if the clinician does not follow a methodic and rational approach for their use. Many of the special enteral formulas available today are much more expensive than standard formulas. Solid evidence supporting their use in many situations is lacking. Clinicians should be aware of the formula choices available and the evidence for their use in clinical situations 216
and should understand the importance of enteral formulary development. In addition to the need to be aware of recommended intakes of macronutrients, it is now more important than ever for clinicians to monitor the micronutrient content of formulas, because some may include high contents of these agents for pharmacologic purposes.
BRIEF HISTORY OF ENTERAL FORMULA DEVELOPMENT Contrary to a commonly held belief; enteral nutrition support is not a new science. Descriptions of enteral feeding techniques have been found in Greek, Roman, and Egyptian texts. Formulas most likelyconsisted of wine, milk, broth, and perhaps pulverized foodstuffs. These feedings had unknown nutrient composition and were given using hollow plants or wooden tubes. During the middle ages, enteral feedings were given using glass or wooden tubes. In the late 19th century, enteral formulas were prepared using broth, whiskey, wine, milk, and water. Eggs were often used as a source of protein. During the late 19th century rectal feedings were attempted in some situations. These formulas were similar to formulas that were fed gastrically, with the possible addition of tobacco, meat, red wine, and occasionally defibrinated blood.' Little thought was given to clean techniques for formula preparation, because the germ theory of disease was still relatively new. Until the early to mid-1950s, health care facilities used formulas that were made on site by pureeing and straining regular foodstuffs. In the mid-20th century, commercial enteral formulas were seen for the first time. Early formulas were often marketed as weight loss aids as well as for use in feeding patients. Allof the products sold until the latter third of the 20th century contained whole proteins and polysaccharides along with com or soy oil. The need for low-residue diets for space flight led to the development of the first monomeric, or elemental, formula in the early 1960s. Hydrolyzed protein formulas that contained a mixture of free amino acids and some short peptide chains were soon developed. In the mid-1980s,
SECTION IV • Principles of Enteral Nutrition
specialty products for children as well as for patients with respiratory failure were developed, followed by other disease-specific products. Shortly after that, enteral formulas became available with added fiber. More recent developments in enteral formula technology include the use of modified fat blends to include what is felt by some to be an optimal mix of fatty acids for a particular patient population. Additionally, newer formulas include an enhanced supply of some nutrients, in particular the antioxidant nutrients, in response to research showing benefits in some patient populations. Early formulas with added fiber only contained small amounts of insoluble fiber because of viscosity limitations. Advances in food technology have allowed increased amounts of fiber, along with a mix of soluble and insoluble fibers better suited to meet the needs of a particular patient population.!
REGULATORY STATUS OF ENTERAL FORMULAS Enteral formulas are classified as medical foods under the 1988amendment to the Orphan Drug Act. This statutory definition, the first for medical foods, reads "a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation." Among other issues, this amendment addresses the development of medical foods for "any disease or condition that occurs so infrequently in the United States that there is no reasonable expectation that a medical food for such disease or condition will be developed without assistance" as defined in the Orphan Drug Act. However, the legislative history of the amendment does not discuss the definition and does not provide further information about products the definition was intended to cover. In 1996 the Food and Drug Administration (FDA) provided an advance notice of proposed rule-making involving the regulation of medical foods.' The purpose of this notice was to "arrive at a regulatory regime that will ensure that: These products are safe for their intended uses, especially since they are likely to be the sole or a major source of nutrients for sick and otherwise vulnerable people; claims for these products are truthful, not misleading, and supported by sound science; and the labeling of these products is adequate.... " The advance notice mentioned the proliferation of products marketed as medical foods and alluded to safety problems with manufacture and quality control and the "potential for fraud" if unsupported claims were made. The Nutrition Labelingand Education Act of 1990incorporated the definition of a medical food and exempted these foods from nutrition labeling, health claim, and nutrient claim requirements. The final rule on mandatory nutrition labeling" exempted medical foods from nutrition labeling requirements and incorporated the statutory definition of medical food into the FDA regulations. The
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specific regulation stated that a food was exempt from nutrition labeling requirements only if it met the following criteria: • Specially formulated and processed for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding by tube • Intended for the dietary management of a patient who, due to therapeutic or chronic medical needs, has limited or impaired ability to ingest, digest, absorb, or metabolize ordinary foods or who has other specially determined nutrient requirements • Provides nutrition support specifically modified for the unique nutrient needs that result from the specific disease or condition as determined by medical evaluation • Intended for use under medical supervision • Intended only for a patient receiving active and ongoing medical supervision wherein the patient requires ongoing care on a recurring basis for, among other things, instructions on use of the medical food Although the advanced notice of proposed rule-making was released in 1996, no decision about further clarification of the medical foods issue has yet been made. Manufacturers continue to follow the guidelines in the 1988amendment.
COMPONENTS OF ENTERAL FORMULAS
Water Enteral formulas that provide 1 kcal/mL have approximately 850 mL of "free" water in each liter of formula. This amount may not be adequate to meet the free water needs for most adults. Additional water to provide a sufficient amount to meet the fluid needs of most patients who do not have alterations in fluid requirements is often provided as tube flushes or with medications. Formulas that provide more than 1 kcal/mL contain less water, with the most concentrated formulas providing approximately 710 mL of water in each liter of formula. Therefore, it is extremely important to monitor fluid status in patients who are receiving concentrated formulas. The chemical form of nutrients determines the osmolality of enteral formulas. Osmolality is determined by the number of osmotically active particles in solution. A formula that contains intact protein and glucose polymers will have a lower osmolality than one with free amino acids and mono- and disaccharides because of the differences in the number of osmotically active particles. In the past, it was thought that formulas with an osmolality higher than normal serum (=275 to 290 mOsm/L) would create a hypertonic environment in the gastrointestinal (GI) tract, thus drawing water into the intestinal lumen and leading to "osmotic diarrhea." For this reason enteral feedings were often started "low and slow" using diluted formulas that were gradually increased to full strength. This paradigm was accepted for many years until it was recognized that normal GImechanisms act to ensure osmotic regulation under a variety of conditions. Studies in both healthy volunteers and patients with
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impaired GI function found that, within a certain range, formula osmolality was not related to GI tolerance.t-' The osmolality of most hypertonic enteral formulas is approximately 650 mOsm/kg, which is significantly lower than the osmolality of many medications as well as that of most of the fluids provided on a standard clear liquid diet. Therefore, when enteral nutrition formulas are administered into the stomach, they do not need to be diluted to isotonicity. Formula dilution is ordered when free water is needed to meet fluid requirements. In the past it was recommended that small intestinal feedings be diluted. However, in most cases, formula dilution is not needed when intestinal feedings are ordered. When formulas are diluted for this reason, it is important to review final nutrient composition of the formula to ensure that adequate levels are provided.
Carbohydrates Because early enteral formulas often used milk as a protein source, these formulas also contained a significant amount of lactose (milk sugar). Early reports of diarrhea associated with enteral feeding were often ascribed to lactose intolerance. A significant percentage of the population has a loss of lactase activity throughout adult life. However, it is not known if lactose intolerance is a significant cause of intolerance. In some populations, lactose intolerance could not be implicated as a cause of GI symptoms following bacterial infections.' Additionally, during illness, lactase activity is often thought to be temporarily lost, thus leading to lactose intolerance during illness. Most formulas now use hydrolyzed starch as a carbohydrate source. Enteral formulas that may be consumed orally contain some simple carbohydrates to enhance palatability. Sucrose is more commonly included to add sweetness to these formulas. Usually they contain a mixture of maltodextrins and sucrose, along with some longer-ehain oligosaccharides. Because these formulas contain a higher percentage of smaller carbohydrate molecules, they tend to have a higher osmolality than formulas that are not meant to be consumed orally. In most cases this is not an issue when formulas are chosen.
Fiber Many enteral formulas are now available with added fiber. The addition of fiber to these products has been suggested to help lessen the occurrence and severity of diarrhea in enterally fed patients. Early products contained only insoluble fibers and produced mixed results, with most studies showing little effect on incidence and duration of diarrhea.I" More recently, soluble fiber has been added either alone or as part of a mixture of fiber. The addition of both soluble and insoluble fibers can both provide stool-bulking properties and stimulate short-ehain fatty acid production." The addition of 22 gil of soluble fiber in the form of partially hydrolyzed guar gum was shown to lead to a significant decrease in the incidence of diarrhea in critically ill tube-fed patients.'? For more information regarding dietary fiber see Chapter 14.
There has been much interest in recent years in the role of pre- and probiotic substances in prevention of GI complications of enteral feeding. Probiotics are those bacteria that playa supportive role in maintaining colonic flora, whereas prebiotics are foods that provide fermentable substrate for healthy colonic bacteria. I I More recently, different types of fructose polymers have been added to some formulas to provide fermentable substrate for colonic bacteria to act as prebiotics. The most commonly added polymers are inulins, which have varying chain lengths, but share ~(2-1) bonds that resist the digestive process in the small bowel." Inulins can have chain lengths of from 2 to 60 fructose molecules. Fructooligosaccharides are inulins with shorter chain lengths of 2 to 10 molecules that can be found naturally in foods or can be synthesized.P Although the optimal dosage remains to be determined, the addition of inulin was somewhat effective in relieving constipation in elderly subjects."
Fat Fat in oral diets as well as in enteral and parenteral nutrition solutions provides energy and essential fatty acids. Dietary fat provides a concentrated source of energy, with 9 kcal/g as opposed to 4 kcallg for either carbohydrate or protein. Although traditional sources of fat for enteral formulas, such as corn or soy oil, require intact digestive and absorptive capabilities, the medium chain triglycerides (MCTs) can be absorbed directly into the portal system. Use of MCTs in enteral formulas can significantly improve tolerance in some patients with malabsorptive disorders. Lipids perform additional, specialized functions and may produce potentially negative side effects; these are discussed in Chapter 9. In enteral formulas fat is added as triglycerides, emulsified to be compatible with the aqueous phase. Most formulas contain soy or corn oil as the main lipid source. Specialized formulas can contain a combination of lipid types, including corn or soy oil with MCT oil or other specialized fats such as marine oils. Because lipid is isotonic and not water soluble, it lowers the osmolality of enteral formulas. Fats also increase palatability and may carry flavoring agents. Fats are traditionally classified as saturated, monounsaturated, and polyunsaturated. MCT oil, with a medium carbon chain length of 6 to 12 atoms, falls within the saturated classification. 00-7 Monounsaturated fats include fish oils; 00-9 monounsaturated fats include canola, safflower, and sunflower oils. The polyunsaturated class includes the well-known 00-6 and ro-3 fatty acids. The former, composed of linoleic and "tlinolenic acids, include corn, soy, safflower, and sunflower, as well as borage and black current oils. The latter, comprising eicosapentaenoic and "tlinolenic acids, include sardine, menhaden, linseed, rapeseed, and soy oils. The shortchain fatty acids (SCFAs), butyrate, acetate, and propionate, can be produced in the colon as end products of the digestion of starch and dietary fiber by colonic flora. They are a principal source of fuel for the colon (particularly the distal portion) and have been shown
SECTION IV • Principles of Enteral Nutrition
by Rombeau and Kripke" to be essential in some populations. SCFAs are not added to enteral formulas because they are completely absorbed in the jejunum and do not reach the colon. However, fiber or prebiotic substances can be added to formulas as an indirect method of providing SCFAs. MCTs were developed by Bach and Babayan" to treat fat malabsorption in enteral feeding. In some situations, MCTs are a more desirable substrate than longer-ehain fats." Use of MCTs may produce side effects. Pure MCT solutions do not provide essential fatty acids, and the speed of oxidation may cause body temperature to rise due to uncoupling of oxidative phosphorylation. MCT solutions may cause ketosis and saturate serum albumincarrying sites, interfering with the normal functions of albumin. For these reasons, MCTs are found in many enteral products marketed for adults and all those marketed for pediatric patients in combination with long-ehain triglycerides (LCTs). In some formulas, esterified mixtures of MCTs and LCTs, known as structured lipids (SLs),are present. SLs contain a triglyceride with various chain lengths of fatty acids bonded to each glycerol backbone. A prospective, randomized, blinded trial of 50 adult patients compared safety, GI tolerance, and clinical efficacy of feeding an enteral formula containing a fish oil/MCT structured lipid with those of an isonitrogenous, isocaloric standard formula in patients undergoing major surgery for upper GI tract malignancies." Patients receiving the experimental formula had no adverse side effects and 50% fewer GI complications and infections than patients given the standard diet; the data suggested that the experimental group had improved liver and renal function, which the authors postulated was due to modulation of urinary prostaglandin levels. w-3 Fatty acids affect hemodynamic functions, the cardiovascular system, immune function, and possibly mortality.P'" Eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6), derived from fish oil, have received the most attention and are present in some enteral formulas. (Humans can synthesize both from linolenic acid, but exogenous intake has effects on prostaglandin and cytokine production as well as on immune function.) These components are present with other substances that may affect outcomes, and thus the exact role played by the ro-3 fatty acids may be difficult to distinguish. However, the data are intriguing. In one study, Gadek and colleagues's used an enteral formula containing eicosapentaenoic acid, MCTs, canola oil, "tlinolenic acid from borage oil, and lecithin (55% of total kilocalories as lipid) in patients at risk of developing adult respiratory distress syndrome. Patients who received the experimental formula had several statistically significant outcomes: gas exchange was improved, whereas time that mechanical ventilation was needed, time in the ICU, and total new organ failures were reduced. Linoleic acid, an ro-6 fatty acid, is a precursor to arachidonic acid and (along with linolenic acid) is considered to be an essential fatty acid. Although the essentiality of linoleic acid is not in doubt, there is some concern about the appropriate amounts to feed in patients who are acutely ill. Arachidonic acid is metabolized to prostaglandins EI and E2, series 4 leukotrienes,
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and prostacyclin.P These metabolites are associated with increased muscle breakdown, increased immunosuppression, and inflammation. The leukotrienes of the 4 series stimulate mucus secretion and are bronchorestrictive.r' For patients who are critically ill or immunosuppressed or those who have a significant inflammatory response, formulas with a high content of linoleic acid may not be a good choice. Enteral formulas contain a varying amount of linoleic acid, ranging from 1.6 to 37 gIL. There is insufficient evidence to recommend the most appropriate level of linoleic acid for these patients. It is generally accepted that provision of from 2% to 4% of total calories as linoleic acid is sufficient to prevent development of essential fatty acid deficiency.
Protein Dietary protein is required for tissue growth, maintenance, and repair. Soy protein isolate and casein are the most common protein sources in standard enteral formulas. Other proteins used include lactalbumin, whey, and egg albumin. Whole proteins used in enteral formulas are large molecules and do not contribute appreciably to formula osmolality. All of these protein sources are often referred to as "intact" protein and require normal or near-normal digestive and absorptive capability. In the past it was thought that if patients demonstrated "intolerance" to enteral feeding a switch should be made to a chemically defined or elemental formula. Early formulas in this category contained only free amino acids, whereas more recently formulas with protein supplied as smaller peptide chains as well as mixtures of di- and tripeptides and free amino acids have become available. It is known that the normal digestive process hydrolyzes dietary protein until a mixture of small peptides and free amino acids is presented to the brush border. Intestinal mucosal cells have transport systems for di- and tripeptides. Peptides of two and three units are preferentially absorbed, thus lending credence to the use of formulas containing small peptides for those patients with impaired GI function. Branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, are essential amino acids which, during periods of acute stress and injury, are mobilized from skeletal muscle." Patients with hepatic encephalopathy (and other critically ill patients) have been shown to have lower than normal serum levels of BCAAs and higher than normal serum levels of aromatic amino acids. Some enteral formulas have been enriched with BCAAs with the goal of normalizing serum BCM levels, but the efficacy of the formulas in achieving this goal is controversial." As with other clinical situations, the investigations of the role of BCM included varied patient populations and protocols, small sample sizes, differing ratios of BCAAs and macronutrients, and varying amounts of energy." The BCM content of specialized enteral formulas marketed in the United States primarily for tube feeding varies from 46% to 50% of total protein, with standard formulations containing approximately 20% of protein from BCAAs.
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Vitamins and Minerals Most enteral formulas provide vitamins and minerals designed to meet estimated requirements for the target population given that a minimum amount of formula is fed. Many of the adult formulas provide the Dietary Reference Intakes (ORIs) or estimated adequate intake in volumes from 1000 to 1500 mL. Pediatric formulas contain amounts of vitamins required to meet the needs of children from 1 to 18 years of age. Supplementation should be considered when low volumes or diluted formulas are fed. When specialized formulas are chosen for some patient populations, it is important to carefully evaluate the vitamin and mineral content. Some, but not all of the formulas for patients with hepatic or renal failure contain very low amounts of some vitamins and minerals, which may need to be supplemented for some patients. There has been heightened interest in the role of the antioxidant nutrients in wound healing and recovery from serious illness. Specialized formulas for this population may contain higher levels of these nutrients, including vitamin A, vitamin C, and zinc. Any time a specialized formula is used, attention should be paid to the vitamin and mineral content.
date there have been no studies of the role of exogenous choline in nutrition support of tube-fed patients.
Nucleotides Nucleotides (purines and pyrimidines) are also synthesized by healthy humans in the amounts needed for growth, development, and maintenance. Nucleotides are the building blocks of DNA and RNA, regulate enzymes, and serve as intermediates and coenzymes in energy transfer reactions. Early work with renal transplant patients receiving parenteral nutrition (with no nucleotide content) demonstrated less rejection despite reduced immunosuppression; the need for immunosuppression increased when patients began an oral diet." The absence of preformed nucleotides was thought to be a cause of the immunosuppression. A significant body of work in animals suggested the need for preformed pyrimidines for development and activation of T cells. Data on the effects of nucleotides added to human diets (enteral formulations) are extremely limited. Nucleotides are added to a few formulas along with arginine, antioxidants, 0>-3 fatty acids, and other components, such that determining the specific role of nucleotides is impossible. More work is needed to specify the role of these dietary components.
Other Nonessential Nutrients Carnitine Carnitine is an amine requiring two essential amino acids and several micronutrients for its biosynthesis. It facilitates l3-oxidation of long-ehain fatty acids by transporting the fatty acids into the mitochondria." Dietary carnitine is found only in animal products. Healthy adults do not require exogenous camitine and deficiencies have not been reported in individuals following vegetarian diets; thus the nutrient is not considered essential. However, exogenous camitine may be required by newborns and adults who are critically ill. Additionally, patients undergoing hemodialysis who have anemia that is refractoryto standard treatment with recombinant human erythropoietin and iron supplementation may require exogenous camitine.P The exact amount of dietary camitine required during these states is unknown. Manyenteral formulas now contain camitine in a range comparable to those in a normal (nonvegan) diet «5 rug/kg/day). Carnitine content of enteral formulas marketed in the United States primarily for tube feeding varies from 0 to 130 rng/I000 kcal.
Choline Choline is biosynthesized from phosphatidylethanolamine and therefore is not essential for healthy humans. Individuals who receive choline-free nutrition (most often, total parenteral nutrition) for long periods may become choline deficient. Malnourished individuals with liver dysfunction may be unable to synthesize choline due to defective methyl transfer reactions.P To
TYPES OF FORMULAS Homemade Formulas Before the ready availability of commercially prepared enteral formulas, recipes for homemade formulas were part of the armamentarium of all nutrition support clinicians. Most of these recipes included milk or eggs as a protein source and com or vegetable oil as a fat source. Formula viscosity was an issue as well as ensuring consistency of nutrient composition. Other problems with the use of homemade formulas include assurance of food safety, because it is difficult to ensure clean and sanitary handling at all points of preparation and delivery. A homemade formula was safely used in a small group of bum patients. The formula contained cottage cheese, eggs, sugar, refined oil, and ragi (a type of millet) flour. There were no differences in tolerance and efficacy, as measured by the number of surgical procedures, days of hospitalization, graft success, and serum protein levels. However, no information was provided about the complete nutrient composition or steps taken to ensure safe preparation and adrninistration.P When homemade formulas are used, strict attention must be paid to clean techniques in preparation, nutrient composition, and monitoring of tolerance.
Standard Polymeric Formulas Most health care facilities would consider a standard enteral formula to be one that contains a moderate
SECTION IV • Principles of Enteral Nutrition
amount of intact protein, provides balanced levels of carbohydrate and fat, and meets the micronutrient requirements of the "average" adult in an acceptable volume. Polymeric formulas are indicated for most patients with normal GIfunction as well as for many patients with some impairment of GI status. When adequate volume is provided, these products would meet the fluid requirements of most patients. Often, flavored varieties of standard formulas are available for use in patients who are able to consume these products orally. When oral supplements are needed, it is important to monitor intake, because it has been suggested that these products can result in decreased food intake. Compliance with oral supplement regimens is often problematic as well. Some patient populations, including those with cardiac, pulmonary, and renal disorders, may require fluid restriction. For this reason, enteral formulas that are more concentrated and can provide adequate macro- and micronutrient levels in a lower volume are available. Fluid concentrated formulas provide 1.5 to 2.0 kcallmL. The choice of formula depends on the patient population most often seen, and the cost-effective enteral formulary should contain only one of these products. The type and amount of fiber added to formulas should be evaluated carefully and the desired effects from the use of a fiber-eontaining formula should be determined. Mostof the purported benefits from addition of fiber are related to normalization of bowel function. Although there is some interest in the role of soluble fiber in enhancing glycemic control in individuals with diabetes mellitus, no benefit from the addition of 20 g of fructo-oligosaccharide was seen in subjects with type 2 diabetes mellitus." There is some controversy over the role of these formulas in preventing diarrhea in acutely ill patients, but much anecdotal evidence suggests that fiber-eontaining formulas can be helpful in normalizing bowel function in patients needing long-term care. Most formulas contain 3 to 4 g of fiber/250 mL, with varying types and ratios of soluble and insoluble fibers. Because soluble and insoluble fibers may have different effects on gastrointestinal function, it is probably preferable to choose formulas that have a blend of fibers with no more than 15 g/L.9,34
Chemically Defined and Elemental Formulas There is continued controversy concerning the content of these formulas. Many feel that a strictly elemental formula must contain nutrients in their most basic form, that is, amino acids, simple carbohydrates, and very little fat. Peptide-based formulas may be referred to as chemically defined formulas. As discussed earlier, there is probably less indication for the use of chemically defined or elemental formulas than previously thought. Most patients can be safely fed standard polymeric formulas. However, when an elemental formula is needed, some controversy about the optimal nitrogen source in this type of formula remains. Some formulas contain only free amino acids, whereas others contain peptides of varying lengths. The
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type and amount of carbohydrate and fat also differ in chemically defined and elemental formulas. Some contain glucose oligosaccharides, whereas others have a higher percentage of simple carbohydrates. The fat blend and amount may also vary, with most offering some amount of MCTs.
Special Formulas Diabetic Before the commercial availability of insulin, diabetes mellitus was a fatal disorder. Survival could be prolonged by strict adherence to a starvation diet. Current medical therapy involves a balance of diet, exercise, and medication. Individuals with type 1 diabetes require exogenous insulin for day-to-day survival. Those with type 2 diabetes may require insulin or oral hypoglycemic agents for control of their disease. The American Diabetes Association has published recommendations for diet of individuals with diabetes." Although there is some controversy regarding the appropriate amount and type of carbohydrate and fat in the diet, it is recommended that carbohydrate and monounsaturated fat together provide 60% to 70% of total calories." Special formulas have been developed for individuals with altered glycemic control. Glycemic control is optimized by avoiding overfeeding of all macronutrients. When an enteral formula is chosen for a patient with diabetes, it is probably appropriate to initiate feedings using a standard polymeric formula unless alterations in digestive capacity are present." If glycemic control becomes problematic despite efforts to avoid overfeeding and optimal use of insulin, then formulas with a lower carbohydrate content can be tried. To date, however, evidence supporting the use of these formulas in all patients with suboptimal glycemic control is lacking.
Renal The acutely ill patient with renal failure presents a unique challenge to the health care team. The choice of an enteral formula will depend on residual renal function, the need for dialysis, and the type of dialytic therapy. There has been much controversy about the role of dietary protein in progression of renal failure. It is currently agreed that in most cases protein should not be restricted in the acutely ill patient with renal failure. There continues to be much debate about the safety of lowprotein diets in the predialysis population." Iflow-protein enteral formulas are to be used for long-term tube feedings, then close monitoring of nutrition status is necessary. Patients with acute or chronic renal failure may have alterations in serum electrolyte levels that may benefit from formulas with lower levels of potassium, phosphorus, and sodium. There are several formulas available that provide less than the standard amounts of these electrolytes. Clinicians should become familiar with the micronutrient content of these formulas, because there can be significant differences between manufacturers. It
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goes without saying that when these formulas are used in critically ill patients or those at risk for the refeeding syndrome, serum electrolyte levels should be closely monitored.
Hepatic Special formulas have been developed based on the theory that alterations in serum levels of BCAAs and aromatic amino acids contribute to the development of hepatic encephalopathy (HE). Formulas developed for patients with HE contain lower amounts of aromatic amino acids and enhanced levels of BCAAs designed to normalize serum levels. The use of these formulas remains somewhat controversial with little research supporting their use in patients with hepatic failure who do not have HE. Use of a BCAA-enriched formula may assist with improvement of mental status in some patients with HEand may be useful in management of patients who are intolerant of levels of dietary protein needed during acute illness." When a formula is chosen for use in a patient with HE, the electrolyte content should be reviewed, because levels may vary, with at least one formula containing minimal amounts of electrolytes and vitamins.
Pulmonary Before the advent of readily available methods to determine resting energy expenditure in the critically ill patient receiving mechanical ventilation, it was noted that the high carbohydrate feedings commonly used led to difficulty in weaning from the ventilator. Specialized enteral formulas containing higher amounts of fat were developed, because lipid oxidation produces a lower respiratory quotient (RQ) than either carbohydrate or protein oxidation. The higher fat content was thought to assist with normalizing the RQ in patients who retain CO2• It has since been noted that in many of the studies supporting the use of higher-fat feedings, patients may have been significantly overfed. Overfeeding of any substrate leads to a higher RQthan that observed from oxidation of any single nutrient. Therefore, it is prudent to avoid overfeeding in critically ill patients, particularly those receiving mechanical ventilation. During ventilator weaning, it is appropriate to decrease feedings temporarily for some patients.
The Enteral Formulary Many facilities develop a defined enteral formulary as a measure to ensure the availability of formulas appropriate for their patient population. Establishment of a specific formulary should also limit or proscribe the use of highly specialized (and often more expensive) formulas. Morgan and associates" described the use of an enteral expert system in the prescription of enteral formulas in a teaching hospital. The formulary system at this facility classified enteral feedings based on criteria such as caloric density and protein type and content. A computer program was designed to prescribe the most inexpensive formula based upon requirements for energy,
protein, fiber, and specific substrate mix. Significant yearly cost savings were projected based on use of this program. An enteral formulary often allows the facility to take advantage of best pricing after a competitive bid process and/or via purchasing contracts." The concept of "therapeutic equivalence" is key to this process. Heimburger and Weinsier'? developed a system for categorizing formulas this way, based upon "major," "minor," and "inconsequential" criteria. Because this system was developed more than 17 years ago, the relative weight given to some of the criteria may have changed. Nonetheless, the scheme provides an excellent model for reviewing and classifying the important constituents of formulas. Coffey and Carey" surveyed a random sample of members of the Clinical Nutrition Management Practice Group of the American Dietetic Association to determine their practices in enteral formulary management. More than 75% of the facilities (primarily private, nonprofit, acute care facilities with 201 to 500 beds) used a formulary, and 95% of the respondents validated the need to establish objective criteria for formula evaluation. In this survey osmolarity, lactose content, and product availability were cited as the most important criteria for evaluation; these factors reflect the practice and economic values of the late 1980s, when the survey was conducted. Feitelsorr" surveyed physicians and dietitians in a community teaching hospital to determine their preferences for formulas included in the formulary, factors used to select a formula for an individual patient, and other factors. Nutrient needs of the patient, high energy density, absence of lactose, and high nitrogen content were rated highly, again reflecting practice in the 1980s. More recently, Silk" presented another view of enteral formula selection, naming several clinical factors that influence choice of formula: intake of patient, nutrient requirements, impairment of GI function (malabsorption or compromised motility) and presence of organ failure. The relative weight given to factors will vary according to the current mix of patients in the facility. In some instances, a formulary may require only three or four categories of formulas; in others a much wider range may be required. If special disease-specific formulas are to be considered, the clinical efficacy and cost effectiveness of these formulas should be reviewed, along with the specific formula components. REFERENCES 1. Harkness L: The history of enteral nutrition therapy: From raw eggs 2. 3. 4.
5.
6.
and nasal tubes to purified amino acids and early postoperative jejunal delivery. J Am Diet Assoc 2002;102:399-404. Food and Drug Administration: Medical Foods. Washington, DC, U.S. Food and Drug Administration, 2000,Vol. 2003. Federal Register. November 29, 1996, Register of Medical Foods, pp.60661-60671. Rees RPG, Keohane PP, Grimble GK, Silk DBA: Tolerance of elemental diet administered without starter regimen. Br Med J 1985; 290:1869-1870. Zarling EJ, Parmar JR, Mobarhan S: Effect of enteral formula infusion rate, osmolality, and chemical composition upon clinical tolerance and carbohydrate absorption in normal subjects. J Parenter Enteral Nutr 1986;10:588-590. Parry SO, Barton JR, Welfare MR: Is lactose intolerance implicated in the development of post-infectious irritable bowel syndrome or
SECTION IV • Principles of Enteral Nutrition functional diarrhoea in previously asymptomatic people? Eur J Gastroenterol HepatoI2002;14:1225-1230. 7. Hart GK, Dobb GJ: Effect of a fecal bulking agent on diarrhea during enteral feeding in the critically ill. JPEN J Parenter Enteral Nutr 1988;12:465-468. 8. Dobb GJ, Towler SC: Diarrhea during enteral feeding in the critically ill: A comparison of feeds with and without fibre. Intensive Care Med 1990;16:252-255. 9. Silk DBA Walters ER, Duncan HD, Green CJ: The effect of a polymeric enteral formula supplemented with a mixture of six fibres on normal human bowel function and colonic motility. Clin Nutr 2001; 20:49-58. 10. Spapen H, Diltoer M, Van Malderen C, et al: Soluble fiber reduces the incidence of diarrhea in septic patients receiving total enteral nutrition: A prospective, double-blind, randomized, and controlled trial. Clin Nutr 2001;20:301-305. II. Bengrnark S: Pre-, pro- and synbiotics. Curr Opin Clin Nutr Metabolic Care 2001;4:571-579. 12. Niness KR: Inulin and oligofructose: What are they? J Nutr 1999;129: 14025-1406S. 13. Duggan C, Gannon J, Walker WA: Protective nutrients and functional foods for the gastrointestinal tract. Am J Clin Nutr 2002; 75:789-808. 14. Kleessen B, Sykura B, Zunft HJ, Blaut M: Effects of inulin and lactose on fecal microflora, microbial activity, and bowel habit in elderly constipated persons. Am J Clin Nutr 1997;65: 1397-1402. 15. Rombeau JL, Kripke SA: Metabolic and intestinal effects of short chain fatty acids. JPEN J Parenter Enteral Nutr 1990;14:1815-185S. 16. Bach AC, Babayan VK: Medium-chain fatty triglycerides: An update. Am J Clin Nutr 1992;36:1823-1829. 17. Stein 1: Chemically defined structured lipids: Current status and future directions in gastrointestinal disease. lnt J Colorectal Dis 1999;14:79-85. 18. Kenler ASA, Swails WS, Driscoll DF: Early enteral feeding in postsurgical cancer patients: Fish oil structured lipid-based polymeric formula versus a standard polymeric formula. Ann Surg 1996;223: 316-333. 19. Schaefer EJ: Effects of dietary fatty acids on lipoproteins and cardiovascular disease risk: Summary. Am J Clin Nutr 1997;65: I6555-1666S. 20. Grimsgaard S, Bonaa K, Hansen J, Myhre E: Effects of highly purified eicosapentanoic acid and docosahexanoic acid on hemodynamics in humans. Am J Clin Nutr 1998;68:91-97. 21. Keely M: Lipids. In Matarese LE, Gottschlich MM (eds): Contemporary Nutrition Support Practice. Philadelphia, Saunders, 2003, pp 115-118. 22. Gadek J, DeMichele S, Karlstad M: Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999;27: 1409-1420.
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23. Sardesai V:The essential fatty acids. Nutr Clin Pract1992;7: 179-186. 24. Wan J, Teo T, Babayan V, Blackburn GL: Invited comment: Lipids and the development of immune dysfunction and infection. JPEN J Parenter Enteral Nutr 1988;12:435-485. 25. Buse M,Reid S: Leucine: A possible regulator of protein turnover in muscle. J Clin Invest 1975;56:1250-1261. 26. Skeie B, Kvetan V, Gil K: Branch-chain amino acids: Their mechanism and clinical utility. Crit Care Med 1990;18:549-571. 27. Matarese L: Rationale and efficacy of specialized enteral and parenteral formulas. In Matarese LE, Gottschlich MM (eds): Contemporary Nutrition Support Practice. Philadelphia, WB Saunders, 2003, pp 267-268. 28. Borum PR, Bennett SG: Camitine as an essential nutrient. J Am Coli Nutr 1986;5:177-182. 29. Pons R, De Vivo DC: Primary and secondary carnitine deficiency syndromes. J Child Neurol 1995;10:2S8-2S24. 30. Shronts E: Essential nature of choline with implications for total parenteral nutrition. J Am Diet Assoc 1996;96:639--649. 31. Van Buren C, Kulkarni A Schandel V, Rudolph F: The influence of dietary nucleotides on cell-mediated immunity. Transplantation 1983;36:350-352. 32. Dhanraj P, Chacko A, Mammen M, Bharathi R: Hospital-made diet versus commercial supplement in postburn nutritional support. Bums 1997;23:512-514. 33. Alles MS, de Roos NM, Bakx JC, et al: Consumption of fructooligosaccharides does not favorably affect blood glucose and serum lipid concentrations in patients with type 2 diabetes. Am J Clin Nutr 1999;69:64-69. 34. Silk DBA: Formulation of enteral diets. Nutrition 1999;15:626-632. 35. American Diabetes Association: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2003;26:S51-S61. 36. American Diabetes Association: Translation of the diabetes nutrition recommendations for health care institutions. Diabetes Care 2OO3;26:S7Q-S72. 37. Mehrotra R, Nolph KD: Treatment of advanced renal failure: Lowprotein diets or timely initiation of dialysis? Kidney Int 2000; 58:1381-1388. 38. Marchesini G, Bianchi G, Rossi B, et al: Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis. J GastroenteroI2000;35:7-12. 39. Morgan SL, Vaughn W, Thompson P: The use of an enteral expert system in the prescription of enteral formulas in a university hospital. Nutrition 1997;13:196-201. 40. Heimburger D, Weinsier RL: Guidelines for evaluating and categorizing enteral feeding formulas according to therapeutic equivalence. JPEN J Parenter Enteral Nutr 1985;9:61-67. 41. Coffey L, Carey M: Evaluating an enteral nutrition formulary. J Am Diet Assoc 1989;89:64-68. 42. Feitelson M: Enteral nutrition: Beliefs and practices of physicians and dietitians in one hospital. J Am Diet Assoc 1985;85:711-713.
Immunonutrition Daren K. Heyland, MD, FRCPC, MSc Rupinder Dhaliwal, RD Ulrich Suchner, MD
CHAPTER OUTLINE Introduction Scientific Basis of Immunonutrition Immune System Special Role of the Gastrointestinal Tract, Regional IschemiajReperfusion Injury, and Reactive Oxygen Species What Are the Implications for Clinical Use of Immunonutrition? Arginine-Supplemented Diets Scientific Rationale Clinical Review Clinical Recommendations Glutamine-Supplemented Diets Scientific Rationale Clinical Review Clinical Recommendations Fish Oils Scientific Rationale Clinical Review Clinical Recommendations Antioxidant Strategies Scientific Rationale Clinical Review Clinical Recommendations Discussion
INTRODUCTION The relationship between nutrient deficiency and altered immune status has been recognized for years. Moreover, certain disease states can further exacerbate nutrient deficiencies, predisposing patients to impaired immune function and a higher risk of developing infectious complications, or organ dysfunction and death. Consequently, over the last few decades numerous experimental studies have explored the immune-modulating
224
properties of nutrients such as glutamine, arginine, 00-3 fatty acids, and others. Several nutrition formulas supplemented with one or more of these nutrients have been developed and are currently available. immunonutrition, immune-enhancing diets, and other terms have been used to describe these products. The purpose of this chapter is to briefly describe the underlying scientific rationale for these nutrients or products and to review the clinical evidence favoring their use in various populations. We use the term immunonutrition as a general term to describe all these enteral products and, where possible, will focus on specific nutrients and products. It is not our intent to do a thorough review of the basic science literature to understand the scientific rationale for these nutrients. Rather, our focus will be on a systematic review of the clinical literature to generate recommendations about which nutrients should be used in specific populations. As health care providers, our objective is to improve the health outcomes of our patients; thus, we should be primarily concerned with studies that evaluate the impact of immunonutrition on clinically important outcomes (outcomes that patients experience and are important to them). Often, surrogate or intermediate end points are used in clinical trials. Several therapeutic interventions have been shown to have a significant positive impact on the surrogate outcome whereas later trials demonstrated that these interventions actually increased mortality rates (e.g., providing growth hormone, 1 suppressing extraventricular premature beats," and maximizing oxygen delivery in critically ill patients.") The problem is that these surrogate end points do not always correlate with clinically important health outcomes.' One can make stronger inferences from studies evaluating clinically important outcomes than from studies evaluating surrogate end points that primarily serve to explain mechanistically what is happening and generate future treatment hypotheses. Although numerous nutrients or substrates have been studied for their effects on immune function or other laboratory parameters (surrogate end points) in humans, we will limit the scope of this review to those agents that have been studied extensively in
SECTION IV • Principles of Enteral Nutrition
humans, namely, arginine, glutamine, fish oils, and antioxidants.
SCIENTIFIC BASIS OF IMMUNONUTRITION Immune System The purpose of this section is to give a cursory overview of the immune system that will enable the reader to understand the scientific rationale for immune-modulating nutrients. In a very simplistic model, the host response to invading microorganisms can be divided into two arms: (1) cellular defense that includes both innate (nonspecific) immunity and adaptive (specific) immunity and (2) the systemic inflammatory response (Fig. 19-1). The cellular defense function includes all functions of polymorphonuclear granulocytes, macrophages, and lymphocytes as well as their proliferation behavior (see Fig. 19-1). In contrast, the systemic inflammatory response works mainly at the tissue level (see Fig. 19-1). The systemic inflammatory reaction is characterized by effects of mediators, free radicals, and activated immune cells on metabolism, the endothelium, platelets, and smooth muscles of the vascular and bronchial systems. The severity of the inflammatory deterioration varies in accordance with the magnitude of the infectious, traumatic, or ischemic insult ("hit").
225
When immune cells encounter microbial by-products after invasion or reactive oxygen species (ROS) after ischemia/reperfusion (UR) injury, these cells become activated. Immune activation is followed by the release of numerous proinflammatory cytokines, such as tissue necrosis factor-a, interleukin (IL)-l~, IL-6, and IL-8, and other mediators including thromboxanes, leukotrienes, platelet-activating factor, prostaglandins, nitric oxide (NO), and complement are released and augment the cellular immune response. In general, there are two cytokine patterns. The first pattern (called the T helper 1 [TH1] cytokine response) governs activation of the cellular branch of the immune response. Cytokines involved in TH1 responses include IL-1, IL-2, and "tinterferon. TH1 responses are associated with increased inflammation and are essential for a successful defense against infections. Uncontrolled TH1 responses, however, can result in self-injury. The second pattern of responses (called the T helper 2 [TH2] cytokine responses) is a regulatory mechanism to prevent excessive inflammation and activates the humoral branch of the immune response. Cytokines involved in TH2 responses include IL-4, IL-lO, IL-13, and transforming growth factor ~. TH2 responses are essential to prevent self-injury caused by inflammation. However, excessive regulation of inflammatory responses by TH2 cytokines can lead to increased immune suppression. This may cause anergy to skin test antigens, impaired antibody production, and diminished phagocytosis, increasing
FIGURE 19-1. The relationship between systemic and cellular immune responses. IL, interleukin; I/R, ischemia/reperfusion; LTB, leukotriene B; MODS, multiple organ dysfunction syndrome; OFR, oxygen free radical; PGE, prostaglanin E; TNF, tumor necrosis factor.
226
19 • Immunonutrition
FIGURE 19-2. The relationship of cellular immune response and systemic inflammatory response to multiple insults.
patients' risk for additional infectious morbidity and mortality! Thus, suppressed immune function of the cellular defense system may lead to a new episode of infection and subsequently may trigger a new peak of the manifestation of the systemic inflammatory response (Fig. 19-2). Indeed, a similar chain of events could be elicited by a renewed episode of ischemia and reperfusion. Over time, patients may move repeatedly between cellular defense activating or suppressing states. Usually, the overshooting release of proinflammatory cytokines is short lived, whereas the suppression of the cellular defense function, mediated by anti-inflammatory cytokines and other mediators, persists much longer. The more insults that are encountered, the more pronounced the suppression will be (see Fig. 19-2). Although it can wax and wane, depending on the severity of the mode of stress (shock, injury, or infection) and whether additional insults occur, the inflammatory response does not usually reach baseline until the critical illness is resolved (see Fig. 19-2). This characteristic might be due to continuously enhanced levels of proinflammatory triggers such as nitric oxide, peroxynitrite, and other free radicals as well as eicosanoids and other lipid mediators. Therefore, the potential exists for a patient to exhibit manifestations of systemic inflammation but also have depressed or hyporesponsive cellular immune function at the same time, a phenomenon known as immunedys-
regulation.
Special Role of the Gastrointestinal Tract, Regional Ischemia/ Reperfusion Injury, and Reactive Oxygen Species Impairment of the gastrointestinal tract plays a central role in the pathogenesis of infection and sepsis, and even in the failure of other distant organs. As summarized by Deitch," the gut is one of the first organs exposed to shock and the last to be resuscitated if circulatory failure occurs. In past years, the focus of gut dysfunction
centered around the concept of bacterial translocation, which has not been well documented. Recent studies suggest that I/R of the gut may play an important role in the initiation and perpetuation of organ dysfunction. Numerous observations in hemorrhagic shock, trauma, and burns suggest that regional I/R injury to the gastrointestinal tract has to be considered a predominant region of ROS formation, mediator generation, and leukocyte priming," Moreover, recent animal studies suggested that these gut-derived factors may reach the systemic circulation via the lymphatic duct rather than the portal/hepatic system and thereby cause distant organ injury." Therefore, not only is early enteral immunonutrition focused on prevention of bacterial translocation and subsequent infection, but also, early nutritional support via the enteral route might be designed for prevention of or protection from gut-derived mediators and primed leukocytes that are exiting intestinal areas of I/R injury. These factors contribute not only to distant organ failure but also to infection because they contribute to the suppression of the cellular defense function. Metabolic resuscitation of the gastrointestinal tract by providing adequate nutrition in general and defined immunomodulating substrates specifically to maintain gut barrier integrity and function and to reduce regional oxidative stress will have to be considered as a key therapeutic strategy. Given the whole range of factors that affect the stressinduced immune response, ROS are assumed to playa key role in the underlying pathophysiologic process. When oxygen availability is limited in the tissue of vital organs by hypoperfusion, the cells shift from aerobic to anaerobic metabolism, thereby lowering the cellular energy charge. As a result, increased adenosine triphosphate (ATP) hydrolysis, a subsequent increase in adenosine monophosphate (AMP) levels, and finally an accumulation of purine metabolites are found in ischemic tissues. At the same time xanthine dehydrogenase is converted to xanthine oxidase, either by reversible oxidation or irreversible proteolytic degradation. During reperfusion, as oxygen is reintroduced, rapid oxidation of purines producing urate and superoxide radicals can develop. This superoxide can then secondarily generate the highly toxic hydroxyl radical, again facilitated via an iron-catalyzed reaction. Reperfusion of ischemic tissues can further generate ROS mainly by the activity of the cellular xanthine oxidase. Furthermore, during activation of the immune response, neutrophils, macrophages, and other competent immune cells may activate a plasma membraneassociated reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system capable of oxidizing NADPH to NAD+, leading to further generation of superoxide radicals. Spontaneous dismutation of the superoxide radical yields hydrogen peroxide and molecular oxygen at physiologic pH. ROS not only lead to direct damage of cellular components but also trigger the release of cytokines that further activate the inflammatory cascades," Free radicals activate resident macrophages or Kupffer cells, which release inflammatory cytokines (tumor necrosis factor-a., IL-1, and IL-6).8 These proinflammatory mediators, in turn, elicit activation and influx of inflammatory cells
SECTION IV • Principles of Enteral Nutrition
227
+----SIRS Endotoxin, bacteria
Ischemia! reperfusion
FIGURE 19-3. The vicious cycle of oxygen free radical production in critically ill patients.
(monocytes and leukocytes) into tissues and organs and may directly cause mitochondrial dysfunction, leading to further ischemia and tissue injury. Furthermore, the activated Kupffer cells also produce large amounts of oxygen free radicals whereby a vicious cycle of inflammation, cellular activation, and ROSgeneration is created (Fig. 19-3).
What Are the Implications for Clinical Use of Immunonutrition? Within a given patient over time or across different patient populations, the severity of "gut failure," the amount of bacterial translocation, the degree of cellular immune dysfunction, the balance of inflammation/antiinflammation, and the regional and systemic generation of ROS will vary. Despite the cause of the initial perturbation, the mechanism of tissue injury is most likely related to the degree of mediator release, ROS formation, and leukocyte activation. Thus, the treatment effect of various substrates or nutrients will vary, depending on the underlying pathophysiologic condition of the host and whether the substrate influences cellular immune function and/or the synthesis of inflammatory mediators and/or the generation of ROS. A minimum level of key nutrients (glutamine, arginine, and 00-3 fatty acids) is required for immunocompetence. However, particularly for arginine via excessive NO production? and 00-3 fatty acids via eicosanoid synthesis.!" excessive amounts of these nutrients may have immunodepressant effects. Given this heterogeneous and variable treatment response, one cannot look at the clinical trials of immunonutrition in surgical patients (or in patients with acquired immunodeficiency syndrome or obese patients)
and generalize the results to other populations, such as critically ill patients. Generally speaking, patients undergoing elective surgery experience minimal activation of cytokines and some degree of suppression of the cellular defense function after the stress of surgery putting them at higher risk for acquired infectious morbidity and mortality. It follows that nutrients that stimulate the cellular defense system may reduce infectious complications in these patients. In contrast, the associated changes to the systemic inflammatory response accompanying critical illness are far more intense, complex, variable, and less well defined but best characterized by an increased TH1 helper response, an overamplified inflammatory reaction, probably due to excess NO and ROS, and excessive availability of lipid mediators. Thus, nutrients that further stimulate the systemic inflammatory response may be deleterious in critically ill patients. In fact, novel therapies that have been shown to be effective in the early phase of critical illness decrease the inflammatory response associated with critical illness, not stimulate it.II What is emerging in the critical care literature is the notion of hyperinflammation and cellular immune dysfunction coexisting in the same patient or patient population at the same time. Hence, for critically ill patients, nutrients that augment cellular defense (specific and nonspecific immune function) and ameliorate ROSwithout a collateral increase in the inflammatory response are most likely to be beneficial. As we will discuss later in this chapter, the treatment effect of various nutrients or diets will vary depending on the underlying pathophysiologic condition (degree of cytokine elaboration, cellular responsiveness, and disruption of gastrointestinal structure and function) of the patient population under study. Given that chapters
228
19 • Immunonutrition
on nutrition support in a variety of disease states are contained elsewhere in this book, we will focus our remarks on the critically ill and elective surgery patient populations, and when sufficient data exist and allow greater specificity, we will comment on subgroups of critically ill patients.
ARGININE-SUPPLEMENTED DIETS
Scientific Rationale Arginine plays fundamental roles in protein metabolism, cellular energetics, and polyamine synthesis and is a major substrate for NO production." NO is produced by a family of enzymes called nitric oxide synthases (NOS), which exist in constitutive and inducible isoforms." Under normal conditions and in some disease states, small quantities of NO that have a beneficial effect on tissue oxygenation and immune function are synthesized by the constitutive forms." Presumably mediated by constitutive NOS, supplemental arginine under these conditions is associated with increased lymphocyte and monocyte proliferation, enhanced T-helper cell formation, activation of macrophage cytotoxicity, reinforcement of the activity of the natural killer cells, and increased phagocytosis." These salutary effects of arginine on cellular defense function led to its inclusion in current concepts of immune-enhancing formulas designed to reduce the incidence of infectious morbidity and mortality in immune-compromised patients. However, uncontrolled production of NO generated from inducible NOS, which is stimulated by endotoxin and/or cytokines, can be detrimental. In sepsis, NO production is variable. Excessive amounts of NO production can lead to excessive inflammation, impaired cellular respiration, nonspecific cytotoxicity, coagulation abnormalities, and worsening hemodynamic status." Irrespective of route of administration, under conditions of endotoxemia and cytokine activation, additional L-arginine is capable of promoting an increase in NO production," which may have an adverse effect in critically ill patients,"
Clinical Review There are several commercially available enteral feeding products that contain varying amounts of arginine in combination with other immunomodulating nutrients (fable 19-1). Arginine, either alone or in combination with other nutrients, has been studied in several randomized trials in elective surgery patients and in critically ill patients. Because arginine is the common ingredient in these various formulas, we elected to statistically aggregate all arginine-eontaining immune-enhancing diets. Our original meta-analysis suggested that the treatment effect of these products is significantly different in critically ill patients compared with elective surgery patients and thus these populations should not be combined in a meta-analysis." Therefore, we have updated our metaanalysis and focus on just those studies of elective
surgery patients. 17-28 When we combined across all these studies of elective surgery patients, we observed no overall effect on mortality (relative risk [RR] 1.05, 95% confidence interval [CI] 0.43, 2.61, P = .9), a significant reduction in infectious complications (RR 0.54, 95% CI 0.42, 0.68, P < .00001) and a significant decrease in length of hospital stay (weighted mean difference in days -3.44,95% CI -4.57, -2.30, P< .00001).29 Thus, in elective surgery patients, who, in general, experience moderate activation of the systemic inflammatory response and a larger degree of suppression of the cellular defense function, providing arginine-containing diets that stimulate the cellular defense system is associated with a significant reduction in infectious complications. There have been no randomized studies of pure arginine supplementation that evaluated clinically important outcomes in critically ill patients. As with the previous case, in all studies in critically ill patients arginine was combined with other immune-modulating nutrients. With recent publication of additional trials of arginine supplementation in the critical care setting,30,31 we have subsequently updated our meta-analysis of arginine-containing diets in critically ill patients." In the revised meta-analysis, 15 studies were included.Pr'" When the results of these 15 trials were aggregated, there was no effect on mortality (RR 1.05, 95% CI 0.82, 1.35, P = .7), no overall effect on infectious complications (RR 0.94,95% CI 0.76,1.16, P= .6), and a trend toward a reduction in length of hospital stay (weighted mean difference in days -3.5,95% CI -8.8, 1.9, P= .20) (Figs. 19-4 and 19-5). The presence of significant statistical heterogeneity across studies weakens the estimate of effect on length of stay. Despite no apparent overall effect of these diets, it is plausible that arginine-containing products may have benefit (or do harm) in specific subgroups of critically ill patients. Because many of the randomized trials of arginine-containing products were in trauma patients, we performed a subgroup analysis of the six studies pertaining to this population 34.36.39-41,43 compared with the nine studies on nontrauma patients. For mortality and infectious complications, there was no difference in rates between studies of trauma (RR 0.93, 95% CI 0.46, 1.89, P=.8 and RR 0.79,95% CI 0.41, 1.50, P= .5, respectively) and nontrauma patients (RR 1.09,95% CI 0.80, 1.49, P= .6 and RR 0.97, 95% CI 0.78, 1.19, P= .8, respectively). Concerns have been expressed that, based on the scientific rationale presented above, arginine-containing products may worsen outcomes in critically ill with patients with sepsis." In a large muIticentered, doubleblind, randomized trial, Bower and colleagues" compared Impact and Osmolite HN in critically ill patients.P Of the 326 patients who were included in the randomization, 47 (14%) were dropped from the primary analysis. When only the patients who received feedings were included, more patients who received the experimental formula died (24 of 153, [15.7%]) than patients who received control formula (12 of 143, [8.4%]), although the investigators did not report the P value is the actual publication (X2 P =.055). In patients stratified as having sepsis at baseline, hospital stay was reduced by 10 days.
lena,.'
Nutrient Breakdown of Arginine-Containing Enteral Products
IntensiCaJ (Mead Johnson)
Impact Recover (Novartis)
Soy protein hydrolysate, hydrolyzed sodium caseinate, L-arginine
Partially hydrolyzed casein, L-arginine
Why protein isolate. L-arginine, L-glutamine
Structured lipid (sardine oil and MCT) canola oil, soy oil Maltodextrin, sucrose, fructooligosaccharides 20,S (51.3) 54.5 (138.5) 25 (28.4) 1 5.5 0
Canola oil, corn oil, oleic sunflower oil, MCToil, menhaden oil Maltodextrin, modified cornstarch
Canola oil, MCT, other
Crucial (Nestle)
Immun-Aid (B Braun)
Impact (Novartis)
Optimental (Ross)
Protein source
Hydrolyzed casein, L-arginine
Caseinates, L-arginine
Fat source
MCT, marine oil, soy oil
Lactalbumin, amino acids (L-arginine, L-glutamine, L- valine, t-leucine, L-isoleucine) MCT, canola oil
Palm kernel oil (MCT), fish oil, sunflower oil
Carbohydrate source
Maltodextrin, cornstarch
Maltodextrin, cornstarch
Hydrolyzed cornstarch
% Protein (giL) % CHO (gIL) % Fat (giL) cal/rnl, Free arginine (g/L) Dietary nucleotides (gIL) n-3 fatty acids (g/L) n-6 fatty acids (g/L) MCT to LCT ratio
25 (94) 36 (135) 39 (68) 1.5 15 0
32 (80) 48 (120) 20 (22) 1 14 1
22 (56) 53 (130) 25 (28) 1 12.5 1.2
25 (81) 46 (150) 29 (42) 1.3 6.5 (8.6 giL)
o
Sugar, hydrolyzed cornstarch, Benefiber 29 (72) 46 (109) 25 (28) 1
17 1.6
V>
m
("l
3.6 7.7 50:50
1.1 2.4 50:50
1.7 2.5 27:63
4.83 4.16 28:62
2.1 6.5 25:75
CHO, carbohydrates; LCT, long-chain triglycerides; MCT, medium-chain triglycerides; n-3 fatty acids, 0>-3 fatty acids, n-6 fatty acids, 00-6 fatty acids.
1.8 4.9 15:85
-l
5 z <:
•
"C
:::!. :::J
c.
'tJ
;;;III o ...... m
:::J .... III
~
Z
c::
~
;::;:
o' :::J
""""
c.c
230
19 • Immunonutrition
Comparison: 01 Arginine containing diets vs. standard (critically III patients) Outcome: 01 Mortality Arginine containing
Standard
nJN
nJN
95/197
85/193
24/153
12/143
0/19
0/18
Capparos Cerra
27/130 1/11
30/105 1/9
Conejero Dent Engel
14/43
9/33
-
~
20/87 7/18
8/83 5/18
9.3 8.2
- I--
5.8
1.40[0.54, 3.60]
1997
Galban
17/89
28/87
13.8
0.59[0.35, 1.00]
Gottschlich Kudsk Mendez
2/17
1/14
1.1
1.65[0.17,16.33]
2000 1990
1/16 1/22
1.06[0.07, 15.60]
1996
0.95[0.06, 14.30]
1997
1/51
.
0.8 0.8
Morre
1/17 1/21 2/47
0.46[0.04, 4.92]
1994
Rodrigo Weimann
2/16 2/16
1/14 4/13
-
1.1 1.1 2.5
1.75[0.18,17.30] 0.41[0.09, 1.88]
1998
100.0
1.05[0.82,1.35]
Study Atkinson Bower x Brown
Weight
RR (95%CI Random)
. ......
Ofo
f--
-
Total (95%CI) 214/885 188/815 ~~ Test for heterogeneity chi-square=17.47 df=13 p=0.18 Test for overall effect z=0.42 p=0.7 I
I
I
I
.01
.1
10
100
Favours arginine
RR (95%CI Random)
Year
28.0 10.3
1.09[0.88, 1.36] 1.87[0.97,3.60]
1998 1995
0.0 16.3
Not estimable 0.73[0.46, 1.14]
1994 2001
0.9
0.82[0.06, 11.33] 1.19[0.59, 2.41] 2.39[1.11, 5.11]
1990 2002 2003
1997
Favours standard
Legend n: Number of patients that died N: Total number of patients in group RR: Relative risk 95% CI: 95% confidence intervals FIGURE 19-4. Effects of diets supplemented with arginine and other nutrients on mortality. n, number of patients who died; N, number of patients in group; RR, relative risk; 9596 CI, 9596 confidence intervals.
However, the mortality rate is the group with sepsis who received the experimental formula was three times that of patients with sepsis who received control formula (11 of 44 [25%] vs. 4/45 [8.9%], P = .051). It may be that the excess mortality associated with immunonutrition is only observed in patients with sepsis. Recent trials added further support to this important interaction between infection, arginine-containing diets, and worse clinical outcomes.tv" In one study," 171 critically ill patients were randomly assigned to receive either an experimental diet containing supplemental arginine or an isonitrogenous control feed. There were significantly more deaths in the group that received the experimental formula (20 of 87 [23.0%]) than in the control group (8 of 83 [9.6%], P = .03). Despite similar baseline demographics, including acute physiological
and chronic health evaluation II (APACHE II) scores, there were more patients with pneumonia at baseline in the group that received the experimental formula than in the control group. In this subgroup (patients with pneumonia at baseline who received experimental diet) more deaths occurred in the experimental formula group (10 of 26 [38.5%]) than in the control formula group (0 of 9 [0%]). Bertolini and colleagues" published an interim analysis of a randomized multicenter trial comparing mortality in patients with severe sepsis who were given either an enteral immune-enhancing formula (extra L-arginine, 00-3 fatty acids, vitamin E, Ikarotene, zinc, and selenium) or parenteral nutrition. This study is, in fact, a subgroup analysis of a larger study that included patients with both severe and nonsevere sepsis. For this larger
SECTION IV • Principles of Enteral Nutrition
231
Comparison: 01 Arginine containing diets vs. standard (critically ill patients) Outcome: 02 Infectious complications
Study Bower Brown Capparos Conejero Dent Engel Galban Kudsk Mendez Moore Rodrigo
Arginine containing
Standard
nIN
nlN
86/153 3/19 64/130 11/43 57/87 6/18 39/89 5/16 19/22 9/51 5/16
90/143 10118 37/105 17/33 52/83 5/18 44/87 11/17 12/21 10/47 3/14
RR (95%CI Random)
Weight %
-I 01(
........
---- '"' -+
~
304/644 291/586 0 Total (95%CI) Test for heterogeneitychi-square=24.51 df=10 p=0.0063 Test for overall effect z=0.55 p=0.6
RR (95%CI Random)
Year
17.3 3.0 13.9 7.5 16.3 3.7 13.9 5.1 11.5 5.1 2.5
0.89[0.74, 1.08] 0.28[0.09, 0.87] 1.40[1.02, 1.91] 0.50[0.27,0.91] 1.05[0.83, 1.31] 1.20[0.45, 3.23] 0.87[0.63, 1.19] 0.48[0.22, 1.08] 1.51[1.01, 2.27] 0.83[0.37, 1.86] 1.46[0.42, 5.03]
1995 1994 2001 2002 2003 1997 2000 1996 1997 1994 1997
100.0
0.94[0.76, 1.16]
I
I
I
I
.1
.2
5
10
Favours arginine
Favours standard
Legend n: Number of patients with infectious complications N: Total number of patients in group RR: Relative risk 95% CI: 95% confidence intervals FIGURE 19-5. Effects of diets supplemented with arginine and other nutrients on infectious complications. n, number of patients with infectious complications; N, number of patients in group; RR, relative risk; 95% CI, 95%confidence intervals.
study, 289 eligible patients from 33 intensive care units (ICUs) were found over a 17-month period. Of this group, 237 were enrolled in the study and 39 patients were deemed to either have severe sepsis or be in septic shock according to established criteria. Eligible patients (older than 18years, with a high level of care and judged to need ventilation and nutrition for at least 4 days) were randomly assigned to receive either enteral nutrition with an immune-enhancing formula (n = 19) or parenteral nutrition (exclusively parenteral nutrition for at least 6 days before initiation of any enteral feeding, n = 17). The group receiving parenteral nutrition had more women, more patients with an unfavorable prognosis, more patients who were older than 60, and more patients with combined cardiovascular and respiratory failure. The ICU mortality was significantly different between the two groups, being 8 of 18 (44.4%) for the treatment group receiving enteral nutrition with the immune-enhancing
formula and 3 of 21 (14.3%) in the treatment group receiving parenteral nutrition (P = .039). Results for 28-day mortality were 8 of 18 (44.4%) for the enteral nutrition group and 5 of 21 (23.85%) for the parenteral nutrition group. These results were not significantly different (P= .179) with an absolute risk difference of 20.6 (95%CI9.4, 50.6) but did show a trend toward harm with the enteral nutrition group. Itshould be noted that the differences in the baseline characteristics of the two treatment groups (more patients with unfavorable prognosis. age older than 60, and combined cardiovascular and respiratory failure in the parenteral nutrition group) would create a bias in favor of increased mortality in the parenteral nutrition group, and yet the group that received total parenteral nutrition (fPN) had a lower mortality. How does one interpret these findings? Are the differences in mortality due to route of administration, differences in caloric intake, or composition of the enteral
232
19 • Immunonutrition
formulas? There is another body of literature suggesting that parenteral nutrition, especially when administered with lipids and at high doses, may be harmful to critically ill patients." Despite the small sample size and marginal statistical significance, the only logical conclusion is that patients with sepsis who received the argininecontaining diet experienced increased mortality! These results contrast with the multicenter study by Galban and colleagues." In this study, 181 lCU patients (APACHE 11 score ~1O) with laboratory or clinical signs of infection (not a strict definition of sepsis) were randomly assigned to receive either Impact or a standard enteral diet. The results suggested that Impact was associated with a significant decrease in ICU mortality (17 of 89 [19.1 %]) compared with that of the control group (28 of 87 [32.2%], P =.05). In the subgroup analysis, it was apparent that all of the treatment benefit was seen in the least sick patients (baseline APACHE 11 score <15) whereas there was no effect in patients with a greater severity of illness (baseline APACHE 11 score >15). The effect of arginine-containing products on critically ill patients with a high severity of illness remains unanswered. To the extent that endotoxin exposure and cytokine activation have led to elevated levels of inducible NOS, supplemental arginine may lead to excessive amounts of NO. This may explain why excess deaths are observed in patients with sepsis who receive arginine-eontaining formulas. Further research needs to be done to define the underlying mechanism by which these products may be harmful and in which (sub )populations.
Clinical Recommendations For elective surgery patients requiring enteral nutrition, we recommend arginine-containing specialized diets for as long as the patient receives enteral nutrition. For critically ill patients, we recommend that arginine-containing specialized diets not be used, particularly in critically ill patients with sepsis. If a critically ill patient receiving an arginine-containing diet develops sepsis, the argininecontaining diet should be discontinued.
GLUTAMINE·SUPPLEMENTED DIETS
Scientific Rationale The amino acid glutamine plays a central role in nitrogen transport within the body, is a fuel for rapidly dividing cells particularly lymphocytes, is an precursor to glutathione, and has many other important metabolic functions. Under normal physiologic conditions glutamine is synthesized in large amounts by the human body and therefore it is considered to be nonessential. It has been hypothesized that glutamine may become a conditionally essential amino acid in patients with catabolic disease.f Several studies have shown that glutamine levels drop after extreme physical exercise," after major surgery,50.51 and during critical illness.52,53 Lower levels of
glutamine have been associated with immune dysfunction 54 and increased mortality." In animal studies, glutamine deprivation is associated with loss of intestinal epithelial integrity'" whereas glutamine supplementation decreases gut mucosal atrophy during TPN nutrition 57-59 and preserves both intestinal and extraintestinal immunoglobulin A levels.50 However, with regard to bacterial translocation in animal models, studies of parenteral or enteral glutamine-supplemented formulas show mixed results. Some have shown decreased translocation61.62 whereas others have demonstrated no such effect.63.64 Still others have demonstrated that glutamine administration in animals can protect against septic shock after endotoxemia. This protection may be mediated via enhanced tissue heat shock protein expression's and/or attenuated proinflammatory cytokine release." Regardless of the mechanism, several animal studies have demonstrated improved survival associated with glutamine supplementation in models of sepsis. 67-7o
Clinical Review Human studies suggested that glutamine supplementation is safe (up to 0.5 g/kg/day)," maintains gastrointestinal structure" and is associated with decreased intestinal permeability compared with standard TPN.73,74 Although increased permeability correlates with the degree of tissue injury and the development of organ dysfunction in critically ill patlents.F" it may not correspond with an increase in bacterial translocation." In humans, glutamine-supplemented formulas have resulted in improved nitrogen balance/" and higher intramuscular glutamine levels." Finally, glutamine plays a crucial role in enhancing immune cell function'" with no elevation in proinflammatory cytokine productlon.s'P Nevertheless, the clinical significance of these findings in critically ill patients has not been clearly established. Studies in other, non-eritically ill populations provide additional evidence that glutamine supplementation is safe and may be beneficial. For example, in very lowbirth-weight infants, glutamine supplementation is associated with a decrease in infectious complications, enhanced tolerance to enteral nutrition, and a reduction in days receiving mechanical ventilation. 83--85 In patients receiving bone marrow transplants, glutamine supplementation is associated with a reduction in infectious complications, a shorter length of hospital stay, and decreased mortality.8&-88 Clinically important outcomes 89 were reported on in several randomized trials of surgical or critically ill adults. In our meta-analysis of glutamine supplementation, we demonstrated that parenteral glutamine supplementation in the elective surgery patient was associated with no effect on mortality (RR 0.99,95% Cl 0.27, 3.58), a reduction in infectious complications (RR 0.36, 95% CI 0.14, 0.92), and a significant reduction in hospital stay (difference between means -3.5,90% CI-5.3, -1.8). In the critically ill population, several other trials have been published or completed since our meta-analysis was published.P'" When the results of these trials were
SECTION IV • Principles of Enteral Nutrition
233
Comparison: 01 Glutamine vs Control Outcome: 01 Mortality
Study x Brantley Dechelotte Garrel Griffiths Hall Houdijk
Glutamine nlN
Control
0/31
0/41
2/58 2/21
2/56
18/42 27/179
RR (95%CI Random)
nIN
Weight
----
12/24 25/42
... -I'-
30/184
Jones Powell-Tuck
14/83
9/24 20/85
Wischmeyer
2/15
5/16
3/39
0.0 1.7
Not estimable 0.97[0.14,6.62]
3.3
0.19[0.05, 0.76] 0.72[0.47,1.11]
2000 2002 2003 1997 2003 1998
1.03[0.50, 2.08] 0.72[0.39, 1.32]
1999
16.4 2.8
0.43[0.10, 1.88]
100.0
0.78[0.61, 0.99]
3.0 12.3
Total (95%CI) 79/496 106/511 ~~ Test for heterogeneity chi-square=24.51 df=10 p=0.0063 Test for overall effect z=0.55 p=0.6
Year
0.93[0.57, 1.49] 1.27[0.30,5.31]
... . I
I
I
I
.01
.1
10
100
Favours glutamine
RR (95%CI Random)
33.5 27.1
I.
4/41 10/26
%
1999 2001
Favours control
Legend n: Number of patients that died N: Total number of patients in group RR: Relative risk 95% CI: 95% confidence intervals FIGURE 19-6. Effects of glutamine supplementation on mortality in critically ill patients. n, number of patients who died; N, number of patients in group; RR, relative risk; 95% Cl, 95% confidence intervals.
combined with previous trials of glutamine supplementation,93-98 we observed a significant reduction in mortality (RR, 0.78, 95% CI 0.61, 0.99, P= .04), a trend toward a reduction in infectious complications (RR, 0.89, 95% CI 0.73, 1.08, P = .2), and no overall effect on length of hospital stay weighted mean difference (in days -1.30, 95% CI-4.77, 2.17, P= .5) (Figs. 19-6, 19-7, and 19-8). Although there were no statistically significant subgroup effects, our subgroup analysis did reveal that for mortality the majority of the treatment effect observed was associated with parenteral glutamine in patients receiving TPN rather than enteral glutamine. The majority of glutamine provided enterally will be metabolized in the gut and liver and, therefore, may not have a systemic effect. The only study that demonstrated a mortality effect with enteral glutamine was a small study in burn patients.f For infectious complications, again the majority of the treatment effect was observed in studies of parenteral glutamine supplementation.v although in a study of trauma patients, enteral formulas supplemented with glutamine were associated with a trend toward a reduced rate of infection compared with control formulas (20 of 35 [57%] vs. 26 of 37 [70%], P= .24).95
Clinical Recommendations For surgical or critically ill patients requiring parenteral nutrition, we recommend parenteral glutamine supplementation as long as the patient receives parenteral nutrition. For patients with major burns or trauma, enteral diets supplemented with glutamine could be considered. Recommendations about glutamine supplementation (enteral or parenteral) in other critically ill patient populations are premature and warrant further study.
FISH OILS
Scientific Rationale For several decades, the immunomodulatory effects of lipids generally, and 00-3 polyunsaturated fatty acids specifically, have been recognized. In a variety of experimental studies, summarized by Grimm and associates." 00-3 fatty acids have been shown to influence a series of inflammatory processes ranging from signal transduction to protein expression. Dietary 00-3 fatty acids, once
234
19 • Immunonutrition
Comparison: 01 Glutamine vs Control Outcome: 02 Infectious Complications
%
RR (950f0CI Random)
Year
8.3
0.51[0.26, 1.00]
2002
32.0
1.08[0.78, 1.48]
1997
43/184
23.2
0.91[0.62, 1.33]
2003
26/37 9/14
26.7
0.81[0.57, 1.16]
1998
9.8
0.91[0.49, 1.68]
2001
100.0
0.89[0.73, 1.08]
Glutamine
Control
nIN
nIN
Dechelotte
10/58
Griffiths Hall
28/42
19/56 26/42
38/179 20/35 7/12
Study
Houdijk Wischmeyer
Weight
RR (950f0CI Random)
Total (95%CI) 103/326 123/333 Test for heterogeneity chi-square=4.45 df=4 p=0.35 Test for overall effect Z= -1.18 p=0.2
.1
.2
Favours glutamine
5
10
Favours control
Legend n: Number of patients with infectious complications N: Total number of patients in group RR: Relative risk 95% CI: 95% confidence intervals FIGURE 19-7. Effects of glutamine supplementation on infectious complications in critically ill patients. n, number of patients with infectious complications; N, number of patients in group; RR, relative risk; 9596 Cl, 9596 confidence intervals.
incorporated into membrane phospholipids, influence membrane structure and function and, thus, play a role in the regulation of cell surface expression, cellcell interactions, cytokine release, and energy supply from lipids. 00-3 and 00-6 fatty acids are competitively metabolized via the cyclooxgenase, Iipoxygenase, and cytochrome P-450 pathways to prostaglandins, thromboxanes, leukotrienes, Iipoxins, and epoxy compounds. Arachidonic acid eAA) is major by-product of or6 fatty acids and results in metabolites associated with a proinf1ammatory, procoagulation state. When fish oils, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are provided, they are preferentially incorporated into the cell membrane phospholipids at the expense of AA. Hence, 00-3 fatty acids result in a production of lipid metabolites or mediators that reduce platelet aggregation, blood clotting, smooth muscle contraction, and leukocyte chemotaxis and adherence and limit the production of proinflammatory cytokines, resulting overall in an anti-inflammatory effect. In summary, if hyperinflammation is to be regarded as "wasting" the antimicrobial capacity of the leu patient, or3 fatty acids protect the host-defense arsenal by ameliorating hyperinflammatory periods, preserving antimicrobial leukocyte capacity, and reducing secondary organ failure by inhibition of uncontrolled leukocyteendothelial interaction. As a result of such diverse effects, it is not surprising that the immunomodulatory role of 00-3 fatty acids has
been tested in a variety of disease states including acute inflammatory disorders (such as burns, postsurgical stress, trauma and acute lung injury) and chronic autoimmune diseases (such as rheumatoid arthritis and inflammatory bowel disease). Although the effects of fish oils on fatty acid metabolism and various immune parameters have been explored in numerous experimental studies, data on their effects on clinically important outcomes are sparse. What further complicates determination of the overall clinical effects of fish oils is the fact that they are often combined with other immuneenhancing nutrients such as arginine or nucleotides (see Table 19-1). What follows includes only those studies in which fish oils as the principal supplement in experimental formulas were evaluated.
Clinical Review Acute Lung Injury/Acute Respiratory Distress Syndrome Acute lung injury/acute respiratory distress syndrome is an acute inflammatory lung disease characterized by marked inflammation, increased capillary permeability and lung edema not associated with left-atrial hypertension, decreased lung compliance, and increased oxygen requirement. The pathophysiologic cause of this syndrome is thought to be the release of AA-related
SECTION IV • Principles of Enteral Nutrition
235
Comparison: 01 Glutamine vs Control Outcome: 03 Hospital Length of Stay
Study
Glutamine Control n Mean(sd) n Mean(sd)
Brantley Houdijk Powell-Tuck Wischmeyer
31 35 83 12
19.50(8.80) 32.70(17.10) 43.40(34.10) 40.00(10.00)
41 37 85 14
WMD (95%CI Random)
20.80(11.50) 33.00(23.80) 48.90(38.40) 40.00(9.00)
Total (95%CI) 161 177 Test for heterogeneitychi-square=0.72 df=3 p=0.87 Test for overall effect z=0.73 p=0.5 -100 -50 Favours glutamine
0
50
Weight
WMD (95%CI Random)
Year
54.7 13.2 10.0 22.2
-1.30[-5.99,3.39] -0.30[-9.83, 9.23] - 5.50[-16.48, 5.48] O.OO[ -7.36, 7.36]
2000 1998 1999 2001
100.0
-1.30[-4.77,2.17]
%
100
Favours control
Legend n: Number of patients in each group SD: Standard deviation WMD: Weighted mean difference RR: Relative risk 95% CI: 95% confidence intervals FIGURE 19-8. Effects of glutamine supplementation on length of hospital stay in critically ill patients. n, number of patients in each group; SO, standard deviation; WMO, weight mean difference; RR, relative risk; 95% CI, 95%confidence intervals.
metabolites from inflammatory cells. Preliminary work in animal models suggested that a diet enriched with fishand borage oils could suppress the degree of proinflammatory mediators and reduce the severity of lung injury.loo,wl Gadek and colleagues'< performed a multicenter, randomized, double-blind, clinical trial to evaluate whether a diet supplemented with EPA, DHA, borage oil (rich in ylinolenic acid), and antioxidants (Oxepa, Ross products, Columbus, OH) would have a favorable effect on markers of inflammation in lung and an improve clinical outcomes. In this study, 146 patients meeting standard definition of acute respiratory distress syndrome with a partial arterial oxygen pressure (Pa02)-to-fractional inspired oxygen (Fi0 2) ratio of less then 250 but more than 100 torr "and" evidence of active pulmonary inflammation as indicated by fluid from a bronchoaveolar lavage (BAL) that contained a neutrophil count greater than 10%, were randomly assigned to receive the experimental diet or a highfat, low-carbohydrate control diet. Study feedings were initiated within 24 hours of a patient's meeting the entrance criteria. All patients received mechanically ventilation using conventional modes; a standard strategy to give ventilation and wean patients from mechanical ventilation was not used. Of the 146 patients initially entered into the study, only 98 were deemed evaluable and were reported on in an efficacy analysis. Not enough information was provided on the baseline characteristics of the study patients to enable readers to judge whether both groups of patients were similar.
In the subset of evaluable patients, as expected, those who received the experimental diet had higher plasma phospholipid fatty acid levels of dihorno-j-linolenic acid and EPA and a higher EPA-to-AA ratio. Patients fed the experimental diet also had fewer total cells and fewer neutrophils recovered from repeated bronchoalveolar lavages performed on study days 4 and 7. In addition, oxygenation measures on days 4 and 7, as judged by Pa02-to-Fi02 ratios, were much improved in patients receiving the experimental diet compared with control patients. With regard to the clinically important outcomes, patients fed the experimental diet experienced a reduction in days receiving supplemental oxygen (13.6 vs. 17.1, P = .078), required significantly fewer days of ventilatory support (9.6 vs. 13.2, P = .027), spent, less time in the ICU (11.0 vs. 14.8, P = .016), and had fewer new organ failures (10% vs. 25%, P =4.018). There was also a trend toward a reduction in mortality associated with the experimental diet (16% vs. 25%, P= .17). This study confirms that short-term administration of dietary lipids in critically ill patients can modify fatty acid levels with a resultant favorable effect on neutrophil recruitment in the lung and subsequent clinical outcomes. Although this study has a modest degree of internal validity, the use of a high-fat control formula and the requirement for a bronchoalveolar lavage with a high degree of neutrophils limits the applicability of these findings to clinical practice. Furthermore, it is difficult to attribute the beneficial effects of the experimental diet to
236
19 • Immunonutrition
varying compositions of fatty acids when antioxidants were added as well.
Burns Nutrition support is recognized as a key component in the care of the patient with severe burns. Standard management includes provision of adequate nutrients enterally early in the resuscitation phase of illness (within 24 hours of injury). The composition of the enteral formula is controversial. Experimental studies in animal models suggest that the fat quality (ratio of n-3 to n-6) and quantity (high-fat vs. low-fat content) may influence subsequent outcomes. 103, 104 Garrel and colleagues 105 randomly assigned 43 patients with thermal injury of greater than 20% body surface area to receive enteral nutrition with varying fat concentrations: (1) 35% of energy as fat derived from soy bean oil (80%) and medium-ehain triglyceride oil (20%); (2) 15% of energy as fat derived from soy bean oil (80%) and medium-ehain triglyceride oil (20%); and (3) 15% of energy as fat derived from 00-3 oil (50%), soy bean oil (40%), and medium-ehain triglyceride oil (10%). There were no differences in baseline characteristics or protein and energy intake across the three groups. There was a significant reduction in the incidence of pneumonia in the groups receiving low fat intake (12.5% vs. 54%, P= .05). However, there was no difference in clinical outcomes (incidence of pneumonia, length of hospital stay, or deaths) across the groups that did and did not receive fish oils.
Postsurgical Stress Protein-ealorie malnutrition is often observed in patients with upper gastrointestinal tract malignancies. Body stores of fat and lean muscle mass can be further depleted by the metabolic stress caused by surgical insult. Postoperative nutritional support in high-risk patients helps to maintain or minimize the loss of lean body mass, thereby preserving organ function and enhancing immune function. The beneficial effects of fish oils on immune function, inflammation, and coagulation may improve the clinical outcomes of such patients. In a blinded study, Kenler and Colleagues'P' randomly assigned 50 patients undergoing major abdominal surgery for upper gastrointestinal tract malignancies to receive either a fish oil-structured lipid-based polymeric formula or a standard polymeric formula. Fifteen patients were excluded from the analysis because intake of more than 40 mUhr of study formula was not achieved. In the remaining patients, the experimental diet was not associated with any untoward effects and resulted in an increase in EPA incorporated in plasma and erthyrocyte phospholipids. Although not designed as an outcome study, patients were followed prospectively for the development of gastrointestinal and infectious complications. The number of patients with gastrointestinal complications was significantly higher in the group receiving control formula (84% vs. 53%. P = .05) but there was no difference in infectious complications (39% vs. 35%, not significant).
Clinical Recommendations Based on one level 1study, the use of Oxepa (enteral formula with fish oils/borage oil and antioxidants) should be considered in patients with acute respiratory distress syndrome. Insufficient evidence exists to support the routine use of nutritional products enhanced with fish oils in other ICU or elective surgery patients.
ANTIOXIDANT STRATEGIES
Scientific Rationale Appreciation of the role of ROS in clinical disease states has been increasing. Although there is a putative beneficial role of ROS in modulating cell signaling (redox signaling) and thus regulating proliferation, apoptosis, and cell protection, oxygen-derived radicals may cause cellular injury by numerous mechanisms including destruction of cell membranes through the peroxidation of fatty acids, disruption of organelle membranes such as those covering lysosomes and mitochondria, degradation of hyaluronic acid and collagen, and disruption of enzymes such as Na+/K+-adenosine triphosphatase or u-proteinese inhibitor. To protect tissues from oxygen free radical (OFR)induced injury, the body maintains a complex endogenous defense system that consists of a variety of extraand intracellular antioxidant defense mechanisms. The first line of intracellular defense is composed of a group of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase including their metal co factors selenium, copper, and zinc. When these enzymatic antioxidants are overwhelmed, OFRs are free to react with susceptible target molecules within the cell, i.e., unsaturated fatty acids of the cell membrane. Thus, there is a need for a second line of defense scavenging the OFRsby means of nonenzymatic antioxidants, which are either water-soluble, such as glutathione and vitamin C, or lipid-soluble, such as vitamin E and lX:arotene. 107 Although organs are protected against oxidative challenges by means of natural defense systems in daily life,lo8 in critical illness, these mechanisms are frequently overwhelmed owing to the local imbalance between OFR production and neutralization. Thus, oxidative stress arises when the balance between protective antioxidant mechanisms and the generation of ROS is disturbed. This imbalance may be caused by excess generation of ROS by means of I/R injury, inflammation, infection, and toxic agents (chemotherapy or drugs) or by low antioxidant capacity. Age, smoking, malnutrition, and chronic diseases, such as atherosclerosis, diabetes mellitus, or rheumathoid arthritis, are associated with an increased production of OFRs or decreased antioxidant capacity or both and have to be considered as premorbid risk factors facilitating oxidative stress in critically ill patients.l'" In addition, critically ill patients are likely to lose substantial amounts of antioxidant (vitamins and micronutrients). Losses are considerable after bums (via
SECTION IV • Principles of Enteral Nutrition
exudates), in patients with large blood loss (hemorrhagic shock), in patients who require renal replacement therapy, and in patients with high volumes of gastric aspirates or intestinal fistula losses."? Finally, nutrient supply is often delayed or interrupted in critically ill patients, contributing to further depletion of antioxidant capacity. Many studies have demonstrated low plasma and intracellular concentrations of the various antioxidants in critically ill patients. The antioxidant levels in critically ill patients decrease rapidly after the initial insult and remain below normal levels for several days or even weeks.III-114 The more severe the underlying illness, the greater the depletion of antioxidant capacity.l'v'!' Furthermore, the clinical consequence of these "low" endogenous stores of antioxidant is associated with increased morbidity and mortality. 112-114 In their entirety, these data naturally give rise to the hypothesis that supplemental antioxidant nutrients may improve clinical outcomes of critically ill patients.
Clinical Review There have been a few randomized, controlled trials assessing the effects of various antioxidants (vitamin AI Ikarotene, vitamin C/ascorbate, vitamin E/a-tocopherol, N-acetylcysteine, selenium, and minerals such as copper and zinc) on clinically important outcomes in critically ill patients. II5-125 In most of these trials the effects of selenium in combination with other antioxidants were studied.l'
Single Antioxidant Nutrients Selenium Alone Selenium is an important cofactor in glutathione enzymatic function and has favorable effects on cellular immune function. In critically ill patients, only a few randomized controlled trials looking at the effects of selenium supplementation alone have been conducted. 116,118-120 In a trial of 17 patients with acute necrotizing pancreatitis, parenteral supplementation of 500 ug of selenium was associated with a significant reduction in ICU mortality (0% vs. 89%).118 The poor methodologic quality of this trial (i.e., non intent to treat, lack of concealed randomization, and unblinded format), however, weakens any inference made from this study alone. In a prospective, randomized trial, Zimmerman and co-workers!" reported a reduction in mortality (15% vs. 40%) after intravenous administration of 1000 flg of sodium selenite for 28 days in patients with systemic inflammatory response syndrome compared with those receiving a placebo. However, no difference in mortality or pneumonia was seen in critically ill trauma/surgery patients given intravenous selenium supplementation (2.9 urnol/day) compared with those receiving a
237
placebo.!" In a trial of 42 patients with systemic inflammatory response syndrome, subjects who received a higher dose of parenteral supplementation of selenium (535 flg for 3 days, 285 flg for 3 days, 155 flg for 3 days, and 35 flg/day thereafter) versus a lower dose (35 flg/day) showed a trend toward reduced hospital mortality (33% vs. 52%, P =.13).120 When the results from the four trials in which supplementation of selenium alone was compared with standard were aggregated,116,118-120 selenium was associated with a trend toward a reduction in mortality (RR 0.52,95% CI 0.21,1.30, P= .16). Zinc Alone Zinc is an essential trace element necessary for normal protein metabolism, membrane integrity, and the function of more than 200 metalloenzymes including enzymes involved in oxidative capacity. In a randomized, prospective, double-blinded, controlled trial in patients with severe head injuries who were receiving mechanical ventilation, those receiving a higher amount of a zinc supplement (12 mg of elemental zinc via parenteral nutrition for 15 days then progressing to 3 months of oral zinc) had a trend toward a reduction in mortality (P = .09) compared with those receiving a placebo (2.5 mg of elemental zinc).123
Combined Antioxidant Nutrients In many randomized, controlled trials a combination of antioxidants has been administered via various routes, thereby making it impossible to attribute the outcomes to a specific nutrient. Among those in critically ill patients in some, selenium was combined with other antioxidants (intravenous selenium with copper and zinc.!" intravenous selenium with a-tocopherol and zinc,'!" and intravenous selenium with oral vitamins E and C and N-acetylcysteine) ,117 Others studied the effects of combined a-tocopherol via the nasogastric route and intravenous ascorbic acid in general surgery/trauma patients.I" N-acetylcysteine combined with ascorbic acid and vitamin E in patients with sepsis.!" the effects of intravenous ascorbic acid and a-tocopherol in blunt trauma patients.!" and a vitamin A and C enriched enteral formula in medical/surgical ICU patients.'!' In these studies, the routes of administration varied and the dosages were different, making comparisons between studies difficult and making it impossible to attribute the effects to one or more nutrients. When all 11 trials of single and combined antioxidants were aggregated, antioxidants overall were associated with a trend toward a reduction in mortality (RR 0.73, 95%CI0.47,1.12, P= .15) (Fig. 19-9) and no effect on infectious complications (RR 0.94,95% CI 0.63, 1.40, P= .8).126
Clinical Recommendations For critically ill patients, selenium supplementation in combination with other antioxidants (vitamin E/atocopherol, vitamin C, N-acetylcysteine, and zinc) may
238
19 • Immunonutrition
Comparison: 01 Antioxidants (combined) vs standard Outcome: 01 Mortality
Antioxidants
Standard
nIN
nIN
7/21 1/10 2/20 11/16 0/8 0/28 5/301
11/21 0/10 1/11 8/14 8/9 0/18 9/294
Preiser
0/9 8/20
0/9 6/17
Young Zimmerman
4/33 3/20
9/35 8/20
Study Angstwurm Berger 1998 Berger 2001 Galley Kuklinski x Maderazo Nathens x Porter
-I-
I-
-i'-
- .....
--
Total (95%CI) 41/486 60/458 Test for heterogeneity chi-square=11.52 df=8 p=0.17 Test for overall effect z=1.45 p=0.15
~~
I
I
I
I
.01
.1
10
100
Favours antioxidants
%
RR (95%CI Random)
18.8 1.9 3.3 24.1 2.4 0.0 11.5
0.64[0.31, 1.32] 3.00[0.14, 65.91] 1.10[0.11,10.81] 1.20[0.69, 2.11] 0.07[0.00, 0.98] Not estimable 0.54[0.18, 1.60]
0.0 16.1 11.6 10.2
Not estimable 1.13[0.49, 2.62]
1999 2000
0.47[0.16, 1.38] 0.38[0.12, 1.21]
1996 1997
100.0
0.73[0.47, 1.12]
Weight
RR (95%CI Random)
Year 1999 2001 1997 1991 1991 2002
Favours standard
Legend n: Number of patients that died N: Total number of patients in group RR: Relative risk 95% CI: 95% confidence intervals FIGURE 19-9. Effects of antioxidants on mortality in critically ill patients. n, number of patients who died; N, number of patients in group; RR, relative risk; 95% CI, 95%confidence intervals.
be beneficial but insufficient data exist currently to support clinical recommendations.
DISCUSSION We have reviewed the scientific rationale and clinical evidence that support the use of selected nutrients in various patient populations. What is clear is that the key nutrients discussed in this chapter do modulate the immune system of seriously ill patients and, therefore, have the potential to improve outcomes if we understand which nutrient at what dose should be given to which patient population for what duration. In developing these clinical recommendations, however, there are some inherent weaknesses in the current approach to evaluating immune-modulating nutrients that limit the inferences we can make from these data. First, particularly in the case of arginine, single substrates are combined together with many other nutrients
such that it is difficult to separate the individual effect of each nutrient or how these nutrients might interact in a product that contains other immune-modulating substrates. In the future we need to evaluate the effect of these nutrients in various disease states on clinically important end points before their inclusion in marketable feeding products. Second, given that the inflammatory status (degree of hyperinflammation vs. immunosuppression) of a given patient varies across time or varies across groups of patients, it is difficult to make recommendations about a fixed nutrition regimen based on an anti-inflammatory principle (or proinflammatory, as the case may be). Unfortunately, the "tools" we need to accurately assess and describe the status of the immune system do not exist or have not been properly evaluated. Hence, the blind administration of immunologically active substance to all sick patients, whose degree of immune dysregulation we cannot accurately characterize or monitor, seems conceptually flawed. Biomarkers, such
SECTION IV • Principles of Enteral Nutrition
239
_ _ Summary of Clinical Recommendations: Which Nutrients for Which Patients? Patient Population Critically III Nutrient
Elective Surgery
General
Sepsis
Trauma
Burns
Acute Lung Injury
Arginine Glutamine
Benefit Possible benefit
No benefit PN beneficial (? receiving EN)
Harm -*
No benefit EN possibly beneficial
No benefit EN possibly beneficial
No benefit
w-3 fatly acids Antioxidants
Possible benefit
*-, insufficient data. EN, enteral nutrition; PN, parenteral nutrition.
as C-reactive protein, procaicitonin, measures of inflammatory cytokines themselves, or ex vivo measurement of leukocyte function, that may enable us to better discriminate among patients who may benefit from immune enhancement from those who would not, require further investigation. In the mean time, substrates that increase systemic inflammation should be avoided in patients with clinical appearances of severe systemic inflammatory response syndrome and sepsis. Third, some of the existing "negative" results of trials of various immune-modulating nutrients may be due to inadequate dosing. By providing the nutrients as a component of enteral formulas, given that some patients have inadequate tolerance of enteral nutrition, underdosage of the key substrates has occurred in most studies. By providing these key substrates independent of nutrition formulas, adequate, variable, and titratable doses can be provided beginning early in the course of critical illness, either enterally or parenterally. These substrates can be provided as a supplement because they can be diluted in small volumes. For enteral provision, nutrition supplements designed as low-volume, lowenergy compounds are easily tolerated and will facilitate the provision of 100% of key nutrients even under conditions of imparied intestinal tolerance. To the extent that enteral or luminal provision of these substrates is important, the nutrients should be delivered directly into the small bowel rather than into the stomach. The objective of these so-called "pharmaconutrition regimens" is not to provide energy or protein to the patient, but rather to provide key substrates to support gastrointestinal tract structure and function and to improve immune function. Further, by the protection of the gut from the sequela of I/R injury the subsequent reduction of mediators and primed leukocytes exiting the gut into the systemic circulation may lead to the reduction in distant organ failure. Indeed, future clinical trials will have to evaluate these new nutritional concepts in critically ill patients. In summary, there is sufficient clinical evidence to support the use of arginine-containing diets in elective surgery patients and parenteral glutamine supplementation in seriously ill patients requiring parenteral nutrition. The use of enteral glutamine in burn and trauma patients and (0-3 fatty acid-enriched diets in patients with acute lung injury may be of benefit as well (Table 19-2). This is an exciting area of future research.
Because there appears to be a large potential mortality effect, evaluating the role of parenteral glutamine in patients receiving enteral feeding and the role of antioxidant strategies in critically ill patients remain important future research questions. REFERENCES 1. Takala J, Ruokonen E, Webster NR, et al: Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785-792. 2. Pratt CM, Moye LA: The cardiac arrhythmia suppression trial: Background, interim results and implications. Am J Cardiol 1990; 65:206-29B. 3. Heyland DK, Cook D, King D, et al: Maximizing oxygen delivery in critically ill patients: A methodologic appraisal of the evidence. Crit Care Med 1996;24:517-524. 4. Fleming TR, DeMets DL: Surrogate end points in clinical trials: Are we being misled? Ann Intern Med 1996;125:605-613. 5. Astiz ME, Rackow EC: Septic shock. Lancet 1998;351:1501-1505. 6. Deitch E: Role of the gut lymphatic system in multiple organ failure. Curr Opin Crit Care 2001;7:92-98. 7. Grimble RF: Nutritional antioxidants and the modulation of inflammation: Theory and practice. New Horiz 1994;2:175-185. 8. Vendemiale G, Grattagliano I, Altomare E: An update on the role of free radicals and antioxidant defense in human disease, Int J Clin Lab Res 1999;29:49-55. 9. Suchner U, Heyland DK, Peter K: Immune-modulating actions of arginine in the critically ill. Br J Nutr 2002;87(suppl I), SI21-S132. 10. Thies F, Nebe-von-Caron G, Powell JR, et al: Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y. Am J Clin Nutr 2001; 73:539-548. 11. Bernard GR, Vincent JL, Laterre P, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. 12. Evoy D, Lieberman MD, Fahey TH, Daly JM: Immunonutrition: The role of arginine. Nutrition 1998;14:611-617. 13. Salzman AL: Nitric oxide in the gut. New Horiz 1995;3:33-45. 14. Muscara MN, Wallace JL: Nitric oxide: Therapeutic potential of nitric oxide donors and inhibitors. Am J Physiol 1999;276: G1313-G1316. 15. Bruins MJ, Soeters PB, Lamers WH, et al: L-Arginine supplementation in hyperdynamic endotoxemic pigs: Effect on nitric oxide synthesis by different organs. Crit Care Med 2002;30:508-517. 16. Heyland DK, Novak F, Drover J, et al: Should immunonutrition become routine in critically ill patients: A systematic review of the evidence. JAMA 2001;286:944-953. 17. Tepaske R, te Velthuis H, Oudemans-van Straaten HM, et al: Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: A randomized placebo-eontrolled trial. Lancet 2001;358:696-701.
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18. Riso S, AluffiP, Brugnani M,et al: Postoperative enteral irnrnunonutrition in head and neck cancer patients. Clin Nutr, 2000;19: 407-412. 19. van Bokhorst-De Van Der Schueren MA, Quak JJ, von Blombergvan der Flier BM, et al: Effect of perioperative nutrition, with and without arginine supplementation, on nutritional status, immune function, postoperative morbidity, and survival in severely malnourished head and neck cancer patients. Am J Clin Nutr 2001;73: 323-332. 20. Daly JM, Lieberman MD, Goldfine J, et al: Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: Immunologic, metabolic, and clinical outcome. Surgery 1992;112:56-67. 21. Braga M,Vignali A, Gianotti L,et al: Immune and nutritional effects of early enteral nutrition after major abdominal operations. Eur J Surg 1996;162:105-112. 22. Gianotti L, Braga M, Vignali A, et al: Effect of route of delivery and formulation of postoperative nutritional support in patients undergoing major operations for malignant neoplasms. Arch Surg 1997; 132:1222-1229;discussion 1229-1230. 23. Schilling J, Vranjes N, Fierz W, et al: Clinical outcome and immunology of postoperative arginine, omega-S fatty acids, and nucleotide-enriched enteral feeding: A randomized prospective comparison with standard enteral and low caloriellow fat i.v, solutions. Nutrition 1996;12:423-429. 24. Senkal M, Mumme A, Eickhoff U, et al: Early postoperative enteral immunonutrition: Clinical outcome and cost-eomparison analysis in surgical patients. Crit Care Med. 1997;25:1489-1496. 25. Braga M, Gianotti L, Radaelli G, et al: Perioperative imrnunonutrition in patients undergoing cancer surgery: Results of a randomized double-blind phase 3 trial. Arch Surg 1999;134:428-433. 26. Senkal M, Zumtobel V, Bauer KH, et al: Outcome and costeffectiveness of perioperative enteral immunonutritional in patients undergoing elective upper gastrointestinal tract surgery: A prospective randomized study. Arch Surg 1999;134:1309-1316. 27. Snyderman CH, Kachman K, Molseed L, et al: Reduced postoperative infections with an immune-enhancing nutritional supplement. Laryngoscope. 1999;109:915-921. 28. Daly JM, Weintraub FN, Shou J, et al: Entemal nutrition during multimodality therapy in upper gastrointestinal cancer patients. Ann Surg 1995;221:327-338. 29. Drover JD, Dhaliwal R, Heyland D: Arginine containing diets in elective surgery patients: A meta-analysis. In press. 30. Caparros T, Lopez J, Grau T: Early enteral nutrition in critically ill patients with a high-protein diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet. The effect on nosocomial infections and outcome. JPEN J Parenter Enteral Nutr 2001;25:299-308. 31. Conejero R, Bonet A, Grau T, et al: Effect of a glutamine-enriched enteral diet on intestinal permeability and infectious morbidity at 28 days in critically ill patients with systemic inllammatory response syndrome: A randomized, single-blind, prospective, multicenter study. Nutrition 2002;18:716-721. 32. Atkinson S, Sieffert E, Bihari D:A prospective, randomized, doubleblind, controlled clinical trial of enteral immunonutrition in the critically ill. Guy's Hosp Intensive Care Group Crit Care Med, 1998; 26:1164-1172. 33. Bower RH, Cerra FB, Bershadsky B, et al: Early enteral administration of a formula (Impact) supplemented with a arginine, nucleotides, and fish oil in intensive care unit patients: Results of a multicenter, prospective, randomized, clinical trial. Crit Care Med 1995;23:436-494. 34. Brown RO, Hunt H, Mowatt-Larssen CA, et al: Comparison of specialized and standard enteral formulas in trauma patients. Pharmacotherapy 1994;14:314-320. 35. Cerra FB, Lehman S, Konstantinides N, et al: Effect of enteral nutrient on in vitro tests of immune function in ICUpatients: A preliminary report. Nutrition 1990;6:84-87. 36. Engel JM, Menges T, Neuhauser C, et al: Effects of various feeding regimens in multiple trauma patients on septic complications and immune parameters [in German]. Anasthesiol Intensivmed Notfallmed Schmerzther 1997;32:234-239. 37. Galban C, Montejo JC, Mesejo A, et al: An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med 2000;28:643-648.
38. Gottschlich MM, Jenkins M, Warden GD, et al: Differential effects of three enteral dietary regimens on selected outcome variables in bum patients. JPEN J Parenter Enteral Nutr 1990;14:225-236. 39. Kudsk KA, Minard G, Croce MA, et al: A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. Ann Surg 1996;224:531-540. 40. Mendez C, Jurkovich GJ, Garcia l, et al: Effects of an immuneenhancing diet in critically injured patients. J Trauma 1997;42: 933-940. 41. Moore FA, Moore EE, Kudsk KA, et al: Clinical benefits of an immune-enhancing diet for early poslinjury enteral feeding. J Trauma 1994;37:607-615. 42. Rodrigo Casanova MP, Garcia Pena JM: The effect of the composition of the enteral nutrition on infection in the critical patient. Nutr Hosp 1997;12:80-84. 43. Weimann A, Bastian L, Bischoff WE, et al: Inlluence of arginine, omega-3 fatty acids and nucleotide-supplemented enteral support on systemic inllammatory response syndrome and multiple organ failure in patients alter severe trauma. Nutrition 1998;14:11'>5-172. 44. Dent DL,Heyland DK,Levy H, et al: Immunonutrition may increase mortality in critically ill patients with pneumonia: Results of a randomized trial. Crit Care Med 2oo3;30:AI7. 45. Heyland DK, Novak F: Immunonutrition in the critically ill patient: More harm than good? JPEN J Parenter Enteral Nutr 2001;25: S51-S55. 46. Bertolini G, lapichino G, Radrizzani D, et a1: Early enteral immunonutrition in severely septic patients: Results of an interim analysis of a randomized multicentre clinical trial. Intensive Care Med 2003;29:834-840. 47. Heyland DK, MacDonald S, Keefe L, Drover JW: Total parenteral nutrition in the critically ill patient: A meta-analysis. JAMA 1998; 280:2013-2019. 48. Wilmore DW, Shabert JK: Role of glutamine in immunologic responses. Nutrition 1998;14:618-626. 49. Rohde T, Asp S, Maclean DA, Pedersen BK: Competitive sustained exercise in humans, lymphokine activated killer cell activity, and glutamine-An intervention study. Eur J Appl Physiol 1998;78: 448-453. 50. Blomqvist BI, Hammarqvist F, von der D, Wernerman J: Glutamine and alpha-ketoglutarate prevent the decrease in muscle free glutamine concentration and inlluence protein synthesis after total hip replacement. Metabolism 1995;44:1215-1222. 51. Parry-Billings M, Baigrie RJ, Lamont PM, et al: Effects of major and minor surgery on plasma glutamine and cytokine levels. Arch Surg 1992;127:1237-1240. 52. Parry-Billings M, Evans J, Calder PC, Newsholme EA: Does glutamine contribute to immunosuppression after major burns? Lancet 1990;336:523-525. 53. Planas M, Schwartz S, Arbos MA, Farriol M: Plasma glutamine levels in septic patients. JPEN J Parenter Enteral Nutr 1993;17:299-300. 54. Oehler R, Pusch E, Dungel P, et al: Glutamine depletion impairs cellular stress response in human leucocytes. Brit J Nutr 2002;87: S17-S21. 55. Roth E, Funovics J, Muhlbacher F, et al: Metabolic disorders in severe abdominal sepsis: Glutamine deficiency in skeletal muscle. Clin Nutr 1982;1:25-41. 56. Potsic B, Holliday N, Lewis P, et al: Glutamine supplemenation and deprivation: Effect on artificially reared rat small intestinal morphology. Pediatr Res 2002;52:430-436. 57. Ardawi MS: Effect of glutamine-supplemented total parenteral nutrition on the small bowel of septic rats. Clin Nutr 1992;11: 207-205. 58. Khan J, Iiboshi Y, Cui L, et al: Ananyl-glutamine-supplemented parenteral nutrition increases luminal mucus gel and decreases permeability in the rat small intestine. JPEN J Parenter Enteral Nutr 1999;23:24-31. 59. Platell C, McCauley R, McCulloch R, Hall J: The inlluence of parenteral glutamine and branched-ehain amino acids on total parenteral nutrition-induced atrophy of the gut. JPEN J Parenter Enteral Nutr 1993;17:348-354. 60. Kudsk KA, Wu Y, Fukatsu K, et al: Glutamine-enriched TPN maintains intestinal interleukin4 and mucosal immunoglobulin A levels. JPEN J Parenter enteral Nutr 2000;24:270-275. 61. Gianotti L, Alexander JW, Gennari R, et al: Oral glutamine decreases bacterial translocation and improves survival in
SECTION IV • Principles of Enteral Nutrition experimental gut-origin sepsis. JPEN J Parenter Enteral Nutr 1995; 19:69-74. 62. Zapata-Sirvent RL, Hansbrough JF, Ohara MM, et al: Bacterial translocation in burned mice after administration of various diets including fiber- and glutamine-enriched enteral formulas. Crit Care Med 1994;22:690-696. 63. Barber AE, Jones WG, Minei JP, et al: Harry M. Vars Award. Glutamine or fiber supplementation of a defined formula diet: Impact on bacterial translocation, tissue composition, and response to endotoxin. JPEN J Parenter Enteral Nutr 1990;14: 335-343. 64. Bark T, Svenberg T, Theodorsson E, et al: Glutamine supplementation does not prevent small bowel mucosal atrophy after total parenteral nutrition in the rat. Clin Nutr 1994;13:79-84. 65. Wischmeyer PE, Kahana MD, Wolfson R, et al: Glutamine induces heat shock protein and protects against endotoxin shock in the rat. J Ap-;' Physio. 2001;90:2403-2410. 66. Wischmeyer PE, Kahana MD, Wolfson R, et al: Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia. Shock 2001;16:398-402. 67. Ardawi MS: Effect of glutamine-enriched total parenteral nutrition on septic rats. Clin Sci (Lond.) 1991;81:215-222. 68. Inoue Y, Grant JP, Snyder PJ: Effect of glutamine-supplemented intravenous nutrition on survival after Escherichia coli-induced peritonitis. JPEN J Parenter Enteral Nutr 1993;17:41-46. 69. Suzuki I, Matsumoto Y, Adjel AA, et al: Effect of a glutaminesupplemented diet in response to methicillin-resistant Staphylococcus aureus infection in mice. J Nutr Sci Vitaminol (Tokyo) 1993; 39:405-410. 70. Naka S, Saita H, Hashiguchi Y, et al: Alanyl-glutamine-supplemen ted total parenteral nutrition improves survival and protein metabolism in rat protracted bacterial peritonitis model. JPEN J Parenter Enteral Nutr 1996;20:417-423. 71. Sacks G: Glutamine supplementation in catabolic patients. Ann Pharmacother 1999;33:348-354. 72. Tremel H, Kienle B, Weilemann LS, et al: Glutamine dipeptidesupplemented parenteral nutrition maintains intestinal function in the critically ill. Gastroenterology 1994;107:1595-1601. 73. Buchman AL, Moukarzel AA, Bhuta S, et al: Parenteral nutrition is associated with intestinal morphologic and functional changes in humans. JPEN J Parenter Enteral Nutr 1995;19:453-460. 74. Van der Hulst RR, Van Kreel BK, Von Meyenfeldt MF,et al: Glutamine and the preservation of gut integrity. Lancet 1993;334:1363. 75. Doig CJ, Sutherland LR, Sandhan JD, et al: Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients. Am J Resp Crit Care Med 1998;158:444-451. 76. Pape HC, Dwenger A, Regal G, et al: Increased gut permeability after multiple trauma. Br J Surg 1994;81:85Q-852. 77. Buchman AL: Glutamine: A conditionally required nutrient for the human intestine? Nutrition 1997;13:240-241. 78. Hammarqvist F, Wemerman J, Ali R, et al: Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Ann Surg 1989;209: 455-461. 79. 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. 80. Ogle CK, Ogle JD, Mao JX, et al: Effect of glutamine on phagocytosis and bacterial killing by normal and pediatric burn patient neutrophils. JPEN J Parenter Enteral Nutr 1994;18:128-133. 81. O'Riordian MG, De Beaux A, Fearon KC: Effect of glutamine on immune function in the surgical patient. Nutrition 1996;12: S82-S84. 82. Aosasa S, Mochizuki H, Yamamoto T, et al: A clinical study of the effectiveness of oral glutamine supplementation during total parenteral nutrition: Influence on mesenteric mononuclear cells. JPEN J Parenter Enteral Nutr 1999;23:541-S44. 83. Barbosa E, Moreira GH, Goes JE, Faintuch J: Pilot study with a glutamine supplemented enteral formula in critically ill infants. Rev Hosp Clin 1999:54:21-24. 84. Neu, J, Roig JC, Meetze WH, et al: Enteral glutamine supplementation for every low birth weight infants decreases morbidity. J Pediatr 1997;131:691-699.
241
85. Lacey JM, Crouch JB, Benfell K, et al: The effects of glutaminesupplemented parenteral nutrition in premature infants. JPEN J Parenter Enteral Nutr 1996;20:74-80. 86. Ziegler RT, Young LS, Benfell K, et al: Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation: A randomized double blind controlled study. Ann Intern Med 1992;116:821-882. 87. Anderson PM, Ramsay NK, Shu XO, et al: Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant 1998;22:339-344. 88. Schloerb PR, Amare M: Total parenteral nutrition with glutamine in bone marrow transplantation and other clinical applications. JPEN J Parenter Enteral Nutr 1993;17:407-413. 89. Novak F, Heyland OK, Avenell A, et al: Glutamine supplementation in serious illness: A systematic review of the evidence. Crit Care Med 2002;30:2022-2029. 90. Dechelotte P, Bleichner G, Hasselmann M,et al: Improved clinical outcome in ICU patients receiving alanyl-glutamine (Dipeptiven) supplemented total parenteral nutrition [abstract]. Clin Nutr 2002; 21:SI. 91. Hall JC, Dobb G, Hall J, et al: A prospective randomized trial of enteral glutamine in critical illness. Intensive Care Med 2003;29: 1710-1716. 92. Garrel 0, Nedelec B, et al: Decreased mortality and infectious morbidity in adult bum patients given enteral glutamine supplements: A prospective, controlled, randomized clinical trial. Crit Care Med 2003;31:2444-2449. 93. Brantley S, Pierce 1: Effects of enteral glutamine on trauma patients. Nutr Clin Pract 2OO0;15:S13. 94. Jones C, Palmer TE, Griffiths RD: Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition 1999;15:108-115. 95. Houdijk AP, Rijnsburger ER, Jansen J, et al: Randomized trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772-776. 96. Powell-Truck J, Jamieson CP, Bettany GE, et al: A double blind, randomized, controlled trial of glutamine supplementation in parenteral nutrition. Gut 1999;45:82-88. 97. Wischmeyer PE, Lynch J, Liedel J, et al: Glutamine administration reduces Gram-negative bacteremia in severemia in severely burned patients: A prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med. 2001;29: 2075-2080. 98. Griffiths RD, Jones C, Palmer TE: Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition, Nutrition 1997;13:295-302. 99. Grimm H, Mayer K, Mayser P, Eigenbrodt E: Regulatory potential of n-3 fatty acids in immunological and inflammatory processes. Br J Nutr 2002;87:S59-S67. 100. Mancuso P, Whelan J, DeMichele SJ, et al: Dietary fish oil and fish and borage oil suppress intrapulmonary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxic rats. Crit Care Med 1997;25:1198-1206. 101. Mancuso P, Whelan J, DeMichele SJ, et al: Effects of eicosapentaenoic and linolenic acid on lung permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats. Crit Care Med 1997:25:523-532. 102. Gadek JE, DeMichele 51, Karlstad MD,et al: Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999;27:1409-1420. 103. Mochizuki H, Torcki 0, Dominioni L. et al: Optimal lipid content for enteral diets following thermal injury. JPEN J Parenter Enteral Nutr 1984;8:638-646. 104. Trocki 0, Heyd IT, Waymack JP, et al: Effects of fish oils on postburn metabolism and immunity. JPEN J Parenter Enteral Nutr 1987;11:521-528. 105. Garrel 0, Razi M, Lariviere F, et al: Improved clinical status and length of care with low-fat nutrition support in bum patients. JPEN J Parenter Enteral Nutr 1995;19:482-491. 106. Kenler AS, Swails WS, Driscoll OF, et al: Early enteral feeding in postsurgical cancer patients: Fish oil structured lipid-based polymeric formula. Ann Surg 1996;223:316-333. 107. Tanswell AK, Freeman BA: Antioxidant therapy in critical care medicine. New Horiz 1995;3:330-341.
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108. Goode HF, Webster NR: Antioxidants in intensive care medicine. ClinIntensive Care 1993;4:265-269. 109. BorhaniM, Helton WS: Antioxidants in critical illness. In Pichard C,Kudsk KA (eds): Update in intensive care and emergency medicine.34: Fromnutritionsupport to pharmacologic nutritionin the ICU. NewYork, Springer-Verlag Heidelberg, 2000, pp. 80-89. 110. Shenkin A: Clinical nutrition and metabolism Group Symposium on "Nutrition in the Severely-injured Patient.Part2. Micronutrients in the severely-injured patient. Proc NutrSoc 2000;59:451-456. 111. Metnitz PGH, BartensC, Fischer M, et al: Antioxidantstatus inpatients with acute respiratory distress syndrome, Intensive Care Med 1999;25:180-185. 112. Goode HF, Cowley HC, Walker BE, et al: Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 1995;23:646-651. 113. Cowley HC, Bacon PJ,Goode HF, et al: Plasmaantioxidant potential in severe sepsis:A comparison of survivors and nonsurvivors. CritCare Med 1996;24:1179-1183. 114. Forceville X, Vitoux D,Gauzit R,et al:Selenium,systemicimmune response syndrome, sepsis, and outcome in criticallyill patients. CritCare Med 1998;26:1536--1544. 115. Berger MM, Spertini F, Shenkin A, et al: Trace element supplementation modulates pulmonary infection rates after major burns: A double-blind, placebo-controlled trial, Am J Clin Nutr 1998;68:365-371. 116. Berger MM, Reymond MJ, Shenkin A, et al: Influence of selenium supplements on the post-traumatic alterations of the thyroid axis: A placebo-controlledtrial.Intensive Care Med2001;27:91-100. 117. PorterJM, lvatury RR, Azimuddin K, Swami R: Antioxidant therapy in the prevention of organ dysfunction syndrome and infectious
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complications after trauma: Early results of a prospective randomized study. AmSurg 1999;65:478-483. Kuklinski B,Buchner M, Schweder R, Nagel R: AkutePancreatitiseine "FreeRadicalDisease: Letalitatssenkung durch Natriumselenit (Na2Se03)-Therapie. Z Gestame Inn Med 1991;46:S145-S149. Zimmermann T, Albrecht S, Kuhne H, et al: Selensubstitutionbei Sepsispatienten [in German]. Med Klin 1997;92(suppI1ll):3-4. Angstwurm MW, Schottdorl J, Schopohl J, Gaertner R: Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care Med 1999;27:1807-1813. Preiser JC, Van Gossum A, Berre J, et al: Enteral feeding with a solution enriched with antioxidant vitaminsA, C, E enhances the resistance to oxidativestress. CritCare Med 2000;28:3828-3832. Nathens AB, Neff MJ, Jurkovich OJ, et al: Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002;236:814-822. Young B,Ott L, Kasarskis E, et al: Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. Neurotrauma 1996;13:25-34. Galley HF, Howdle PD, Walker BE, Webster NR: The effects of intravenous antioxidants in patients with septic shock. Free Radic BioiMed 1997;23:768-774. Maderazo EG, Woronick CL, Hickingbotham N, et al: A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma. J Trauma 1991;31:1142-1150. Heyland DK, Dhaliwal R, Suchner U, Berger M: Antioxidant nutrients:systematic review of trace elements and vitaminsin the critically ill patient. Cril CareMed 2003;31:A83.
Administration of Enteral Nutrition: Initiation, Progression, and Transition Sheila Clohessy, RD, LD, CNSD Julie L. Roth, MD, CNS, PT
CHAPTER OUTLINE Introduction Initiation of Enteral Nutritional Support Methods of Delivery Monitoring Transitioning to an Oral Diet
INTRODUCTION Enteral nutrition is defined as nutrition provided through the gastrointestinal tract. Tube feeding is enteral nutrition provided through a tube, catheter, or stoma that delivers nutrients distal to the oral cavity.I Enteral nutrition has been practiced for more than 400 years but has become more tolerable for patients during the last 20 years. Enteral nutrition is preferred to parenteral nutrition when no contraindications exist. Enteral nutrition is more cost-effective, has decreased infectious complications, maintains gut integrity, and supports the immune function of the gut.2
INITIATION OF ENTERAL NUTRITIONAL SUPPORT Before the initiation of enteral feedings, several factors must be considered. These factors include the patient's medical and surgical history, results of physical examination and nutrition assessment, fluid needs, date of longterm feeding tube placement, and location of the tip of the tube (gastric, duodenal, or jejunal). Knowledge of the implications of gastrointestinal surgery on gastric and intestinal motility and absorption is essential, and these must be fully recognized. The physical examination should focus on assessment of aspiration risk and
gastrointestinal function, specifically gastric output, preexisting nausea and vomiting, usual bowel habits, stool and fistula output(s), and the presence of abdominal distention and bowel sounds. The absence or presence of anyone factor should not be considered a deterrent to enteral feeding. For example, jejunal feeding does not guarantee that aspiration will not occur, particularly if the pylorus has been resected. Gastric residual volumes in the range of 200 to 400 mL may be well tolerated in some patients, and the absence of bowel sounds cannot, in isolation, determine that the patient must continue to receive nothing by mouth. When the clinician determines that the patient is ready to be fed enterally, formula and fluid requirements are calculated, the method of delivery is chosen, and feedings are started. For feeding into the stomach, the administration of full-strength formula is preferred because dilution of formula does not ensure tolerance to feedings. In addition, with administration of diluted formula, reaching of nutritional goals is delayed. Most clear liquids offered to patients are hypertonic. Thus, it is generally accepted that feedings should be initiated at a rate of 20 to 50 mUhr and advanced by 20 to 30 mUhr every 4 to 6 hours, as tolerated by the patient, until the goal rate is reached. If the formula of choice is hypertonic, full-strength feeding into the stomach may be acceptable if the feeding is started slowly and advanced as tolerated. However, feeding into the small bowel may be best tolerated if a full-strength isotonic formula is used first, advanced to 75% to 100% of the goal rate, and then changed to the more hypertonic formula. It is possible to achieve the goal rate within 24 to 72 hours.'>" To ensure adequate nutrient delivery and timely advancement to the goal rate, it is advised that enteral protocols be developed. In critically ill patients, the use of infusion protocols has been shown to improve accurate tube feeding prescription, increase tube feeding volume 243
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administration, and supply a greater percentage of the tube feeding goa1. 18,19 These protocols should clearly define the tube feeding goal, indicate how to advance tube feedings, and provide standards for monitoring tolerance.
Methods of Delivery The choice of a method of delivery is based on the location of the feeding tube tip, the patient's tolerance to tube feedings and preexisting medical conditions, and caretaker and lifestyle needs. Information about various methods of delivery are presented in Table 20-1.
Continuous Enteral Feedings Continuous tube feedings are administered via an infusion pump, deliveringa constant volume per unit of time.20 This is the preferred method of delivery for patients fed through a jejunostomy and for those with a critical illness, poor glycemic control, intubation due to respiratory failure, and poor tolerance to intermittent feedings. Feedings are initiated at a rate of 20 to 50 mUhr, and the amount is increased every 4 to 6 hours until the goal rate is achieved.
_ _ Methods of Delivery
Continuous Tube Feedings: Tube feedings are administered via infusion pump delivering constant volume per unit time Preferred for the following patients with: Poor glycemic control Refeeding syndrome Jejunostomy Intubation due to respiratory failure Poor tolerance to intermittent gravity drip feedings
Intermittent Gravity Drip Tube Feedings: Administration of 240-720 mL of enteral formula over 2Q..60 minutes Number of feedings per day is dependent upon formula requirements Preferred for patients requiring long-term nutritional support Allow patients to be mobile, without confinement to an infusion pump Contraindicated with jejunal feeding tubes
Intermittent Gravity Drip Feedings Intermittent gravity drip tube feeding is the administration of 240 to 720 mL of enteral formula over 20 to 60 minutes every 4 to 6 hours. The number and volume of feedings over 24 hours depend upon the patient's nutritional requirements." Intermittent gravity drip feeding is preferred over bolus administration, because with this method tolerance is improved and gastrointestinal complications are minimized. Intermittent gravity drip feedings are preferred for patients requiring long-term nutritional support with gastric tube placement. Intermittent feedings allow patients to be mobile without the confinement that use of an infusion pump entails. This method of feeding is contraindicated in patients with small bowel feeding tubes, because the small intestine does not have the reservoir capacity of the stomach. In addition, the stomach regulates the passage of food into the duodenum and dilutes the substances. A large volume infused into the small intestine over 20 to 60 minutes may result in increased diffusion of free water from the intestinal wall into the lumen, causing dumping syndrome or osmotic diarrhea.' Intermittent feedings may be initiated at 50% of the goal volume and the amount can then be advanced to full nutritional support as tolerated. For example, if a patient requires eight cans (240 mUcan) of formula over 24 hours, one should initiate feedings with one can four times a day. If the patient tolerates this rate of administration, then the amount of feeding can be advanced to two cans four times a day.
Bolus Method Although not common in the acute care setting, the bolus method can provide an individual receiving enteral nutrition on an outpatient basis with the convenience of portability of supplies and easy feeding delivery while at work, at school, or on vacation. This method delivers 240 to 480 mL of formula over a 10- to 20-minute time period via a syringe. As with intermittent feedings, this method is reserved for gastric feedings. Nausea, vomiting, and abdominal distention are common complications of this method, and it should therefore be reserved for the tube-fed patient whose condition is stable.
Bolus Feeding: Administration of 240-480 mL of enteral formula over 10-20minutes Number of feedings per day is dependent upon formula requirements Preferred for patients requiring long-term nutritional support Allow patients to be mobile, without confinement to an infusion pump Contraindicated with jejunal feeding tubes Reserved for the patient on a stable tube feeding regimen
Cyclic Tube Feedings: Tube feedings are administered via an infusion pump over a specified period of time Preferred for patients requiring supplement tube feedings Recommended for patients with jejunal tube feedings, to allow time off of the infusion pump
Cyclic Feedings Cyclic feedings are administered via an infusion pump over a specified period of time. Cyclic tube feedings are preferred for patients with jejunal feeding tubes because they allow for time without use of the infusion pump and can be used for supplemental tube feedings in patients whose oral intake is inadequate. Continuous tube feeding over 24 hours may suppress the patient's appetite, resulting in suboptimal oral intake. To transition a patient's feeding from a continuous, 24-hour infusion to cyclic feedings, the rate of feeding should be increased in 30 to 50 mL increments as the time with the feeding pump decreases. Patients may cycle
SECTION IV • Principles of Enteral Nutrition
their tube feeding over 12 to 18 hours and may tolerate a rate of up to 150 mUhr.
Monitoring Regardless of the method of delivery, patients receiving enteral nutrition should be routinely monitored for tolerance. There are several parameters that should be monitored during initiation, advancement, and duration of therapy. These parameters include nausea, vomiting, gastric residual volumes, bowel pattern, frequency and number of bowel movements, findings on an abdominal examination, and biochemical markers. It was originally thought that patients receiving enteral nutrition should remain in a semirecumbent position at a 30 to 45 degree angle to minimize gastroesophageal reflux. One study, using radiologic tracer detection of gastroesophageal reflux, however, showed that the presence of a nasogastric tube was a risk factor for reflux and that semirecumbency did not prevent reflux but reduced it compared with that seen with supine positioning. A conservative approach would be to place the patient receiving tube feeding in a semirecumbent position if the patient tolerates having the head of the bed elevated."
Nausea, Vomiting, and Gastric Residual Volumes The etiology of nausea and vomiting with tube feeding administration may be multifactorial. Gastroparesis is common in critically ill patients and in those with head trauma. Delayed gastric emptying may result from narcotic administration (slowing gastrointestinal transit time), catecholamine secretion, hyperglycemia, the recumbent position, and sepsis.P In addition, constipation may also result in gastric retention. Decreasing the use of narcotics or initiating a bowel stimulant regimen to promote daily bowel movements may help improve gastric emptying. Gastric retention can be identified by monitoring gastric residual volumes, especially in sedated or nonresponsive patients. Residual volumes are often used as a marker for gastric tube feeding tolerance, but the residual threshold for poor gastric tube feeding tolerance is not well defined. One study conducted by Davies and colleagues" demonstrated good gastric tube feeding tolerance in critically ill patients with a gastric residual volume threshold of 250 mL. This study showed that 67% of patients tolerated gastric tube feedings versus 48% observed in other studies using 15Q-mL residual volumes as the threshold for poor gastric tube feeding tolerance. Unfortunately, high gastric residual volumes usually result in cessation of tube feeding administration for 2 to 4 hours, leading to inadequate nutrient delivery," Prokinetic agents, such as erythromycin and metoclopramide, may help improve gastric tube feeding tolerance by increasing gastricemptying. Erythromycinenhances motilin release, whereas metoclopramide serves as a dopamine D2 receptor antagonist, resulting in peristaltic contraction of the esophagus, antrum, duodenum, and jejunum." Cisapride is a prokinetic agent that was previously used
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for gastroparesis. However, this medication was recently removed from the market because of adverse side effects. Boivin and Levy" demonstrated that critically ill patients receiving 20 mg of erythromycin intravenously every 8 hours with gastric tube feedings received an equivalent amount of calories as those patients receiving postpyloric enteral feedings-" If a patient continues to have high gastric residual volumes despite the use of prokinetic agents, the clinician should evaluate the enteral formula administered. A change to a low-fat, fiber-free formula might be warranted, because formulas high in fat or fiber may delay gastric emptying. If high gastric residual volumes persist despite a change in formula, the clinician should obtain small bowel access for enteral nutrition." If emesis occurs with continuous tube feeding advancement, feeding should be resumed with the previously tolerated rate for 8 to 12 hours. Once the patient tolerates this lower rate, then the clinician can advance tube feedings by 20 mL every 4 hours up to the calculated goal infusion rate. If a patient vomits with intermittent gravity drip feedings, the clinician should lengthen the infusion rate to 1 hour per feeding. If emesis persists despite the longer infusion times, then the clinician should decrease the volume administered at each feeding and increase the frequency of feedings. If the patient continues to vomit with intermittent gravity feedings despite these changes, continuous tube feedings should be started. Nausea may be a common side effect of many medications, chemotherapy, and radiation therapy, and these patients may benefit from administration of antiernetics."
Diarrhea A review of the literature by Zimmaro and colleagues" demonstrated that there are 14 different definitions for diarrhea. The commonality between the definitions includes three important parameters: stool frequency, stool consistency, and stool quantity. However, there are no universal guidelines to describe this phenomenon. Zimmaro and colleagues" showed that diarrhea might be under-reported or over-reported, depending upon the guidelines used. One clinically useful guideline for defining diarrhea is to consider any abnormal stool volume or consistency that results in electrolyte, fluid, or acid-base abnormalities as diarrhea." Unfortunately, tube feedings are commonly blamed for causing diarrhea, and thus other factors resulting in high stool output might be overlooked. Infections (such as colitis caused by Clostridium difficile) and medications (such as sorbitol-eontaining elixirs, antibiotics, laxatives, antacids, and those containing potassium, magnesium, and phosphorus) may cause increased stool output. In a study evaluating the causes of diarrhea in tube-fed patients, 61% and 17% of the reported cases of diarrhea were found to be due to medications and C. ditticile colitis, respectively.P Diarrhea that occurs with enteral nutrition should be evaluated and treated with the following approach: 1. Evaluate medications and eliminate potential culprits when possible.
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20 • Administration of Enteral Nutrition: Initiation, Progression, and Transition
2. Rule out causes from infectious agents, such as C. difficile. 3. Change to an iso-osmolar formula if a hyperosmolar formula is being administered. 4. Switch to a fiber-eontaining enteral formula. Fiber promotes colonic fluid absorption. More specifically, soluble fiber contains short-chain fatty acids that help improve water and electrolyte absorption and promote bacterial proliferation." 5. If an infectious agent as the cause is ruled out as the cause, consider antidiarrheal medications. 6. If diarrhea persists with electrolyte and fluid abnormalities, consider initiating parenteral nutritional support while infusing trophic tube feedings to maintain gastrointestinal integrity.
Abdominal Examination Examination of the abdomen is essential in assessing a patient's tolerance of tube feeding. Signs considered indicative of intolerance include abdominal pain, abdominal distention, bloating, diarrhea, and vomiting. A study by McClave and co-workers" examined the use of residual volume as a marker for enteral feeding intolerance. They found that despite the presence of bloating, abdominal distention, and increased tympany, regurgitation only occurred in one volunteer subject (immediately after feeding tube manipulation), and no subjects had obvious aspiration.P A patient's physical condition should be monitored serially during enteral nutrition along with intake, output, and residual volumes.
Biochemical Markers A comprehensive metabolic profile should be obtained at baseline before enteral nutritional support is initiated. If a patient's condition is medically stable and he or she is not at risk for developing refeeding syndrome, the clinician should monitor results from a basic metabolic panel weekly for the duration of enteral therapy." Please refer to Chapter 23 for a discussion on refeeding syndrome. To assess the efficacy of the chosen nutritional care plan, the clinician should monitor prealbumin and transferrin levels weekly. Notably, prealbumin and transferrin have half-lives of 2 to 3 days and 8 to 10 days, respectively. Albumin is not an ideal indicator of nutrition status because it has a 20-day half-life and is acutely affected by hydration status and intection."
TRANSITIONING TO AN ORAL DIET When a transition from enteral nutrition to an oral diet is made, tube feedings should be changed to nocturnal continuous infusion to avoid appetite suppression. Studies have shown that providing supplemental tube feedings nocturnally has improved voluntary oral intake and baseline nutritional pararneters.P-" In conjunction with monitoring supplemental tube feedings, a food record or calorie count, should be kept with an assessment of oral
intake. Nasoenteric tube feedings should not be discontinued until the patient is consistently meeting at least 75% of his or her estimated nutrient needs with oral intake alone. Patients may benefit from oral supplements during this transitional period to help maximize oral intake. For patients with long-term feeding access ports, the tube should remain in place until the patient is able to achieve weight maintenance and nutritional parameters with oral intake alone. Moreover, patients should maintain these parameters for 1 month. REFERENCES 1. ASPEN: Definition of terms used in ASPEN guidelines and standards. Nutr Clin Pract 1995;10:1-3. 2. Shike M:Enteral feeding. In Shils ME,Olson JA, Shike M,et al (eds): Modern Nutrition in Health and Disease, 9th ed. Philadelphia, Lippincott, Williams & Wilkins, 1999, pp 1643-1656. 3. Randall, HT: Enteral nutrition: tube feeding in acute and chronic illness. J Parenter Enteral Nutr 1984;8:113-136. 4. Detsky A, Smalley P, Chang J: Is this patient malnourished? JAMA 994;27:154-158. 5. American Gastroenterological Association: Technical review on tube feeding for enteral nutrition. Gastroenterology 1995; 108:1282-1301. 6. Minard G, Lysen LK: Enteral access devices. In Gottschlich MM, Fuhrman MP (eds): The Science and Practice of Nutrition Support: A Case-Based Curriculum. Dubuque, lA, Kendall/Hunt, 2001, pp 167-188. 7. Neumann DA, DeLegge MH: Gastric versus small-bowel tube feeding in the intensive care unit: A prospective comparison of efficacy. Crit Care Med 2002;30:1436-1438. 8. Kearns PJ, Chin D, Mueller L, et al: The incidence of ventilatorassociated pneumonia and success in nutrient delivery with gastric versus small intestinal feeding: A randomized clinical trial. Crit Care Med 2000;28:142-146. 9. Zaloga GP: Aspiration-related illnesses: Definitions and diagnosis. J Parenter Enteral Nutr 2002;26:S2-S8. 10. Metheny NA, Aud MA, Wunderlich RJ: A survey of bedside methods used to detect pulmonary aspiration of enteral formula in intubated tube-fed patients. Am J Crit Care 1999;8:160-167. 11. Solomon S, Kirby D: The refeeding syndrome: A review. J Parenter Enteral Nutr 1990;14:90-97. 12. McClave S, Snider H: Use of indirect calorimetry in clinical nutrition. Nutr Clin Pract 1992;7:207-221. 13. Frankenfield D: Energy and macrosubstrate requirements. In Gottschlich MM, Fuhrman MP (eds): The Science and Practice of Nutrition Support: A Case-Based Core Curriculum. Dubuque, lA, Kendall/Hunt, 2001, pp 31-52. 14. Nutrition Assessment of Adults. In Rychlec G (ed): Manual of Clinical Dietetics, 6th ed. Chicago, American Dietetic Association, 2000, p 29. 15. Keohane PP, Attrill H, Love M,et al: Relation between osmolality of diet and gastrointestinal side effects in enteral nutrition. BMJ 1984;288:678-680. 16. Rees RGP, Keohane PP, Grimble GK, et al: Tolerance of elemental diet administered without starter regimen. BMJ 1985;290: 1869-1870. 17. Charney P: Enteral nutrition: Indications, options, and formulations. In Gottschlich MM, Fuhrman MP (eds): The Science and Practice of Nutrition Support: A Case-Based Curriculum. Dubuque, lA, Kendall/Hunt, 2001, pp 141-166. 18. Spain D, McClave S, Sexton L, et al: Infusion protocol improves delivery of enteral tube feeding in the critical care unit. J Parenter Enteral Nutr 1999;23:288-292. 19. Adam S, Batson S: A study of problems associated with the delivery of enteral feed in critically ill patients in five ICU's in the UK. Intensive Care Med 1997;23:261-266. 20. Ciocan J, Galindo-Ciocon D, Tiessen C, et al: Continuous compared to intermittent tube feeding in the elderly. J Parenter Enteral Nutr 1992;16:525-528.
SECTION IV • Principles of Enteral Nutrition 21. Ibanez J, Penafiel A, Raurich JM, et al: Gastroesophageal reflux in intubated patients receiving enteral nutrition: Effect of supine and semirecumbent positions. J Parenter Enteral Nutr 1992;16: 41~22.
22. Tarling MM, Toner CC, Withington PS, et al: A model of gastric emptying using paracetamol absorption in intensive care patients. Intensive Care Med 1997;23:256-260. 23. DaviesA, Froomes P, French C, et al: Randomized comparison of nasojejunal and nasogastric feeding in critically ill patients. Crit CareMed 2002;30:586-590. 24. Maclaren R, Kuhl D, Gervasio JM, et al: Sequential single dose of cisapride, erythromycin, and metoclopramide in critically ill patients intolerant to enteral nutrition: A randomized, placebo-controlled, crossover study. Crit Care Med 2000;28:
438-444. 25. Boivin M, Levy H: Gastric feeding with erythromycin is equivalent to transpyloric feeding in critically ill. Critical Care Med 2001;29: 1916-1919. 26. Russell M, Cromer M, Grant J: Complications of enteral nutrition therapy. In Gottschlich MM, Fuhrman MP (eds): The Science and Practice of Nutrition Support: A CaseBased Core Curriculum. Dubuque, lA, Kendall/Hunt, 2001, pp 189-210.
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27. Zimmaro Bliss D, Guenter PA, Settle RG: Defining and reporting diarrhea in tube-fed patients-What a mess! Am J Clin Nutr 1992;55: 753-759. 28. EdesT, Walk B, Austin J: Diarrhea in tube-fed patients: Feeding formula not necessarilythe cause. Am J Med 1990;88:91-93. 29. Fuhrman P: Diarrhea and tube feeding. Nutr Clin Pract 1999: 1483-1484. 30. McClaveSA, Snider HL, Lowen CC, et al: Use of residual volume as a marker for enteral feeding intolerance: Prospective blinded comparison with physical examination and radiographic findings. JPEN J Parenter Enteral Nutr 1992;16:99-105. 31. Lykins TC: Nutrition support clinical pathways. Nutr C1in Pract
1996;11:16-20. 32. Shopbell JM, Hopkins B, Shronts E: Nutrition screening and assessment. In Gottschlich MM, Fuhrman MP (eds): The Science and Practice of Nutrition Support: A Case-Based Core Curriculum. Dubuque, lA, Kendall/Hunt, 2001, pp 107-140. 33. Hebuteme X, Vaillon F, Peroux JL, et al: Correction of malnutrition following gastrectomy with cyclic enteral nutrition. Digest Dis Sci
1999;44:1875-1882. 34. Hebuteme X, Broussard JF, Rampal P: Acute renutrition by cyclic enteral nutrition in elderly and younger patients. JAMA
1995;273:638-643.
II Dietary Supplements Joseph I. Boullata, PharmD, BCNSP
CHAPTER OUTLINE Introduction Definitions Current Usage Regulatory Issues Clinician's Role Efficacy and Safety of Dietary Supplements Nutrients Herbals Other Compounds Implications for Nutrition Support Practice Summary
definitions, usage patterns, and regulations to safety, efficacy, and product quality, will be provided. The role that nutrition support clinicians can play and the implications for clinical practice will also be discussed. It is not difficult to understand the concept that nutrients, or even other active substances from food, can be delivered to a patient in a variety of vehicles or "dosage forms"-eonventional foods, dietary supplements, medical foods, and prescription products. However, the concept of nondietary substances being included as extensions of the healthy diet (i.e., dietary supplements) has been more difficult to appreciate. Although nutrition support clinicians feel comfortable with the more common nutrient ingredients of dietary supplements, surveys indicate that health care professionals in general are less knowledgeable about all dietary supplements including the plethora of non-nutrient dietary supplements available,I-3 although a greater effort is being made to include this knowledge in professional education.P
INTRODUCTION Use of dietary supplements in patients requiring nutritional support may parallel the widespread use of dietary supplements in the general population. This use, particularly outside of the hospital or alternate care site, is often part of a patient's self-care but may be supported by some clinicians. The fact that dietary supplements are associated with nutrition has meant that nutrition support specialists are expected to have a good working knowledge of the topic. It is no longer possible to simply dismiss dietary supplements outright, just as it is not acceptable to recommend, dispense, or administer them without considering the current state of knowledge. Thus, the objective of this chapter is to provide nutrition support clinicians with an awareness of the varied issues involved with dietary supplement use. It will not be an exhaustive presentation of all clinically relevant information on dietary supplements, which continues to be generated. For more complete information on the tens of thousands of dietary supplements currently on the market in the United States, the reader is referred to the specialized sources available. However, common products in use will be covered in brief to provide examples of the issues described. In this chapter a framework for understanding and evaluating dietary supplements, from
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DEFINITIONS The term dietary supplement is defined by statute as a "product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (8) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described... "6 This term is further defined as a product that is labeled as a dietary supplement and is not represented for use as a conventional food or as a sale item of a meal or the diet, but is intended for ingestion in the form of a capsule, powder, softgel, gelcap, tablet, liquid, or, indeed, any other form so long as it is not represented as a conventional food or as the sale item of a meal or of the diet," Most people are not aware of this extensive definition, which is currently used by regulatory agencies to classifyand distinguish dietary supplements from other therapies. Laypersons and health care professionals alike often refer to dietary supplements by other terms. The term complementary and alternative medicine has been used
..
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to describe a wide range of nontraditional forms of therapy from acupuncture and aromatherapy to energy healing, homeopathy, and massage. The use of biologically based therapies such as vitamins and herbs is often included in such a broad classification." However, it is valuable for health care professionals to consider dietary supplements as a class by themselves and avoid lumping them in with other nonpharmaceutical modes of alternative therapy. Furthermore, any dietary supplement that truly complements established medical approaches or is considered an equivalent alternative to accepted medicine will be integrated into the database of more traditional, evidence-based medicine. Indeed, some specific dietary supplements are considered part of reasonable medical practice by some specialties." Without adequate evidence to support their use, other dietary supplements remain as yet unproven remedies when administered in a dosage form. The term nutritional supplement has also been used in reference to dietary supplements but does not fullydescribe all supplements because some include many non-nutrient ingredients. The term food supplement does not allow for non-nutrient products either and instead is best used to represent products used for meal replacement. The additional terms nutraceutical and functional food have no regulatory meaning, and different constituencies define them differently. From an academic point of view, these terms can best be understood as follows: Nutraceutical can refer to nutrient(s) or other active food ingredient(s) delivered in a pharmaceutical dosage form, whereas an active ingredient(s) delivered within a food matrix may be considered a functional food whether those ingredients are nutrients, herbals, or other compounds. The U.S. Food and Drug Administration (FDA) may consider novel ingredients introduced into a food product as a drug if the substance is not generally recognized as safe. It is clear why vitamins, minerals, amino acids, and other nutrients fulfill the definition of dietary supplements, but the reason is less clear for the other non-nutrient ingredients. The terms herbs, herbals, and herbal medicine are often used interchangeably. Technically, herbs are defined as non-woody, seed-producing plants that die to the ground after their season or those vegetable products used to add flavor to foods." Herbal medicine can refer to the group of products or the approach to care that uses them for maintaining or improving health. These products contain active ingredients exclusively from plant sources and thus are also referred to as phytomedicine. They are commercially available as bulk plants or parts of those plants but more commonly as powders or extracts from the plants then used in capsules, tablets, and liquids. Storage as plant extracts prolongs the life span of active substances from the otherwise perishable, harvested botanical material. The discussion of dietary supplements in this chapter will be based on the regulatory definition and refer to active ingredients delivered in an oral pharmaceutical dosage form that are intended to supplement the diet or enhance health but are not conventional foods or meal replacements, infant formulas or medical foods, or drugs. Given the broad interpretation of dietary supplement
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Commonly Used Dietary Supplement Ingredients
Nutrient
Herbal
Other
Multivitamin Multimineral Ascorbic acid Vitamin E I3-Carotene Calcium
Ginkgo St. John's wort Garlic Ginseng Echinacea Saw palmetto
Glucosamine Chondroitin Melatonin Coenzyme Q> S-Adenosylmethionine Creatine>
>Although found in the diet and considered a nutrient by some, not yet recognized as such.
ingredients, the compounds are further subclassified into three somewhat arbitrary categories, regardless of their purported uses (Table 21-1): nutrients (e.g., vitamins, minerals, and amino acids), herbals (i.e., botanical source), and other (Le., non-nutrient, nonherbal ingredient including some hormones). These subclasses are differentiated in part by raw material source, physicochemical complexity, dosing provisions, and amount of supportive data for each. Although useful, even this simple classification is not perfect. Among herbals there are some that are much more like foods (e.g., garlic and soy), whereas others are clearly much more like drugs (e.g., St. John's wort and ephedra). The line of distinction between dietary supplement and drug has even disappeared in some cases. 10 The U.S. marketplace consists of some dietary supplement products that contain ingredients solely from one class and others with combinations across these three classes. Although tens of thousands of products fit into the definition of dietary supplements used in this chapter, the reader should keep in mind that there are countless more products that are unpackaged traditional or folk remedies and other products containing dietary supplement ingredients (e.g., fortified food, meal supplements and substitutes, and sports foods).
CURRENT USAGE The secular trend to use complementary and alternative medicine started at least 50 years ago; however, the use of dietary supplements began in earnest in the 19605 and 19705, with use rapidly increasing after passage of the Dietary Supplement Health and Education Act (OSHEA) in 1994. 11 According to recent surveys up to 55% of Americans regularly use a dietary supplement. 12 Sales of dietary supplements account for at least 15 billion dollars annually in the United States and occur in traditional retail markets and pharmacies, as well as on the Internet. In the United Kingdom about 350 million pounds are spent annually on dietary supplements." The prevalence of use varies with the surveyed population, setting, and definition of dietary supplement used. National Health and Nutrition Examination Survey (NHANES) III data, collected from more than 33,000 participants between 1988 and 1994, identified vitamin and mineral use in about one third of those surveyed,
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21 • Dietary Supplements
encompassing more than 2000 different products." Use of non-nutrient dietary supplements was identified incidentally as part of NHANES III with several hundred different herbal and nonherbal products being used." Data from the Continuing Survey of Food Intake of Individuals (CSFlI) suggested that 34% of adolescents use micronutrient dietary supplements." Even health care professionals and students report use of dietary supplements at a rate of about 30% to 50%.17-21 A telephone survey of more than 2000 subjects found that herbal use occurs in 12% of the general population, although a smaller percentage use megavitamins." This percentage was significantly higher than that seen in a similar survey conducted 7 years earlier.P Many of these data reflect use before the law that increased dietary supplement availability to American consumers was enacted. A more recent nationwide survey of more than 2500 subjects indicated that 40% of adults use vitamin/ mineral supplements and 14% use herbals compared with 50% using prescription medications." Close to 60% of outpatients seen in clinics report using a dietary supplement (vitamin/mineral in 69% and herbal in 24%).25 More than 40% of the general population including clinic patients used herbal medicine." Use during pregnancy and in children has also been documented at about 15% and 20%, respectively.F'" A survey of the general population found that 33% of parents had given dietary supplements to their children in the previous year." Interestingly, although 45% of pregnant women reported use of herbal medicine, 20% did not comply with their prenatal vitaminmineral supplement regimen." Of patients regularly taking prescription drugs about 16% to 20% concurrently take at least one dietary supplement.P-" Of critical importance is the fact that the majority of patients do not reveal their use of dietary supplements to their health care providers, including those patients involved in clinical drug trials.22,31 Patients with chronic conditions and limited options for remission are likely to use dietary supplements. For example, up to one quarter of patients infected with human immunodeficiency virus (HIV) use herbal medicine, with many taking more than one and some being unable to identify the product they are using, whereas about 70% use nutrient supplernents.t'r" It appears that among HIVinfected adults, those with a college education and those who identify themselves as non-Hispanic whites are more likely than other groups to use vitamins and herbal medlclnes.F-" This same statistic for consumption patterns is seen for dietary supplements in the general populatlon.It-" A survey of patients with cardiovascular disease revealed herbal medicine use in 17%, multivitamin/mineral use in 23%, and single entity vitamin/mineral use in 38%.34 Elderly patients followed in clinics may have usage rates as high as 50%.35 A survey of older persons at a Veterans Affairs medical center revealed that 23% use dietary supplements with users consuming an average of three products each compared with six prescription medications each." About one quarter of patients seen in the emergency department use herbal medicine." Many patients undergoing surgery were identified as using dietary supplements before their procedures (herbal medicine in 22% and vitamins in
51%).38 More than 17% of patients identified use of one dietary supplement from a limited list on a preoperative questionnaire, with many using multiple products." About 20% of inpatients reported using herbal products, with some surreptitiously continuing use during their hospital stay." More than 40% of patients being admitted to a hospital reported use of alternative medicines (excluding vitamins and calcium)." Although 41 % of these patients had not disclosed use to their primary care provider, a much greater number of them (79%) did not volunteer the information at their time of admission." An estimated 16,000 to 29,000 different dietary supplement products, including at least 2,000 botanical species, are available commercially. A relatively small number of ingredients make up a large portion of the most popular products. Nutrients commonly used in dietary supplement form are familiar to nutrition support practitioners and include multivitamins, multivitamins-multiminerals, and single nutrients (see Table 21-1). It is interesting to note that many women who self-administer nutrient supplements are those who have the best dietary intake and are least likely to need supplementation.f Although it is difficult to understand exactly how intake of herbal medicine supplements the diet, a small number of herbals are responsible for more than 1 billion dollars in U.S. sales annually (see Table 21-1). Several non-nutrient, nonherbal supplement ingredients continue to be popular as well (see Table 21-1). Dietary supplement use occurs for a large number of reasons, but, generally, consumers have become more involved in their own care, and use of dietary supplements is intended to help achieve their self-care goals. These goals may include ensuring good health and wellbeing, improving energy levels, and preventing or treating specific disorders. The disorders may be the same as those for which they require nutritional support or may be complications of their nutrition support regimens. Patients may assume that all dietary supplements are "natural" and therefore are suited to their broadened identity of self. Patients rarely tum to health care professionals as sources of information on dietary supplements; they tum instead to family and friends and are swayed by advertising, which can be misleading.v/" Some nonhealth professionals may offer inappropriate advice.f When surveyed, most (55% to 68%) laypersons mistakenly assumed that the FDA approves dietary supplements before they are marketed, requires label warnings, and does not allow manufacturers to make claims without supporting evidence."
REGULATORY ISSUES Surprisingly, dietary supplements are less tightly regulated by the FDA than are conventional foods, food additives, and over-the-counter and prescription medicines. The FDA has regulatory authority over dietary supplements pursuant to the Food, Drug, and Cosmetic Act as amended by the DSHEA. Although a complete discussion of drug regulation is not the intent of this chapter, a
SECTION IV • Principles of Enteral Nutrition
quick review will help place current issues with dietary supplements into perspective. Regulation of pharmaceutically active products in the United States in the 20th century began with the Pure Food & Drug Act (1906), which prohibited adulterated or misbranded products and the Sherley amendment (1912), which prohibited fraudulently labeled products. The Food, Drug, and Cosmetic Act (1938) required that a product be safe, and the subsequent amendmentsDurham-Humphrey (1951) and Kefauver-Harris (1962)created the category of prescription drugs and required that products be shown to have efficacy. A further amendment-Rogers-Proxmire (1976)-prohibited the regulation of nutrient content and excluded vitamins and minerals from being classified as drugs, as they were in many other countries. In 1990 the Nutrition Labeling and Education Act was promulgated to help regulate labeling and health claims of food products including dietary supplements. At about the same time, findings of an extensive review of over-the-counter products revealed many for which safety and effectiveness were not able to be documented. These products, including many ingredients found in dietary supplements, were at risk of losing their place on store shelves. This convergence of events would have created an environment unfavorable for dietary supplement users and manufacturers. However, the DietarySupplement Act (1992) delayed the implementation of the Nutrition Labeling and Education Act and exempted dietary supplements from the regulation, requiring instead the enactment of specific legislation. Thus, the OSHEA (1994), which defined dietary supplements broadly, created the National Institutes of Health (NIH) Office of Dietary Supplements, exempted manufacturers from submitting premarket safety data to the FDA (as required for food additives and medications), and placed the burden of proof on the FDA for product safety, adulteration, and misleading labeling. The intent was to allow consumers improved access to dietary supplements without government interference. It is not fair, however, to say that the products are unregulated. The FDA makes regulations pursuant to the OSHEA that cover two areas: product labeling and product claims. These regulations created the uniform use of the Supplement Facts label on every dietary supplement product. They also provided for specifically defined terminology used on the product. The label separates nutrient from non-nutrient ingredients, with a requirement that the Percent Daily Value be provided for nutrient ingredients. For herbal ingredients, the specific plant species and the part of the plant used need to be listed. These regulations also require that a disclaimer appear on each product to explain that the product and its claims are not evaluated by the FDA and that the product is not intended for disease prevention, treatment, or cure. A product not meeting these labeling regulations can be removed from the market if identified. Given the limited number of personnel able to enforce the regulations, the public is expected to help identify and report products not meeting the requirements to the FDA. Regulations allow manufacturers of dietary supplements to make nutrient content claims, health claims, and
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structure-function claims. The labeling can characterize the level of a nutrient contained in a product. If the product contains an ingredient for which the FDA has received compelling data to allow a health claim (e.g., calcium and osteoporosis), this can be included. Use of an unapproved health claim turns the dietary supplement product into a drug that is therefore on the market illegally and is subject to seizure. The regulation related to a structure-function claim allows the characterization of the effect of the dietary supplement ingredient(s) on the body's structure or function without suggesting a health benefit or treatment of a disease. The wording of such claims has been the subject of significant discussion. Many consumers and health professionals cannot distinguish between health and structure-function claims." However, beyond the regulation of labeling and claims, there is no FDAevaluation of safety, efficacy, or product quality. Calls for improved regulation of dietary supplements for the sake of public health and safety in the United States continue.f-" In comparison, in the United Kingdom the Food Standards Agency rather than the Medicines Control Agency regulates dietary supplements because most are seen as foods." Great variability in dietary supplement regulation continues to exist throughout the rest of the European Union, including some nations in which the Recommended Dietary Allowance (RDA) or a multiple thereof determines the cutoff for regulating a nutrient as a food or as a medicine, although the European Commission is trying to standardize these across states. Herbals are typically regulated as medicinal products in Europe if they are intended for prevention or treatment of a condition although regulation of an individual herb may differ from one state to another." The degree of authority over the marketed dietary supplement products is greater in both Europe and Australia than in the United States. In the United Kingdom, the regulatory authority recently issued advice to consumers about the safety of long-term vitamin-mineral use." The regulatory authority in Australia was able to recall more than 200 dietary supplement products and suspend the license of the products' sole manufacturer, the country's largest, because of poor production and quality control procedures." Ideally the consumer and clinician in the United States should be confident that what is listed on the dietary supplement label is contained in each dose of the product and that everything in the dosage unit is described on the label. Furthermore, there should be confidence that the dose is clinically appropriate and bioavailable. Any manufacturing practice that does not confirm the identity, purity, strength, and quality of the marketed supplement will not instill confidence in consumers and health care professionals alike. The assurance of product quality in the dietary supplement industry currently depends on selfregulation using good manufacturing practices (GMPs). A few reputable manufacturers perform their own product analysis, although they are not required to do so, but fewer still submit their lots for independent testing to at least verify the labeling claim. The GMPs should result in products of adequate and reproducible quality, thereby limiting related adverse effects and improving
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the methodologic quality of trials using them. Unfortunately, many products of poor quality continue to flood the U.S. marketplace.F The FDA has recently proposed a new regulation, 6 years after making advance notice that they would propose such a rule and 8 years after being required to do so, mandating GMPs.53 This would require manufacturers, packers, and holders of dietary supplement ingredients and products to evaluate the identity, purity, quality, strength, and composition of their product. Hopefully the final rule will result in practices being put into place to assure quality at each step along the entire manufacturing process from raw material synthesis or extraction to actual production, product packaging, and the finished product. This is seen as a positive move toward providing consumers with quality products. It should be kept in mind that the process from proposal of the rule to adoption of the final regulation will take many months and possibly longer, after public and industry comment and subsequent revision, with a multiple-year phase-in likely from that point. The U.S. Pharmacopeia (USP)54 sets standards for quality of drug products, including quite a number of dietary supplements. This valuable source is also recognized in the OSHEA as the representative of the official standards for dietary supplements in the United States. General standards exist for product labeling, microbial limits, weight variation, and disintegration and dissolution, as well as ingredient-specific information. However, although USP standards for dietary supplements exist, there is currently no statutory requirement for compliance with those standards. Products claiming to meet USP standards may not necessarily meet all the applicable standards set forth in the compendia. In addition, the proposed FDA rule for GMPs does not address the issues of safety or clinical value of the dietary supplement products. Government bodies providing oversight of dietary supplements include the FDA for product regulation within the constraints of the OSHEA and the NIH for research into many aspects of dietary supplement ingredients and products. The FDA Center for Food Safety and Applied Nutrition oversees dietary supplements among its other areas and provides regulatory information with public safety in rnind." At the request of the FDA, the Institute of Medicine has issued a report describing a framework for evaluating the safety of dietary supplement ingredients and developing prototype monographs for six ingredients (chaparral, chromium picolinate, glucosamine, melatonin, saw palmetto, and shark cartilagej." The focus will be on the process by which FDA can screen ingredients, set priorities, and critically evaluate available safety information to make regulatory decisions about dietary supplements. This will allow the FDA to use its very limited resources in a methodical approach, but will also necessarily limit the number of ingredients evaluated. At the NIH, the National Center for Complementary and Alternative Medicine was established in 1998, replacing the Office of Alternative Medicine that had been established in 199J.7 However, the Office of Dietary Supplements (ODS), established as part of the OSHEA, is the center for promoting the study of dietary supplements at
the NIH.57 Although not having the authority to directly grant funds for research projects, the ODS instead partners with other institutes for that purpose and provides several additional functions. These include developing fact sheets on about two dozen dietary supplements, posting safety notices, and providing a bibliographic database on dietary supplements and an annual annotated bibliography. The ODS also supports research programs and conferences and provides advice to other federal agencies on dietary supplements. Funds were recently allocated to help ODS develop and disseminate validated analytical methods (qualitative and quantitative) for many of the most common dietary supplement ingredients to be used for clinical as well as basic science research. This work is being carried out with the AOAC International (Association of Analytical Communitiesj'" and will allow for meaningful certificates of analysis for raw materials going to manufacturers, quality assurance testing during the manufacturing process, and finished product analysis to determine product quality.
CLINICIAN'S ROLE More than ever, nutrition support practitioners are being placed in a decision-making position when it comes to dietary supplements, if for no other reason than these products relate to the diet. This role is clearly recognized by professional organizations.P'" The clinician's role may include a number of responsibilities. First and foremost is in the assessment of individual patient use of dietary supplements as part of the history taking. Currently only about one third of patients are asked about their use of dietary supplements on admission or during their hospital stay." The history should include targeted questions about vitamins, minerals, amino acids, herbals, and non-nutrient/nonherbal products. Questions about remedies used for chronic condi. tions (e.g., arthritis or cardiovascular disease) or those conditions not helped by usual therapy (e.g., the common cold or premenstrual syndrome) often uncover dietary supplement use. Few patients will acknowledge their consumption of dietary supplement products as "alternative remedies" but will respond to names of specific nutrients, herbals, or other products. A focused history taking can yield three to four times the information on use of herbal products compared with the typical history.P Besides identifying the specific supplements used, the brand name, dosing regimen, and the rationale for use should be included." Another responsibility of the clinician is to become familiar with new information on dietary supplements. Numerous articles are published each month on dietary supplement ingredients and may be of significant interest to nutrition support clinicians. The professional journals that represent nutritional support and its various disciplines are replete with articles on dietary supplements that require review and interpretation. Information provided may go beyond supplement efficacy or safety to include issues of dosing, bioavailability, and product quality.
SECTION IV • Principles of Enteral Nutrition
Another key role for nutrition support clinicians is to protect patients from any unwanted or adverse effects from inappropriate use of dietary supplements and allow patients the opportunity for informed decision making. An interdisciplinary effort is required and has been suggested. 59.60 Unbiased professionalism is also an expectation. However, some clinicians have actually become involved in marketing dietary supplements directly to patients.P Guidelines for both recommending and selling dietary supplements have been issued." Liability issues related to dietary supplement counseling have been discussed as well. 64 Individual patients may ask for an evaluation of a specific dietary supplement ingredient or product, especially if they sense that the clinician's assessment will be evidence-based rather than emotionally driven. Just as likely is the possibility that an institution or health care system will request that nutrition support clinicians evaluate specific dietary supplements for inclusion on a formulary. In fulfilling their professional responsibility to evaluate dietary supplements, nutrition support clinicians will make use of more detailed information than will many of their colleagues. Some issues not often addressed about dietary supplements involve the dosing, bioavailability, and formulation of the products. Once in a pharmaceutical dosage form, dietary supplement products have the characteristics of drugs. Clearly these less commonly addressed issues can have an impact on the perceived benefits or risks of use of a dietary supplement. Dosing that is either inadequate or excessive influences the effect of the product. Dosing standards for dietary supplement ingredients depend on their classification-nutrient, herbal, or other compound. Nutrients can be represented by the dosing standards contained within the Dietary Reference Intakes (DRIs).65419 The RDA or the Adequate Intake (AI) level for a nutrient as recognized by the Institute of Medicine in its evidence-based approach to defining human needs may be the best guide for dosing of these nutrients. These dosing standards, however, are intended for healthy persons as part of the normal diet and not from dietary supplements. Additionally, the Upper Tolerable Intake Level (UL) for each nutrient may be used as a maximum dose to avoid, although again the risk assessment on which these values are determined may not always be based on dietary supplement use. Similar safe upper limits have been provided elsewhere." A point of confusion can occur when nutrient dosing as it appears on the label of a dietary supplement is evaluated. The percent Daily Value (%DV) listed is based on FDA labeling standards, which are not necessarily synonymous with the percent RDA or AI (dosing standards). This discrepancy also accounts for the use of outdated units of measure on the labeling (e.g., international units [IU] of fat-soluble vitamins instead of micrograms or milligrams). The best approach for determining appropriateness is to compare the nutrient dose (micrograms, milligrams, or grams) listed on the dietary supplement label with the standards listed in the DRI volumes. Even so, the bioavailability of nutrients from supplements may differ from that of foods on which the DRI recommendations are most often based.
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The majority of ingredients found in dietary supplements are not covered by the DRIs. Dosing of some of the well-studied herbal medicines and the non-nutrient, nonherbal supplement ingredients may be found in official monographs in the United States and Europe'<" and in other sources. 49,72,73 Much less information is available on many other dietary supplement ingredients. The data that support these doses have not always come from dosefinding trials, and, therefore, doses may need to be adjusted as more data are generated. Although a number of sources are available to guide dosing and use, the quality of individual data should be assessed by the clinician. Bioavailability also needs to be taken into consideration. Even when the dose of a dietary supplement ingredient seems acceptable, the proportion of the consumed dose that is absorbed, retained, and available for effect (i.e., bioavailability) is not guaranteed. The bioavailability will depend on the solubility and permeability of the ingredient, as well as on physiologic factors that also affect the bioavailability of any other pharmaceutical product. Determination of bioavailability is more complex for products administered through an enteral access device, particularly when the distal tip is beyond the stomach. Some products may contain nutrients in a form that limits their bioavailability. For example, zinc oxide, found in many mineral-eontaining dietary supplements, is virtually insoluble and unlikely to be absorbed systemically compared with the much more soluble sulfate or chloride salts. An NIH-sponsored conference on dietary supplements identified the limited degree of attention paid to studying the bioavailability of nutrients and herbals as found in supplements. Proceedings of this conference provide an indication of how little information is truly known about this critical topic." Formulation of a quality product is inherent to an ingredient's bioavailability. Several requirements should be met for the subsequent formulation of an acceptable pharmaceutical dosage form. The physicochemical properties of the active ingredient(s) should be known, and an acceptable assay for that ingredient should be developed.1f the active ingredient(s) and structure are known, then dissolution and permeability can be optimized." When this information is available it can be used to create the optimal mix of active ingredient(s) with excipients that allow for disintegration, dissolution, and availability for absorption. This formulation could be patented if it is unique in its delivery of ingredients. For multiple component products, the potential for interaction between each active ingredient should also be assessed. After the final formulation is derived and created, trials evaluating bioavailability can then be carried out. This step requires validated analytical methods for the ingredient in biologic samples. These bioavailability studies can then rationally be followed by clinical trials to determine efficacy and safety. Many reputable manufacturers are working toward the day when this procedure will be followed for all dietary supplement products. However, dietary supplement studies in which the formulation used is not described or its contents are not verified continue to be published.Y" It is unclear how many inconclusive findings from dietary supplement
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trials are due to inappropriate formulation or to poor study design or true lack of benefit. Unexpected clinical outcomes may result from an inappropriately formulated product as well as other factors. Given the current regulatory climate, information on product formulation is mandatory to better evaluate a clinical trial. The ideal process to create a quality dietary supplement product that inspires the confidence needed to recommend it for patient use would begin with a characterization of the active ingredient(s). Some active ingredients (e.g., nutrients) are well characterized and have validated methods for analysis. However, for many non-nutrient products, including herbals, the active or marker compounds have not been well characterized yet or universally accepted methods for analysis are not clearly recognized. For uncharacterized active compounds that cannot be assayed, it is not clear how a formulation can be designed and evaluated, yet this is the case for a large number of dietary supplement products currently on the market. The more complex a product is (e.g., botanicals or multi-ingredient products), the more difficult analysis can be. The known characteristics of the raw materials may not remain true once the material is processed and in the final product. Methods of analysis need to be developed and validated. As mentioned earlier, this process, spearheaded through the ODS, remains in the early stages. 57.58 The USP establishes standards for medications including dietary supplements. It publishes both informational and standards monographs for a number of nutrient, herbal, and other dietary supplement ingredients, including methods of analysis. Official monographs for botanicals continue to be added to the established monographs for nutrients and other nonbotanicals (Table 21-2).54 Unfortunately, there is currently no requirement that marketed products in the United States meet these standards, so that very few products are known to meet USP specifications. The USP has recently established a dietary supplement verification program, whereby manufacturers may voluntarily submit their products to be tested against
..
standards and allow their manufacturing processes to be reviewed.P A product deemed passable is so indicated for quality only, not for safety and efficacy. Until the FDA implements final regulations on the manufacture of dietary supplements, certification programs, including that of the USP, can help guide clinicians and consumers alike in product selection.P ConsumerLab has evaluated approximately 700 brands of various dietary supplements since it was founded in 1999, although its results are only based on the lots evaluated." Other quality assessment programs include those of the Good Housekeeping Institute, NSF International, and the National Nutritional Foods Association.P It should be made clear that the approval of a dietary supplement by any of these programs does not attest to safety and effectiveness but only to product quality. Beyond identifying quality ingredients and products, the need still exists to establish clinical value through clinical trials. All of the above information can help a clinician evaluate dietary supplements. Sharing the information with patients can allow them to make more informed decisions about using dietary supplements. Several questions about the patient's intent to use a dietary supplement can guide a counseling session with the patient: Is use of the dietary supplement better than doing nothing? Is it as safe as doing nothing? Do the benefits outweigh the risks (i.e., adverse effects and interactions)?
EFFICACY AND SAFETY OF DIETARY SUPPLEMENTS Despite what may be declared by various supporters or detractors of dietary supplement products, no generalizations can be made about dietary supplement efficacy. Considering the many thousands of products on the market and the countless ingredients and their permutations, the data supporting the value of a dietary supplement will vary with the individual ingredient and the product
Dietary Supplement Ingredients for Which Official U.S. Pharmacopeia/National Formulary Monographs Exist·
Nutrients
Combinations Calcium/vitamin D, minerals, oil-soluble vitamins, oil-soluble vitamins/water-soluble vitamins, oil-soluble vitamins/water-soluble vitamins/minerals, water-soluble vitamins, water-soluble vitamins/minerals Individual Alanine, arginine, ascorbic acid, aspartic acid, Ikarotene, biotin, calcium (10 different salts), cholecalciferol, choline, copper, chromium, cyanocobalamin, cysteine, dexpanthenol, ergocalciferol, folic acid, glutamine, glycine, histidine, hydroxycobalamin, iron (3 different ferrous salts), isoleucine, leucine, t-carnltlne, lysine, magnesium, methionine, niacin, niacinamide, panthenol, phenylalanine, phytonadione, potassium (2 different salts), proline, pyridoxine, riboflavin, selenomethionine, serine, sodium ascorbate, thiamine (2 salts), threonine, tryptophan, tyrosine, valine, vitamin A, vitamin E, zinc
Botanicals American ginseng, Asian ginseng, chamomile, cranberry, echlnacea (3 species), eleuthero, feverfew, garlic, ginger, ginkgo, goldenseal, hawthorn, horse chestnut, licorice, milk thistle, red clover, saw palmetto, 51. John's wort, valerian (several others proposed)
Other Chondroitin, cod liver oil, glucosamine, Iipolic acid, lutein, ubidecarenone (several others proposed, none official yet) 'Products on the U.S. market are not required to meet the U.S. Pharmacopeia/National Formulary standards.
SECTION IV • Principles of Enteral Nutrition
containing it. The critical evaluation of supporting data, as well as the quality of the data source, must be performed as with any therapeutic substance before incorporating it into practice. No clinician would consider adopting a new therapeutic substance and incorporating it into practice outside of a clinical trial without at least some evidence for benefit. Given the differing regulatory environment among countries, it is especially important to pay attention to the setting in which a clinical study is performed and the pharmaceutical grade of the product used. As with prescription drugs used in clinical practice, the data continue to accumulate and often result in changed perceptions over time. The evidence for dietary supplement use can include epidemiologic data or animal data with defined mechanisms of action. Although many of these data merely generate hypotheses, reproducible and well-powered clinical studies can best support the effectiveness of a dietary supplement. The volume of information from peerreviewed research with a specific supplement ingredient or combinations of ingredients, using an appropriately designed dosage form, is limited for many dietary supplements. Otherwise, consumers and clinicians alike are exposed to a great deal of pseudo-science and marketing hype. The identification of some pharmacologic action for an available ingredient, without any other data, does not provide enough of a rationale to suggest general use. Traditional use or dietary consumption patterns of a given ingredient cannot be equated with the pharmaceutical dosage regimens used in dietary supplements. Certainly anecdotes are of interest, but the accumulation of anecdotes is not a substitute for clinical data. This information can, however, encourage the process of scientific inquiry. The need for authoritative, evidence-based reviews on dietary supplement claims to assist professionals in counseling the public is recognized." Criticalreviews of groups of dietary supplements for use by specific patients or in select disorders are becoming more widespread. 82,83 These can help to distinguish specific ingredients and patient groups for further study to better define their future use. The methods for determining improved outcome also need to be refined (e.g., assays for functional status of nutrients). Although efficacy data would be desirable, they are not required before an individual chooses to use a dietary supplement. However, a patient should be able to select high-quality products that are reasonably safewhether effective or not. The safety issue with dietary supplements is different from that with the traditional use of an ingredient based only on dietary exposure for a number of reasons. One particular factor is the special populations using dietary supplements such as those requiring nutrition support. Additionally, higher doses, the different matrix, and chronic exposures present unique circumstances requiring safety evaluation. Ideally, active substances used in maintaining or improving health should be free of adverse effects. Of course, this standard cannot be met for over-the-counter or prescription medications, which is no different for dietary supplements. This is contrary to the view held by many consumers that natural products are always safe.
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Given their physiologically active ingredients, dietary supplements also have the potential for adverse or unwanted effects, depending again on the ingredient and the product. Age, gender, nutritional status, genetics, disease, and other treatments may influence the risks for adverse effects. A major difference between adverse effects from dietary supplements and those from drugs is that the former are not always well characterized, recognized, or reported, and certainly there is no requirement to do so from a regulatory standpoint. The adverse effects can be classified as either being intrinsic to the active ingredient (i.e., pharmacologic) or extrinsic to the active ingredient (i.e., product quality). In reports of adverse effects to dietary supplements, particularly herbals, it is often unclear whether adverse effects are intrinsic or extrinsic to the active ingredient(s). Intrinsic adverse effects can be dose related or idiosyncratic or can be due to interactions-no different from those for prescription drugs. The interactions between dietary supplements and other medications may be pharmacodynamic or pharmacokinetic in nature (e.g., altered enteric absorption, enzyme induction or inhibition, altered plasma protein binding, or altered excretion). Resources exist to help identify actual and potential interactions.&Hl6 Evidence-based reviews that balance the risks and benefits of dietary supplements are also becoming more available.87,88 Adverse effects of the extrinsic type are a rare finding with drugs, thanks to quality assurance in the manufacturing process. However, this is a significant issue with dietary supplements because ingredient misidentification, the presence of impurities, and incorrect product formulation has been reported. A number of reports describing nutrient dietary supplements that do not meet standards for content, disintegration, or dissolution exist.80,8~92 Plant misidentification can occur in the harvesting, preparation, and distribution of botanicals. Impurities can be caused by contamination, substitution, or adulteration of a product. Dietary supplements may be contaminated with waste products, microorganisms, pesticides, and heavy metals. There is the potential for one herbal to be substituted for another. Additionally a number of dietary supplements have been adulterated with prescription drugs from across therapeutic categories (e.g., analgesics, antimicrobials, benzodiazepines, corticosteroids, diuretics, and hormones). Even the simplest issue, such as the chemical form of a dietary supplement ingredient used in a product, will determine its value.P Numerous problems with the quality of dietary supplements have been documented.P Of course, either a dose-related effect (intrinsic) or an effect caused by product impurity (extrinsic) can influence patient outcome. Given the discussion above, it is clear that aside from a benefit that may be afforded by a dietary supplement product, there is the potential that a product could also have untoward effects. The voluntary, dietary supplement adverse event reporting system through the FDA has been described as an inadequate safety valve, capturing only a few thousand adverse events in close to 10 years." The system detects relatively few adverse events, probably less than 1% of the actual incidence. The FDA received
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about 7000 dietary supplement-related adverse event reports through the voluntary system since 1993. The difficulty in generating a signal relates to the few reports from health care professionals, inadequate medical records available, unknown ingredients and unknown manufacturers for many products, and lack of product labels or product samples for the majority of existing reports. This voluntary system makes determining a numerator figure for actual events nearly impossible. Furthermore, it is difficult to determine an incidence given poor denominator figures describing overall exposures to each dietary supplement on the market. Recommendations have been made to improve the reporting system by requiring manufacturers and poison control centers to report events, requiring all products to be registered with the FDA, and increasing public disclosure on the potential for adverse effects." In the absence of any other system to monitor adverse events of dietary supplements, patient case reports and case series form the basis for identifying safety concerns with these products. Recent reports through poison control centers have provided some insight into revealing adverse events of varying severity that affect organ function and occur across all age groups. At least one half of calls about exposures to dietary supplements described symptoms, 62% of which were probably associated with the supplement." A recent report of hospitalized patients revealed that 23% of those using dietary supplements had experienced an adverse reaction, including 2% whose admission may have been due to such a reaction." Forty-eight percent of dietary supplement users, had potential interactions with a prescription drug, one third of which were considered clinically significant." Anaphylaxis requiring hospitalization has been associated with a multi-ingredient, weight loss supplernent." The National Toxicology Program is studying adverse effects of prolonged use of specific herbal agents." General precautions should be taken to avoid the use of dietary supplements in specific patient populations in the absence of adequate safety data. These would include children, pregnant or lactating women, patients undergoing elective surgery, and those with a history of allergy. Although the benefits and risks of several nutrients have been studied in these populations, those of most herbals and other dietary supplement ingredients have not. Patients who use herbal medicines may need to discontinue them at defined intervals before any planned surgical procedures, particularly if the products are associated with cardiovascular, respiratory, or hemostatic side effects. Others may induce a withdrawal syndrome and should be tapered off accordingly. A government report indicated that dietary supplements are risky for senior citizens for both economic and health reasons." Research and education on the subject of dietary supplements, including herbal medicines, need to continue so that the many unanswered questions can be addressed." What follows is a brief overview of a number of commonly used nutrients, herbals, and other compounds found in dietary supplement products.
Nutrients Data exist to support the use of specific nutrients to prevent or manage deficits seen in clinical practice. Beyond that, a number of specific nutrients have been used in the prevention or treatment of chronic disorders. The use of nutrient supplements does not overcome the effects of poor diet and lifestyle. There are a number of clinical situations in which dietary supplements may be applied by nutrition support clinicians (e.g., poor wound healing). Beyond adequate nutrition to maintain or improve nutritional status, the concept of therapeutic doses of specific nutrients, particularly micronutrients (e.g., ascorbic acid or zinc for wound healing), has been considered. The clinical data supporting the use of these supplements remains scant with the possible exception of supplementation in patients with specific vitamin C or zinc deficits.IOO,101 The potential risks of such supplementation should be taken into account. More problems can arise with high doses of a single nutrient if its impact on homeostasis is unknown. Not all health care professionals are prepared to answer relevant questions about an individual nutrient. 102 Intended use is an aspect that FDA considers in regulating these products as drugs or as supplements. For example, zinc sulfate 22Q-mg oral capsules (containing 50 mg of elemental zinc) as may be recommended for use in patients receiving enteral nutrition is a prescription drug, whereas zinc gluconate 50 mg (containing about 7 mg of elemental zinc) for support of the immune system is considered a dietary supplement.
Multivitamins with Minerals Patients unable to maintain adequate oral intake or those receiving enteral nutrition that provides an insufficient amount of vitamins and minerals at the goal rate may benefit from supplementation. Although most health-eare institutions routinely supply a multivitamin product that often contains minerals for patient use, rarely is the decision on which product to carry made at a scientific level. Actually, few institutions develop criteria to determine which vitamins and minerals should be included and the dose range for each. Thus, it is not uncommon, particularly for unit-dose liquid preparations, for the product to change based on what the wholesaler for the institution carries from time to time. One month the product may contain only a handful of vitamins; the next month the product may be more appropriate. One liquid multivitamin preparation contained no vitamin E, folic acid, or biotin, while the ULs for vitamin A and niacin were exceeded. From a nutrition support perspective, it is best to use liquid dosage forms that contain a defined set of vitamins and minerals in the most bioavailable chemical form with the least likelihood of interaction among ingredients. Solid dosage form products do not always meet label claims for content or disintegratlon.P Only two thirds of multivitamin products met product quality criteria, with the failed products containing insufficient or inordinate
SECTION IV • Principles of Enteral Nutrition
levels of ~-carotene, vitamin A, folic acid, and niacin disintegrating poorly.P One multivitarnin-rnultirnineral product containing more than 500 times the labeled selenium content was identified in a case of toxicity.P" Many clinicians may be unaware of problems related to product quality of folic acid-eontaining supplements.w'" Even with commercially available renal multivitamin products used for patients receiving hemodialysis, there could be significant variability in the ability of the solid dosage form to disintegrate." The long-term use of multivitamins may not be innocuous.l?' A multivitaminmultimineral product was the probable cause of hepatitis in a recently reported case, although the causative ingredient could not be determined, given additional non-nutrient ingredients. lOS
Ascorbic Acid Ascorbic acid functionally serves as an antioxidant in aqueous environments and as a cofactor for several enzymes involved in carnitine, neurotransmitter, and collagen synthesis/" This is an ingredient that is always ready to give up an electron, especially in the presence of a transition metal (e.g., copper or iron), and increase oxidative reactivity. The complex system of absorption and transport of ascorbic acid into various tissues remains incompletely understood. However, gastrointestinal absorption is a saturable process, with less than 90% absorbed at doses greater than 200 mg and decreasing significantly further with higher doses. In fact, plasma steady-state concentrations increase little at doses greater than 200 mg/day, although this has not been evaluated specifically in patients requiring nutrition support. There are insufficient data in chronic disease prevention on which to base the RDA. The current RDA in the United States is set as 90 mg for men, 75 mg for women, and an additional 35 rng for smokers." The 2000 mg UL includes total daily intake from food sources as well as supplementation and is based on gastrointestinal side effects. At higher doses, vitamin C has the potential to cause significant gastrointestinal complaints (e.g., nausea, abdominal cramps, bloating, flatulence, and diarrhea), probably related to the osmotic effect of the remaining vitamin in the lumen after the absorption has been saturated. In addition, patients with glucose-6-phosphate dehydrogenase deficiency may be at risk for increased oxidant stress and potential hemolysis if they are given high daily doses of vitamin C. The effect of increasing oxalate excretion, as a by-product of ascorbic acid degradation, may be important in patients with renal impairment. High doses should be avoided in patients with cancer. 106 About 15% of vitamin C products did not meet quality standards either for content or disintegration, although a more recent evaluation found that all products met label clairns.t"
Vitamin E Although often considered as an antioxidant, protecting membrane lipids from peroxidation, vitamin E exhibits
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additional intracellular activity of clinical importance. 67.107 The data for vitamin E are not yet adequate to set the RDA based on disease risk reduction or effects on immunity. The term vitamin E can represent any of the tocopherols or tocotrienols, although most attention has been focused on a-tocopherol. The current RDA in the United States is set at 15 mg of a-tocopherol, defined as that available from the natural isomer, RRR-a.-tocopherol, and the three other, synthetic, 2-R stereoisomers of atocopherol. The contributions of ~-, "t, or Stocopherot or the tocotrienols are not considered. In the United States the UL is set at 1000 mg/day from all a-tocopherol sources and in the United Kingdom at 800 mg/day. Although the international unit is no longer recognized as a dosing unit for vitamin E, it is often still found on labeling, and conversion to a milligram dose is required for comparison with the RDA. Besides confusion about the use of international units, it is often unclear which isomeres) is present in a dietary supplement product, but all-racemic a-tocopherol is used most often. The allracemic a-tocopherol, often still incorrectly referred to as d/-a-tocopherol, is a mixture of eight isomers, only one of which is RRR-a-tocopheroi. The tocopherols are most often included as the acetate or succinate salts in dietary supplements to prevent oxidation and extend shelf life. For a dose of all-racemic-a.- tocopherol acetate (or succinate) expressed in international units, divide the value by 2.2 to obtain the dose in milligrams of a-tocopherol. For a dose of RRR-a.-tocopherol acetate (or succinate) expressed in international units divide the value by 1.5 to obtain the dose in milligrams of a-tocopherol. The bioavailability of vitamin E depends on the form used and the fat content of the food matrix it is consumed with. Doses above the DRI can increase the risk of adverse effects. These include reducing the circulating levels of y-tocopherol, considered valuable to the tissues. An anticoagulant effect, thrombocytopenia, hemorrhagic stroke, increased respiratory infection severity, and gynecomastia have been reported. The vitamin E contents of products may not meet the label claim, with some being as low as 41% and others as high as 157%, and are likely to vary from lot to lot of the same prodUCt. 92 About 15% of vitamin E products do not meet criteria for a quality product.'" The best recommendation is to use a product that contains RRR-a-tocopherol with y-tocopherol as active ingredients. However, the doses recommended will depend on those found in clinical trials for uses beyond preventing deficiency. ~-Carotene
The most common form used in dietary supplements, all-trans-/3-carotene, is only one of many isomers of !3-carotene. This carotenoid is one of several hundred others with possible health implications. Numerous carotenoids are found in the diet and are likely to have health benefits, but no specific benefit has been shown for all-trans-/3-carotene alone as a dietary supplement. The evidence did not allow for an establishment of a DRI for /3-carotene beyond its pro-vitamin A activity." It is not clear why no other isomer (e.g., 9-cis-/3-carotene) has
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been evaluated. Most multi-ingredient supplements rarely contain more than 2 to 5 mg of Ikarotene per dose. In comparison, dietary intakes of 3 to 6 mg daily are considered adequate, although the bioavailability from a pharmaceutical dosage form can be significantly greater than that from foods." Although the Institute of Medicine chose to set no dosing standards, the United Kingdom has set a UL of 7 mg daily. The dose in dietary supplements is often given as a percentage of the vitamin A dose, requiring conversion. Certainly at doses greater than 20 mg daily, all-trans-Ikarotene increases the risk for lung and prostate cancer. It may also decrease the bioavailability of other carotenoids consumed in the diet. IOB Moderate alcohol intake may increase the risk of Ikarotene toxicity, which depends in part on the dosage form.I09 [3-Carotene is not teratogenic and does not contribute to osteoporosis, factors that complicate dosing of vitamin A.IIO
Calcium Calcium plays a structural role in bones and teeth, as well as roles in vascular, neuromuscular, and glandular function." It can be absorbed by both active and passive diffusion; the latter is more important at high doses as seen with dietary supplements. Bioavailability from dietary sources varies with the food content and matrix, but bioavailability from supplements depends on disintegration and solubility. Bioavailability is estimated to be 25% to 35% with the best efficiency from single doses of 500 mg of elemental calcium or less. The AI level is set at 1000 mg for adults up to 50 years of age and 1200 mg for those 51 years of age and older/" Side effects described include the potential for hypercalcemia, nephrolithiasis, and reduced absorption of other minerals (e.g., iron, magnesium, phosphorus, and zinc). Lead content continues to be an issue for those taking calcium supplements chronically.'!' It is best to avoid products whose source of calcium is bone meal, dolomite, or oyster shells because of the potential for contamination with lead, arsenic, and mercury. Calcium carbonate from natural sources also tends to be much more expensive. Given the presence of calcium, lead contaminants are less likely to be absorbed. About 90% of calcium products evaluated met quality criteria, although several products that did not meet label claims for content were labeled as meeting USP standards." Most multi-ingredient products do not contain substantial doses of calcium, because of the tablet size limitations and the interaction potential, which means that patients who rely on nutrient supplements can have inadequate intakes.!"
Herbals Herbal medicine resources that more fully describe safety and efficacy for many products are available and should be consulted for further information.49,72.87.113,114 What follows is a brief overview of the more common herbal medicines. This section will need modification as data continue to be generated and evaluated. Also included is a brief list of herbal ingredients found in dietary supplements whose risks outweigh benefits based on
•
Some of the Dietary Supplement Ingredients for Which Risks Outweigh Benefit
Ingredient
Potential Toxicity
Blue-green algae Blue cohosh Calamus Chaparral Coltsfoot
Hepatotoxic, neurotoxic Hypertension, cardiotoxic Carcinogenic, nephrotoxic Hepatotoxic Hepatic veno-occlusive disease, carcinogenic Hepatic veno-occlusive disease, carcinogenic Anticoagulant, carcinogenic Coma, respiratory depression
Comfrey Dong quai "thydroxybutyrate (GHB)*, "tbutyrolactone (GBL), butanediol Germander Germanium Lobelia Ma huang (ephedra) Pennyroyal Sassafras
Hepatotoxic Nephrotoxic Hepatotoxic, coma Cardiotoxic, hepatotoxic Neurotoxic, multiorgan dysfunction Hepatocarcinogenic, genotoxic
*Considereda controlled substance by the DrugEnforcementAgency.
current data (Table 21-3). The classification of herbal substances to avoid also changes as new data emerge.
Gingko
Ginkgo (Ginkgo biloba) contains more than 40 identified constituents, including terpene lactones (e.g., ginkolides and bilobalide) and flavonoids. Together they contribute to antiplatelet vasodilatory and free radical scavenging activity to improve microcirculatory flow. As a result ginkgo has been used for memory impairment, dementia, tinnitus, and intermittent claudication.P-" Numerous studies have been performed, and results have been published. At the present time there is no compelling evidence that ginkgo enhances memory or improves tinnitus, but it may increase walking distance in claudication." Although a delay in the clinical deterioration in dementia of the Alzheimer's type has been suggested, a large, well-powered trial will be needed to confirm this effect. The effect of purported improvements in blood flow on wound healing or nutrient delivery to tissues has not been studied except for in patients with chronic ulcers." The benefit is probably product specific, with suggested doses of 40 to 80 mg three times daily of a product containing the standardized leaf extract EGb-761 or LI-1370. Bioavailability is not affected by food intake.f Reported side effects are generally mild and have included headache, dizziness, palpitations, allergic skin reaction, and gastrointestinal symptorns.!" As expected, it may increase the effect of antiplatelet and anticoagulant medications, and significant bleeding episodes have been reported." It should be avoided by those with seizure disorders or poorly controlled hypertension.P Although about 75% of products passed quality control criteria in an earlier evaluation, only 22% (two of nine brands) contained adequate levels of expected marker compounds." It should be noted that there are 16 different methods of analysis currently being evaluated."
SECTION IV • Principles of Enteral Nutrition
St. John's Wort St. John's wort (Hypericum perforatum) contains a num-
ber of naphthodianthrones (hypericins), phloroglucinols (hyperforins), and f1avonoids, among other ingredients. The, as yet, unidentified active ingredient(s) probably contribute to inhibition of central serotonin, norepinephrine, and dopamine reuptake. St. John's wort is used for short-term management of mild depression, a benefit which seems to be supported by the literature that equates the herbal with low-dose antidepressant medication." The suggested dose is 300 mg three times daily (or 450 mg twice daily) of a product containing a flower extract standardized to 4% to 5% hyperforin and/or 0.3% dianthrones (total hypericins). Although it is reasonably well tolerated, reported adverse effects from St. John's wort include headache, dizziness, fatigue, dry mouth, gastrointestinal complaints (nausea, vomiting, constipation, diarrhea, abdominal bloating, and pain), hypomania, sexual dysfunction, allergic skin reactions, and photosensitivity.49,113,114 Additionally, a constituent of St. John's wort is a very strong inducer of the enzymes cytochrome P450 3M and P-glycoprotein. Numerous clinically relevant drug interactions have been documented that result in decreased drug concentrations (e.g., cyclosporine, digoxin, oral contraceptives, protease inhibitors, tacrolimus, and warfarin). I 14 At least one third of tested products failed to meet label claims for content or were contaminated with cadmium well above the acceptable limit.44,80,115 A survey of patients using St. John's wort revealed that although 84% experienced subjective improvement in their symptoms, 47% experienced side effects resulting in some discontinuing therapy and one admission to the emergency department. 116 Adverse reactions occurred in those concomitantly using other serotonergic drugs and sympathomimetics or consuming tyramine-rich foods. Until recently, when one official method was selected, there were about 22 methods described for analyzing St. John's wort.58
Garlic Garlic (Allium sativum) contains numerous lipophilic and hydrophilic sulfur-eontaining compounds derived after the conversion of a natural component, alliin, to allicin under the enzymatic activity of allinase. The compounds from fresh garlic are active in lipid reduction and inhibition of platelet aggregation. In the United States, garlic is generally recognized as safe for its use as a food or food additive. Not surprisingly garlic supplements have been used in hyperlipidemia, mild hypertension and even in cancer prevention, among other uses. Many studies of garlic and its preparations have been published.F Most dietary supplement trials used 600 to 900 mg/day of a concentrated, freeze-dried garlic powder standardized to 0.6% allicin yield. There appears to be only limited clinical benefit from garlic supplements at this time, however.l-!'? One factor not taken into account when studies on the efficacy of garlic supplements were evaluated is the formulation used in the study. J 18--120 Aside from being derived from freeze-dried fresh garlic, the product would have to be enteric-eoated
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to protect it from gastric acid."! A dietary supplement would also have to be able to provide a significant amount of allicin to generate a therapeutic benefit, and it is unlikely that most dO.1I8,119 A large majority of garlic supplements evaluated had virtually no release of allicin. 118,119 Garlic preparations made from extracts or oil macerates or odorless products may be devoid of the pharmacologic actions of fresh garlic. Dose-related side effects associated with garlic, both the food and the supplement, include heartburn, nausea, vomiting, diarrhea, diaphoresis, lightheadedness, odoriferous breath and skin, hematoma, and hypotension.s'" Contact dermatitis has been reported, as have additive effects on anti platelet and anticoagulant medication. There is an increased risk of bleeding in patients undergoing surgery. Clearly a poorly formulated product will not deliver active ingredients, which creates a bias in determining any potential benefit. The allicin yield varies tremendously from product to product.'"
Ginseng Ginseng (Panax ginseng [Asian] or Panax quinquefolius
[American]) contains a large number of ginsenosides that vary with the species, growing conditions, timing of harvest, and postcultivation processing. These compounds found in the dried roots may cause central nervous system stimulation or suppression and have anti-inflammatory, antioxidant, and immunomodulatory properties. Ginseng is used as a panacea, but evidence from sound clinical trials does not support its use as a dietary supplement for any therapeutic indication, even when an extract standardized to 4% ginsenosides is used. 13,72,87 Reports of adverse effects from ginseng have included headache, insomnia, visual disturbances, hypotension and hypertension, nausea, diarrhea, mastalgia, vaginal bleeding in postmenopausal women, and allergic skin reactions." Hypoglycemia may occur with use of the American ginseng. About 50% to 60% of ginseng products do not meet quality criteria including label content claims, and the variability in marker compounds can be tremendous. 80,122 Contamination with pesticides and lead continues to hamper the quality of many of the products available."
Echinacetl Echinacea (Echinacea purpurea, Echinacea pallida, Echinacea angustifolia) contains numerous polysaccha-
rides, alkylamides, and caffeic acid esters among other constituents with none yet being described as the active ingredient(s) responsible for immunomodulation. The plant species are not interchangeable. Individual content and concentration vary between species and plant parts.I 13 A polysaccharide from E purpurea may increase cytokine production from macrophages in oitro." It has been used to prevent and treat upper respiratory infection. The data are currently insufficient to support its use in prevention, and the modest benefits it may offer in treatment require further confirmatlon.F' The otherwise unremarkable safety profile includes possible fatigue, dizziness, headache, gastrointestinal disturbances including a change in taste
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perception, allergic skin reactions, and rarely anaphylaxis. It is suggested that its use be limited to 2 to 8 weeks because of the potential for immunosuppression and that individuals immunosuppressed by drug or disease avoid its use altogether. Just over one half of U.S. products evaluated met the criteria for a quality product. Products failed because of content not meeting label claims, microbial contamination, and inappropriate plant or plant parts used."
Saw Palmetto
Saw palmetto or sabal fruit (Serenoa repens or Sabol serrulata) contains fatty acids and sterols within its berries that can inhibit the in vitro activity of 5-u-reductase. This led to its use for management of benign prostatic hyperplasia. The available data suggest a benefit in reducing nocturia and improving urinary flow similar to that of the prescription drug finasteride, without changing prostate size or serum prostate-specific antigen levels.87.114 Products used in trials lasting 3 to 6 months were given at a dose of 320 mg/day of a product standardized to 70% to 95% fatty acids of a liposterolic extract.!" Headache, insomnia, hypertension, gastrointestinal complaints (anorexia, nausea, vomiting, diarrhea, and constipation), estrogenic effects, decreased libido, and cholestatic hepatitis have been reported with its use. About 60% of products studied met criteria for a quality product." Nine analytical methods have been looked at.58
Other Compounds Glucosamine and Chondroitin
Glucosamine with or without chondroitin is used for joint complaints, especially pain from osteoarthritis. Glucosamine and chondroitin each provide substrate used to synthesize cartilage. Several studies have been conducted using dosing regimens of glucosamine 500 mg three times a day and chondroitin 400 to 1200 mg daily. Studies performed in Europe suggest a benefit from glucosamine, and some limited benefit from chondroitin in osteoarthritiS. 13,113.124,125 However, in a meta-analysis of effectiveness of the combination for use in osteoarthritis, formulation of the products involved was not included as a criterion for analysis." This oversight occurs despite reports of many If.S. products not meeting label claims for content and having poor bioavailability.!" Just over one half of chondroitin products (some with glucosamine) failed to meet quality standards." Glucosamine may increase blood glucose levels although this effect has not been reported with oral dosage forms. Glucosamine and chondroitin can both cause gastrointestinal (nausea and diarrhea) complaints. Combination products may also include manganese, although at doses above the UL. Patients with an elevated prostate-specific antigen level or prostate cancer should avoid the use of chondroitin. Furthermore, because animals are the source of chondroitin, consideration should be given to transmission of infectious agents. Currently eight analytical methods are being reviewed for glucosamine and seven for chondroitin."
Melatonin
Melatonin is an endogenous hormone. As a dietary supplement it has been used to promote sleep, among other uses. Although melatonin may have no effect on sleep efficiency in elderly subjects with normal sleep patterns, it may improve sleep in those with insomnia at doses of 0.1 to 0.3 mg before bedtime based on results from several small trials. 1l3,127 It has the potential to cause daytime drowsiness, infertility, hypothermia, retinal damage, hypertension, migraine headaches, and depression. Melatonin may interfere with hormone replacement therapy and should be avoided in patients with depression or immunosuppression. Synthetic products are preferred to those of animal origin. A number of products failed to meet both disintegration and dissolution criteria; most of these were products with a high ratio of excipient to active ingredient.P'
Coenzyme Q
Coenzyme Q (or coenzyme QIO or ubiquinone) is a mitochondrial enzyme involved in electron transport and ATP generation. It can be found in the diet but probably contributes less to coenzyme Q status than does endogenous synthesis. Synthesis requires adequate tyrosine, methionine, and acetyl-coenzyme A. Its antioxidant function accounts for its widespread use as a dietary supplement. It has been used for cardiac disease, Parkinson disease, HIV infection, and cancer. Dailydoses of 50 to 200 mg have been studied with a possible benefit reported in heart failure." Less benefit was realized in well-designed studies, but further study in rigorous trials may be justified.13,1l3 Consideration may need to be given to assessing the likely benefit based on each subject's ubiquinone status. Besides complaints of anorexia, nausea, and vomiting, it has been reported to cause headache, dizziness, fatigue, skin reactions, thrombocytopenia, and a decrease in the effect of warfarin, possibly related to a structure that is similar to that of menaquinone. Most products tested met in vitro quality criteria, although because of difficulty with bioavailability, they should be further evaluated in vivo. 80
S-Adenosylmethionine
S-Adenosylmethionine (SAMe) normally acts as a methyl donor in methyl transferase reactions. As a dietary supplement it has been used for osteoarthritis and for depression at doses of 200 up to 1600 mg/day. It has also been used for cholestasis of pregnancy and alcoholic cirrhosis. Its use in osteoarthritis and depression is based on a number of poorly designed studies including some using an intravenous preparation not available in the United States.'!" A review of more than 100studies, many with small numbers of patients and of variable quality, revealed some limited benefit from SAMe over placebo for depression and for osteoarthritis.P' This finding supports further systematic evaluation of the ingredient in well-designed studies. About one half of products tested either did not meet the label claim for content or were not enteric-coated." There are currently six methods of
SECTION IV • Principles of Enteral Nutrition
analysis being evaluated for SAMe. 58 Adverse effects noted include headache, anorexia, nausea, vomiting, diarrhea, flatulence, and hypomania. Use with antidepressant medications should be avoided.
Creatine
Creatine is found in foods from animal sources but is also synthesized endogenously from arginine, glycine, and methionine. Most is stored in skeletal muscle. As creatine phosphate, it is a high-energy phosphate source during anaerobic metabolism. As a dietary supplement it has been used to improve muscle strength, performance, and recovery during exercise. Studies in exercise continue to be equivocal, with the best evidence seen for conditioned athletes in short-duration, high-intensity activity.l" There may be a possible benefit for patients with neuromuscular disorders. Maintenance doses of 2 to 5 g daily have been used. Reported side effects have included diarrhea, cramps, and dehydration. Creatine should be used cautiously, if at all, in patients with poor hepatic or renal function, and it contributes to serum creatinine levels. About 15% of creatine products failed to meet quality product criteria with the predominant problem being contamination with dicyandiamide.t"
IMPLICATIONS FOR NUTRITION SUPPORT PRACTICE Adequate appreciation of the issues addressed in this chapter can be valuable to nutrition support clinicians in their responsibilities related to dietary supplements. These may vary depending on practice site, formulary involvement, and counseling privileges. A number of issues need to be addressed in the evaluation of dietary supplements and certainly before they are made available for use.!" It can be valuable to proactively establish specific criteria for evaluating dietary supplements. Any dietary supplement already on the formulary or being considered for addition should be reviewed and approved based on those criteria. Some group purchasing organizations have added dietary supplements to their contracts for health system members. Patient demand and availability for purchase does not nullify the obligation of knowledgeable clinicians to be part of the decision-making process as with any other therapy considered for addition to a formulary. Some health systems have decided that supplements with unsubstantiated claims cannot be administered to their patients.P' At one hospital, an initial pharmacy and therapeutics committee policy allowed patients to continue taking their dietary supplements after admission to the hospital if so ordered by the physician, with the patient's family being responsible for purchase and administration. However, upon recognizing that the potential risks outweighed the potential benefits, a new policy disallowed the use of dietary supplements within the health system. 132 The reversal was based on concerns related to safety, efficacy, and ethics, as well as liability. The Joint Commission on Accreditation of Healthcare Organizations expects health care systems to apply
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medication use standards to dietary supplements such as herbals, treating them like any other drug. The institution is responsible for any dietary supplements brought in by the patient or their outside caregivers. The institutional committee charged with oversight of therapeutic products introduced into practice (e.g., formulary committee or pharmacy and therapeutics committee) should have a specific policy and procedure for dietary supplements. The policy would define the products, with the definition ideally being parallel to the legal definition used by the FDA, as well as state that they need to go through a review and approval process before use within an institution or health system as do all other medications intended for patient use. The procedures could include a review of all dietary supplement products (nutrients, herbals, or others) already being used within the institution, as well as requests for formulary review of any additional products. Generally, before inclusion on the formulary, substantial proof of safety should exist, along with a reasonable expectation of efficacy based on product- and manufacturer-specific data. For supplements selected with a therapeutic expectation in mind, only the specific product studied in a clinical trial, with confirmed outcome data, would be considered. Products are not interchangeable. Further, product quality standards need to be met for all nutrient, herbal, or other dietary supplements accepted onto the formulary. Only those dietary supplements that meet current USPspecifications as assured by the manufacturer or an independent quality assessment program in writing or product labeling would be considered. Specific criteria should be set for nutrient supplements in accordance with accepted dosing standards. When available, a nutrient product labeled with Nutrition Facts is likely to have undergone more rigorous quality control than one labeled with Supplement Facts. Dietary supplement ingredients or products containing ingredients that have not been well characterized or have no validated methods of analysis cannot be considered until more data become available. The issues about administering dietary supplements for which there are few data on efficacy, safety, or product quality, particularly for patients bringing in their own supply, can be a dangerous practice because the institution takes on significant liability. The widespread use of dietary supplements within a health care setting without adequate safeguards and in most cases without the informed consent of the patient poses liability concerns. The organization's lawyers may need to be consulted about the potentialliability to a specific institution or health system for allowing the use of dietary supplements during patient care without being able to ensure safety, efficacy, or product quality. Products accepted onto the formulary should be handled like any other new therapeutic agent in terms of prescribing, order evaluation, dispensing, administration, and monitoring. A survey of hospitals indicated that although 70% allowed some use of dietary supplements, some discouraged use or indicated rare use. 133 Of those allowing dietary supplement use, 79% allowed patients' own supply to be used, with some institutions even allowing
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patient self-administration. Only five institutions indicated that they had requirements for product quality and integrity, but even in those settings the criteria were limited to checking for expiration date, clear labeling, and no obvious degradation. In a survey specific for herbal supplements, 76% of hospitals stated that they had policies and procedures for herbals, but only 4% reported having them on their formulary.P' One quarter of those without policies allowed patients use of their own supply while in the hospital. For institutions with policies allowing use of herbals, a physician's order and a pharmacist's review of the product label was the extent of the procedure for most. Amazingly, only one hospital required institutional review board protocol and patient consent before allowing use of herbals. In that instance, the formulary process required review of safety and efficacy data with subsequent approval by the pharmacy and therapeutics committee. Advice provided to patients should be based on the available evidence. If the benefit is unknown or is outweighed by the risks from the use of a dietary supplement product, this should be communicated to the patient and the product should be avoided. In the absence of specific data describing safe use, dietary supplements should especially be avoided in childhood, pregnancy, lactation, and surgery. New onset of any complications thought to be associated with a nutrition support regimen may need to be further evaluated based on the patient's use of dietary supplements. Reviews designed to summarize counseling information forspecific patients (e.g., those with cancer) are becoming commonplace but are still limited by the suitability of the evidence.P" Guidelines for weaning or discontinuing herbal medicines during perioperative care are also available.F"
SUMMARY Although the widespread, indiscriminate use of dietary supplements may not be justified, there are clinical benefits of selected ingredients for specific indications using appropriate products when their benefits outweigh the risks. The nutrition support clinician can make use of available detailed, evidence-based resources to manage patients' use of dietary supplements. Appreciating the regulatory framework for these agents and understanding the data supporting individual products will go a long way to help sustain patients cared for by nutrition support clinicians. REFERENCES I. Bacon MM: Nurse Practitioners' Views and Knowledge of Herbal Medicine and Alternative Healing Methods [Dissertation] Lowell, MA, University of Lowell, 1997. 2. Murtaza M,Singh M, Dimitrov V, Soni A: Awareness of CAM among residents: A long way to go. Arch Intern Med 2001;161:1679-1680. 3. Chang ZG, Kennedy DT,Holdfod DA, Small RE: Pharmacists' knowledge and attitudes toward herbal medicine. Ann Pharmacother 2000;34:710-715. 4. Wetzel MS,Eisenberg OM, Kaptchuk TJ: Courses involving complementary and alternative medicine at U.S. medical schools. JAMA 1998;280:784-787.
5. Rowell OM, Kroll OJ: Complementary and alternative medicine education in United States pharmacy schools. Am J Pharm Educ 1998;62:412-419. 6. U.S. Congress: Dietary Supplement Health and Education Act of 1994. Pub Law No. 103-417, 108 Stat 4325. 25 October 1994. 7. National Center for Complementary and Alternative Medicine: What is CAM? Available at http://nccam.nih.gov/health, accessed 2002. 8. Berman BM, Bausell RB, Lee WL: Use and referral patterns for 22 complementary and alternative medical therapies by members of the American College of Rheumatology. Arch Intern Med 2002; 162:766-770. 9. Robbers JE, Tyler VA: Tyler's herbs of choice: The therapeutic use of phytomedicinals. Binghamton, NY, Haworth Press, 1999. 10. Havel RJ: Dietary supplement or drug? The case of cholestin. Am J Clin Nutr 1999;69:175-176. 11. Kessler RC, Davis RB, Foster OF, et al: Long-term trends in the use of complementary and alternative medical therapies in the United States. Ann Intern Med 2001;135:262-268. 12. Roe BE, Derby BM, Levy AS: Demographic, lifestyle, and information use characteristics of dietary supplement user segments. In Department of Health and Human Services: Report of the Commission on Dietary Supplement Labels, Washington, DC, 1997. 13. Mason P: Dietary supplements, 2nd ed. London, Pharmaceutical Press, 200I. 14. Balluz LS, Kieszak SM, Philen RM, Mulinare J: Vitamin and mineral supplement use in the United States: Results from the third National Health and Nutrition Examination Survey. Arch Fam Med 2000;9: 258-262. 15. Radimer KL, Subar AF, Thompson FE: Nonvitarnin, nonmineral dietary supplements: Issues and findings from NHANES Ill. J Am Diet Assoc 2000;100:447-454. 16. Stang J, Story MT, Harnack L, Neumark-Sztainer 0: Relationships between vitamin and mineral supplement use, dietary intake, and dietary adequacy among adolescents. J Am Diet Assoc 2000;100: 905-910. 17. Willet W, Sampson L, Bain C, et al: Vitamin supplement use among registered nurses. Am J Clin Nutr 1981;34:1121-1125. 18. Frank E, Bendich A, Denniston M: Use of vitamin-mineral supplements by female physicians in the United States. Am J Clin Nutr 2000;72:969-975. 19. Johnson JB: Pharmacists' health habits are disheartening. Am J Hosp Pharm 1990;47:429. 20. Harvard School of Public Health: 1989 Health Professionals Followup Study Newsletter. Boston, Harvard School of Public Health, 1989. 21. Ranelli PL, Dickerson RN, White KG: Use of vitamin and mineral supplements by pharmacy students. Am J Hosp Pharm 1993;50: 674-678. 22. Eisenberg OM, Davis RB, Ettner SL, et al: Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey. JAMA 1998;280:1569-1575. 23. Eisenberg C, Kessler RC, Foster C, et al: Unconventional medicine in the United States: Prevalence, costs, and patterns of use. N Engl J Med 1993;328:246-252. 24. Kaufman OW, KellyJP, Rosenberg L, et al: Recent patterns of medication use in the ambulatory adult population of the United States. JAMA 2002;287:337-344. 25. Lacy MK, Metcalf SA, Howard PA, et al: Vitamin supplementation and natural or herbal product utilization among ambulatory clinic patients at a university medical center. Pharmacotherapy 1999; 19:1204. 26. Klepser TB, Doucette WR, Horton MR, et al: Assessment of patient's perceptions and beliefs regarding herbal therapies. Pharmacotherapy 2000;20:83-87. 27. Kristoffersen SS, Atkin PA, Shenfield GM: Uptake of alternative medicine. Lancet 1996;347:972. 28. Cala S, Crimson ML, Baumgartner J: A survey of herbal use in children with attention-
SECTION IV • Principles of Enteral Nutrition 31. Kassler WJ, Blanc P, Greenblatt R: The use of medicinal herbs by human immunodeficiency virus-infected patients. Arch Intern Med 1991;151:2281-2288. 32. Fairfield KM, Eisenberg OM, Davis RB,et al: Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIV-infected patients. Arch Intern Med 1998;158: 2257-2264. 33. Smith SR, Boyd EL, Kirking OM: Nonprescription and alternative medication use by individuals with HIVdisease. Ann Pharmacother 1999:33:294-300. 34. Pharand C, Ackman ML, Jackevicius CA, et al: Use of OTC and herbal products in patients with cardiovascular disease. Ann Pharmacother 2003;37:899-904. 35. Anderson DL, Shane-McWhorter L, Crouch Bl, Anderson SJ: Prevalence and patterns of alternative medication use in a university hospital outpatient clinic serving rheumatology and geriatric patients. Pharmacotherapy 2000;20:958-966. 36. LyJ, Percy L,Dhanani S: Use of dietary supplements and their interactions with prescription drugs in the elderly. Am J Health-Syst Pharm 2002;59:1759-1762. 37. Gulla J, Singer AJ: Use of alternative therapies among emergency department patients. Ann Emerg Med 2000;35:226-228. 38. Tsen LC, Segal S, Pothier M, Bader AM: Alternative medicine use in presurgical patients. Anesthesiology 2000;57:708-714. 39. Meyer TA, Baisden CE, Roberson CR, et al: Survey of preoperative patients' use of herbal products and other selected dietary supplements. Hosp Pharm 2002;37:1301-1306. 40. Leady MA, Wolsefer JS, Sweet BV: Survey of alternative supplement use within a hospitalized population. Hosp Pharm 2002;37: 1295-1300. 41. Chhay C, Rynes R, Kajimura-Beck M, Broekemeier R: Alternative medicine use in a community hospital. Am J Health-Syst Pharm 2002;59:2452-2453. 42. Kirk SFL, Cade JE, Barrett JH, Conner M: Diet and lifestyle characteristics associated with dietary supplement use in women. Publ Health Nutr 1999;2:69-73. 43. Drazen JM: Inappropriate advertising of dietary supplements. N Engl J Med 2003;348:777-778. 44. Glisson KJ, Rogers HE, Abourashed EA, et al: Clinic at the health food store? Employee recommendations and product analysis. Pharmacotherapy 2003;23:64-72. 45. Harris Poll: Widespread ignorance of regulation and labeling of vitamins, minerals and food supplements. Harris Interactive Health Care News Dec 23, 2002. 46. Office of the Inspector General: Dietary supplement labels: An assessment. Available at http://www.hhs.gov/oig/oei/reports/oel01-DI-D012I.pdf, accessed 2003. 47. Marcus DM, Grollman AP: Botanical medicines-The need for new regulations. N Engl J Med 2002;347:2073-2076. 48. Fontanarosa PB, Rennie D, DeAngelis CD: The need for regulation of dietary supplements-Lessons from ephedra. JAMA 2003;289: 1568-1570. 49. Barnes J, Anderson LA, Phillipson JD (eds): Herbal Medicines, 2nd ed. London, Pharmaceutical Press, 2002. 50. Food Standards Agency: New FSAadvice on safety of high doses of vitamins and minerals. Available at www.foodstandards.gov.uk/ news/pressreleases/vitsandminspress, accessed 2003. 51. Therapeutic Goods Administration: Pan Pharmaceuticals LimitedRegulatory action and product recall information. Available at www.health.gov.au/tga/recalls/pan.htm. accessed 2003. 52. Larimore WL, O'Mathuna DP: Quality assessment programs for dietary supplements. Ann Pharmacother 2003;37:893-899. 53. U.S. Food and Drug Administration, Department of Health and Human Services: Proposed Rule: Current good manufacturing practice in manufacturing, packing, or holding dietary ingredients and dietary supplements. Fed Register 2003;68:12157-12206. 54. United States Pharmacopoeial Convention: United States Pharmacopoeia/National Formulary, Edition 27/22. Rockville, MD, United States Pharmacopoeial Convention, Inc, 2004. 55. U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition. Available at http://vm.cfsan.fda.gov, accessed 2003. 56. Institute of Medicine, Food and Nutrition Board: Proposed framework for evaluating the safety of dietary supplements. Available at http://www.nap.edu/catalog/l0456.html, accessed 2002.
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57. National Institutes of Health, Office of Dietary Supplements. Available at http://dietary-supplements.info.nih.gov, accessed 2003. 58. AOAC International (Association of Analytical Communities): Dietary supplement community. Available at http://www.aoac.org, accessed 2003. 59. American Dietetic Association: Position of the American Dietetic Association: Food fortification and dietary supplements. J Am Diet Assoc 2001;101:115-125. 60. American Dietetic Association/American Pharmaceutical Association: Special report: A healthcare professional's guide to evaluating dietary supplements. Available at http://www.aphanet.org/ education/specialrptslDietarySupplements.pdf, accessed 2000. 61. Thomson C, Diekman C, Fragakis AS, et al: Guidelines regarding the recommendation and sale of dietary supplements. J Am Diet Assoc 2002;102:1158-1164. 62. Nester TM, Hale LS: Effectiveness of a pharmacist-acquired medication history in promoting patient safety. Am J Health-Syst Pharm 2002;59:2221-2225. 63. Davis KM, Clark D, Koch KE: Physician marketing of nutritional supplements. JAMA1998;280:967-968. 64. Cohen MH, Eisenberg DM: Potential physician malpractice liability associated with complementary and integrative medical therapies. Ann Intern Med 2002;136:596-603. 65. Institute of Medicine, Food and Nutrition Board: Dietary reference intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC, National Academy Press, 1997. 66. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC, National Academy Press, 1998. 67. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC, National Academy Press, 2000. 68. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC, National Academy Press, 2001. 69. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes: Macronutrients and Energy. Washington, DC, National Academy Press, 2002. 70. Expert Group on Vitamins and Minerals: Safe upper levels for vitamins and minerals. Available at http://www.foodstandards.gov.uk/ multimedia/pdfs/vitmin2003.pdf, accessed May 2003. 71. European Scientific Cooperative on Phytotherapy (ESCOP): Monographs on the Medicinal Uses of Plant Drugs. Exeter, UK, ESCOP, 1996-1999. 72. Blumenthal M, Goldberg A, Brinckmann J (eds). Herbal medicine: Expanded Commission E Monographs. Newton, MA, American Botanical Council Integrative Medicine Communications, 2000. 73. Jellin JM, Batz F, Hitchens K: Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. Stockton, CA, Therapeutic Research Faculty, 2002. 74. NIHConference Proceedings: Bioavailability of nutrients and other bioactive components from dietary supplements. J Nutr 2001;131: 13295-14OOS. 75. Aungst BJ: Intestinal permeability enhancers. J Pharm Sci 2000;89: 429-442. 76. The Heart Outcomes Prevention Evaluation Study Investigators: Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342:154-160. 77. Berthold HK, Sud hop T, von Bergmann K: Effect of a garlic oil preparation on serum lipoproteins and cholesterol metabolism: A randomized control trial. JAMA 1998;279:1900-1902. 78. McAlindon TE, Lavalley MP, Gulin JP, Felson DT:Glucosamine and chondroitin for treatment of osteoarthritis: A systematic quality assessment and meta-analysis. JAMA 2000;283:1469-1475. 79. United States Pharmacopeia: Dietary Supplement Verification Program. Available at http://www.usp-
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82. Steen SN, Coleman E: Selected ergogenic aids used by athletes. Nutr Clin Pract 1999;14:287-295. 83. Kronenberg F, Fugh-Berman A: Complementary and alternative medicine for menopausal symptoms: A review of randomized, controlled trials. Ann Intern Med 2002;137:805--813. 84. Fugh-Berrnan A: Herb-drug interactions. Lancet 2000;355:134-138. 85. Izzo M, Ernst E: Interactions between herbal medicines and prescribed drugs. Drugs 2001;61:2163-2175. 86. Harkness R, Bratman S: Handbook of Drug-Herb and DrugSupplement Interactions. Philadelphia, Mosby, 2003. 87. Ernst E: The risk-benefit profile of commonly used herbal therapies. Ann Intern Med 2002;136:42-53. 88. Barnes J: Quality, efficacy and safety of complementary medicines: Fashions, facts and the future. Part II: Efficacy and safety. Br J Clin Pharmacol 2003;55:331-340. 89. Al-Achi A, Greenwood R, York L: Testing commercially available folic acid capsules. Am J Health-Syst Pharm 1998;55:1415-1416. 90. Hoag SW, Ramachandruni H, Shangraw RF: Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution. J Am Pharm Assoc 1997;37:397-400. 91. Stamatakis MK, Meyer-Stout PJ: Disintegration performance of renal multivitamin supplements. J Renal Nutr 1999;9:7~3. 92. Feiler AH, FIeshner NE, Koltz L: Analytical accuracy and reliability of commonly used nutritional supplements in prostate disease. J Urol 2002;168:150-154. 93. Baker DH: Cupric oxide should not be used as a copper supplement for either animals or humans. J Nutr 1999;129:2278-2279. 94. Office of the Inspector General: Adverse event reporting for dietary supplements: An inadequate safety valve. Available at http://www.hhs.gov/oig/oeilreports/a519.pdf, accessed April 2001. 95. Palmer M, Haller C, McKinney P, et al: Adverse events associated with dietary supplements: an observational study. Lancet 2003; 361:101-106. 96. Boullata JI, McDonnell PJ, Oliva CD: Anaphylactic reaction to a dietary supplement containing willow bark. Ann Pharmacother 2003;37:832-835. 97. National Toxicology Program. Available at http://ntp-server.niehs. nih.gov/htdocs/liason/factsheets/HerbMedFacts.pdf, accessed 2004. 98. United States General Accounting Office: Health products for seniors: Potential harm from "anti-aging" products. Available at http://www.gao.gov, accessed September 2001. 99. Matthews HB,Lucier GW,Fisher KD: Medicinal herbs in the United States: Research needs. Environ Health Perspect 1999;107:773-778. 100. Ter Riet G, Kessels AG, Knipschild PG: Randomized clinical trial of ascorbic acid in the treatment of pressure ulcers. J Clin EpidemioI1995;48:1453-1460. 101. Malone AM: Is supplemental zinc beneficial in wound healing? Am J Clin Dermatol 2001;50:17-20. 102. Lynch SM: Assessment of student pharmacists' knowledge concerning folic acid and prevention of birth defects demonstrates a need for further education. J Nutr 2002;132:439-442. 103. Clark RF, Strukle E, Willams SR, Manoguerra AS: Selenium poisoning from a nutritional supplement. JAMA 1996;275: 1087-1088. 104. Zhang SM,Giovannucci EL, Hunter OJ, et aI: Vitamin supplement use and the risk of non-Hodgkin's lymphoma among women and men. Am J EpidemioI2001;153:1056-1063. 105. Sleeper RB, Kennedy SM: Adverse reaction to a dietary supplement in an elderly patient. Ann Pharmacother 2003;37:83-86. 106. Weiger WA, Smith M, Boon H, et al: Advising patients who seek complementary and alternative medical therapies for cancer. Ann Intern Med 2002;137:889-903. 107. Chan AC: Vitamin E and atherosclerosis. J Nutr 1998;128: 1593-1596. 108. van den Berg H: Carotenoid interactions. Nutr Rev 1999;57:1-10. 109. Leo MA, Lieber CS: Alcohol, vitamin A, and Ikarotene: Adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 1999;69:1071-1085. 110. Michaelsson K,Lithell H, Vessby B, Melhus H: Serum retinol levels and the risk of fracture. N Engl J Med 2003;348:287-294.
111. Ross EA, Szabo NJ, Tebbett IR: Lead content of calcium supplements. JAMA 2000;284:1425-1429. 112. Ervin RB, Kennedy-Stephenson J: Mineral intakes of elderly adult supplement and non-supplement users in the third National Health and Nutrition Examination Survey. J Nutr 2002;132:3422-3427. 113. Rotblatt M, Ziment I: Evidence-Based Herbal Medicine. Philadelphia, Hanley & Belfus, 2002. 114. De Smet PAGM: Herbal remedies. N Engl J Med 2002;347: 2046-2056. 115. de los Reyes GC, Koda RT: Determining hyperforin and hypericin content in eight brands of St. John's wort. Am J Health-Syst Pharm 2002;59:545-547. 116. Beckman SE, Sommi RW, Switzer J: Consumer use of St. John's wort: Asurvey on effectiveness, safety, and tolerability. Pharmacotherapy 1999;19:1219. 117. Stevinson C, Pittler MH, Ernst E: Garlic for treating hypercholesterolemia: A meta-analysis of randomized clinical trials. Ann Intern Med 2000;133:420-429. 118. Lawson LD: Garlic for total cholesterol reduction. Ann Intern Med 2001;135:65-66. 119. Lawson LD,Wang ZJ, Papadimitriou 0: Allicin release under simulated gastrointestinal conditions from garlic powder tablets employed in clinical trials on serum cholesterol. Planta Med 2001;67:13-18. 120. Staba EJ, Lash L, Staba JE: A commentary on the effects of garlic extraction and formulation on product composition. J Nutr 2001;131:11185-1119S. 121. Krest I, Keusgen M: Quality of herbal remedies from Allium sativum: Differences between allinase from garlic powder and fresh garlic. Planta Med 1999;65:139-143. 122. Harkey MR, Henderson GL,Geshwin ME, et al: Variability in commercial ginseng products: An analysis of 25 preparations. Am J Clin Nutr 2001;73:1101-1106. 123. Barrett BP, Brown RL, Locken K, et al: Treatment of the common cold with unrefined echinacea: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002;137:939-946. 124. Reginster JY, Deroisy R, Rovati LC, et al: Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomized, placebo-controlled clinical trial. Lancet 2001;357:251-256. 125. Leeb BF, Schweitzer H, Montag K, Smolen JA: A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000;27:205-211. 126. Adebowale AO, Cox OS, Liang Z, Eddington NO: Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. J Am Nutraceut Assoc 2000;3:37-44. 127. Zhdanova IV, Wurtman RJ, Regan MM, et al: Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001;86: 4727-4730. 128. Hahm H, Kujawa J, Augsburger L: Comparison of melatonin products against USP's nutritional supplements standards and other criteria. J Am Pharm Assoc 1999;39:27-31. 129. Agency for Healthcare Research and Quality: S-Adenosyl-Lmethionine for treatment of depression, osteoarthritis, and liver disease. Evidence ReportlTechnology Assessment, Number 64. Available at http://www.ahrq.gov/clinic/evrptfiles.htm#same. accessed 2002. 130. Feldman EB: Creatine: A dietary supplement and ergogenic aid. Nutr Rev 1999;57:45-50. 131. Borum PR: Supplements: Questions to ask to reduce confusion. Am J Clin Nutr 2000;72(suppl):5385-540S. 132. Walker PC:Evolution of a policy disallowing the use of alternative therapies in a health system. Am J Health-Syst Pharm 2000; 57:1984-1990. 133. Anderson PO, Morris PO: Policies on the use of dietary supplements in teaching hospitals. Am J Health-Syst Pharm 2003;60: 90-91. 134. Ansani NT, Ciliberto NC, Freedy T: Hospital policies regarding herbal medicines. Am J Health-Syst Pharm 2003;60:367-370. 135. Ang-Lee MK, Moss J, Yuan CS: Herbal medicines and perioperative care. JAMA 2001;286:208-216.
Pre-, Pro-, and Synbiotics in Clinical Enteral Nutrition Stig Bengmark, MD, PhD
CHAPTER OUTLINE Introduction Modulation of the Gut Immune System Bioactive Prebiotics Increased Mucosal Growth Increased Insulin Sensitivity Prevention of Infection Provision of Antioxidants Improvement in Colitis Prevention and Healing of Peptic Ulcer Reduction of Diarrhea Probiotics Plus Prebiotics Equals Synbiotics Synbiotic Compositions One Lactic Acid Bacteria Strain/One Fiber Composition Four Lactic Acid Bacteria Strains/Four Fiber Composition Clinical Experience in Acute Diseases Acute Diarrhea Antibiotic-Associated Diarrhea Acute Pancreatitis Abdominal Surgery Liver Transplantation Clinical Experience in Chronic Diseases Human Immunodeficiency Virus Infections Inflammatory Bowel Disease Progressive Liver Disease Renal Failure Conclusion
INTRODUCTION Humans have two separate digestive systems, one based on their own upper digestive tract enzymes and another, much more complex and less understood, based on bacterial fermentation in the lower gastrointestinal (GI) tract. (See also Chapter 14 for a discussion on gut flora.)
The main substrates for bacterial fermentation are consumed fruit and vegetable fibers, which are indigestible by regular human digestive enzymes and thus reach the colon mainly undigested. In the colon, this extra energy, and perhaps more importantly, numerous substances including vitamins, antioxidants, coagulation factors, growth factors, and signal substances are released and made available to the body."? It is well known that the human body contains approximately 65,000 genes and less well known that the flora within the lower GI tract contain between 300,000 and 2 million genes," indicating not only the size but also the enormous complexity of the bacterial flora in the digestive system.
MODULATION OF THE GUT IMMUNE SYSTEM Lifestyle, physical exercise, control of stress, and eating habits all have profound effects on the immune system and the body's ability to resist disease. Several hundred thousand molecules are regularly released in the lower GI tract after microbial fermentation: short-ehain fatty acids (SCFAs) and other fatty acids, amino acids, peptides, polyamines, carbohydrates, vitamins, and antioxidants, compounds which, in addition to their nutritional effects, also exhibit strong immunomodulatory effects. However, the probiotic bacteria supplied as enteral supplements, the commensal flora, and the supplied prebiotic fibers have also direct and distinct immunomodulatory effects. It is sometimes forgotten that the majority of nutrients for the lower GI tract can only reach the mucosa from the intestinal lumen, because the colonic mucosa in particular has a limited ability to nourish itself from the blood. This explains why the need for nutrients by the mucosa can only be met through local fermentation of consumed plant fiber, the substrate for fermentation. Consumption of a variety of fresh, uncooked, plant foods is the best way to provide the molecules needed for optimal functioning of the body. It is regrettable that, for various reasons, such a demand many times cannot
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be met for the sickest patients. Even if industry-made enteral nutrition formulas have improved considerably in recent years, they are still far from adequate replacements for natural food. Difficulties in maintaining hygienic standards have made Western hospitals abandon the use of hospital-made formulas based on natural foods. It is especially regrettable that no controlled study comparing outcomes with industry- and hospital-made formulas is available in the world literature. As we know that fibers are crucial, attempts should always be made to supply as many fibers as possible depending on the clinical condition. It is recommended that a variety of types of fibers be supplied and, whenever possible, that the diet be supplemented with bioactive probiotic bacteria (see later).
BIOACTIVE PREBIOTICS The human digestive tract depends for its growth and function on a rich and regular supply of prebiotics. Human breast milk, in contrast to cow's milk, is very rich in fiber-like molecules. Apart from elephant milk, no other mammalian milk is known to contain as many molecules (such as oligosaccharides) as breast milk." The complex fucosylated oligosaccharides in human milk, which are structurally similar to immunomodulating cell surface glycoconiugates, are thought to protect breast-fed infants against infection and inflammation.! but they also serve as prebiotics to provide key nutrients to breast-fed infants and stimulate growth of the nonpathogenic health-supporting gut microflora. A large variety in the types of prebiotics supplied is important because the availability and content of various fibers restrict the number of synbiotic compounds produced. Among the many fibers available for use in clinical nutrition as prebiotic supplements are ~glucans (oat gum), pectin, resistant starch, glucomannan, algal fibers, and various oligosaccharide, among them inulin and fructo-oligosaccharides. (For further information, see references 6 to 8.) Over the last decade it has become clear that a group of nondigestible, but fermentable, oligosaccharides play an important nutritional role. 9,10 Plants such as artichoke, onions, garlic, banana, and soy and other beans are rich in these fibers. However, significant clinical effects are not limited to those containing oligosaccharides. Similar effects can be expected from a supply of various other prebiotics that have been less well investigated. Oligofructans such as inulin and phleins are difficult to ferment and only a few lactic acid bacteria (LAB) are able to do so. When the ability to ferment oligofructans was studied." only 16 of 712 different LAB were able to ferment phlein and only 8 could ferment inulin-type fiber. Only Lactobacillus plantarum and 3 other LAB species, Lactobacillus paracasei subsp. paracasei, Lactobacillus brevis, and Pediococcus pentosaceus, had the ability to ferment these quite resistant oligosaccharides. The clinical effect of supplying oligosaccharides thus depends to a large extent on whether these LAB happen
to be present in the colon of the receiver, which is not often the case. It seems advisable to supply such LAB concurrent with supplementation of oligosaccharides. The following paragraphs discuss some benefits of fiber in the diet.
Increased Mucosal Growth Fruit and vegetable fibers are known in most mammals to have a strong influence on intestinal function. Supplying fermentable fibers (beet pulp and oligofructose) to experimental animals for 6 weeks increased the 01 surface area by 28%, the mucosal mass by 37%, the mucosal weight by 35%, and the capacity for carriermediated glucose uptake by 95%.12 The human gut is known to have great plasticity, and treatment with fibers is likely to have a potentially large benefit in some patients such as those with short bowel syndrome.
Increased Insulin Sensitivity Insulin resistance is a significant characteristic of the metabolic syndrome. Increased intake of dietary fibers (celluloses, hemicelluloses, pectins, and starches), the main substrates for SCFA production, increases insulin sensitivity dramatically in humans.
Prevention of Infection Fiber is known to block receptors and prevent colonization by potentially pathogenic microbes. Mixing 2.5% of o-mannose into drinking water reduces significantly the colonization of newborn chicks with Salmonella.P and supplying fiber (glucans) to patients with severe trauma may significantly reduce the mortality rate in those with hospital-acquired infections."
Provision of Antioxidants Fibers such as oat are known to be strong antioxidants. Before the introduction of synthetic antioxidants, oatmeal was used because of its potent food preserving properties. Pectin isshown to be a strong antioxidant, but it is also an important mucosa protectant (pseudomucin) and a good carrier and protectant of flora during transport from the mouth to the large intestine. Resistant starch (amylose maize) is also a good vehicle for transportation of LAB through the acid- and bile acid-rich upper GI tract. Bifidobacterium species adhering to resistant starch granules show increased survival in the upper GI tract and a sixfold increase in content in feces. IS
Improvement in Colitis Fructo-oligosaccharides are known to increase the numbers of certain LAB, particularly Bifidobacterium species
SECTION IV • Principles of Enteral Nutrition
and to significantly decrease the number of Enterobacteriaceae in the intestine of healthy humans. Adding 10% of fructo-oligosaccharides into the diet of experimental animals provided both protective and therapeutic effects against sodium sulfate-induced colitis. 16 Giving patients with inflammatory bowel disease (IBD) supplements of 30 g of fructo-oligosaccharides per day increased significantly the amount of luminal SCFAs,16 and other fibers such as psyllium husk" and Plantago ovata seeds" have similar effects. A dramatic improvement in induced colitis is obtained when germinated barley, the aleurone and scutellum fraction of the grain, which is rich both in hemicellulose fibers and in glutamine-rich proteins, is supplied to experimental animals, an effect further attenuated by a combination with LAB.19
Prevention and Healing of Peptic Ulcer Bananas, when green and immature, are rich in pectin, cellulose, and phospholipids and were shown to have a strong protective effect against peptic ulcers. 20.21 This knowledge led us to test pectin alone and in combination with phospholipids in various animal models. 22.23 Pure pectin also provided a strong preventive effect against peptic ulcers, even greater than that observed when only the fruit was supplied.P The preventive and healing effects observed were seemingly not inferior to those of histamine H2 blockers, proton inhibitors, or surfaceprotecting agents. We use pectin commonly in patients with esophagitis, gastritis, and peptic ulcer and often in patients in intensive care units to prevent peptic ulcer.
Reduction of Diarrhea Recently 250 gIL of green (unripe) banana (equivalent to two bananas) or 2 g pectin per kg of food was given as a supplement to a rice diet in children in Bangladesh with persistent diarrhea. The amount and frequency of stools, duration of diarrhea, episodes of vomiting, use of oral rehydration, and amounts of intravenous fluid solutions given were all significantly reduced in the two treatment groups." Recovery on the third day was seen in 59% of the green banana group and in 55% of the pectin group compared with 15% of the rice only group.
PROBIOTICS PLUS PREBIOTICS EQUALS SYNBIOTICS Genetically a very large difference exists between the various bacteria known as LAB; the difference between one strain of LAB and another can be greater than that between a fish and a man. Most of the LAB used by the food industry have limited ability to ferment strong fibers such as inulin or phlein, have poor antioxidant systems,
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have no ability to adhere to human mucus, and most important, do not survive the acidity of stomach and bile acid content of the small intestine. Strong bioactivity can usually not be expected from LAB such as the bacteria found in yogurt, known for their ability to grow in fiberfree environments and chosen mainly for their palatability. Instead, LAB living and growing on plants, often under harsh conditions, can be expected to exhibit much stronger health-promoting abilities. It is a key condition that plant LAB, for the purpose of their own nourishment and survival, can also ferment rather resistant fibers. Greater clinical success in severely ill patients can be expected from using LAB collected from growing plants, silage, sourdough, sauerkraut, or some ethnic foods. Attempts will probably be made in the future to systematically study the various plant-derived LAB. Increasing interest has already been shown in LAB growing on grains such as oat and rye. When the microbiologic character of growing rye recently was investigated, more than 180 LAB species were found, some of which showed unique biologic properties (see later). The glucose and insulin responses of different rye products are invariably reported to be lower than those for wheat products" and are the lowest for cereal products with intact kernels such as pumpernickel breads and alternatives to raw rice based on rye, barley, and whole wheat. The intact botanical structure protects the encapsulated starch from hydrolysis in the small intestine and preserves it for bacterial fermentation in the colon. Similar effects are obtained with low temperature/long baking time and production of pasta. These processes increase the retrogradation of amylose and hence increase the amount of resistant starch in the toed." Important for prevention of disease, especially chronic diseases, is the availability of strong antioxidants such as phenolic acids and derivatives of benzoic acid and hydroxycinnamic acids (caffeic acid, sinapic acid, ferulic acid, and p-coumaric acid), which are particularly rich in rye, and also f1avonoids, which are also rich in rye. All of these compounds are also released by bacterial fermentation in the colon of rye and other antioxidant-rich fibers." Phenolic structures (f1avonoids) exhibit in the body a wide range of important biologic activities: antibacterial, anti thrombotic, vasodilatory, anti-inflammatory, and antlcarcinogenic." The most common LAB strain in the intestine of rural Asians and Africans who consume large quantities of fresh plant-based foods is Lb. plantarumP A Western lifestyle and diet do not favor colonization with Lb. plantarum, a LAB always present in the stool of persons with a rural lifestyle. Lb. plantarum was identified in two thirds of vegetarian North American Seventh-Day Adventists but only in approximately one fourth of omnivorous North Americans." A recent study reported that the dominant clusters isolated from mucosal biopsies of healthy Westerners (Scandinavians) still were Lb. plantarum (found in 24% of individuals), Lactobacillus rhamnosus (12%), and Lactobacillus casei subspecies pseudoplantarum (10%).31 Lb. plantarum was identified in the stool of approximately one third of healthy 3- to 8-week-old Swedish infants."
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SYNBIOTIC COMPOSITIONS One Lactic Acid Bacteria Strainj One Fiber Composition The first synbiotic enteral nutrition formula available on the market was produced by fermentation of oat meal with Lb. plantarum strain 299, a LAB strain chosen after extensive studies of several hundred isolated LAB strains obtained mainly from the human gut. Fermented oat containing a mixture of 19 carefully selected humanspecific Lactobacillus strains (density: 5 x 108 colonyforming units [cfu] of each strain) was supplied to healthy volunteers, and mucosal biopsies were taken from jejunum and rectum before and 11 days after the last administration. After 11 days 5 of 19 strains could be identified in the stools, most commonly Lb. plantarum strain 299.33 Lb. plantarum strain 299 has the ability to ferment oat to a density of 4.7 x 109 and has no difficulty in surviving the acidity of the stomach and the bile acid content of the small intestine."
Four Lactic Acid Bacteria Strainsj Four Fiber Composition More powerful synbiotic effects can probably be obtained with the use of a combination of several LAB and several different prebiotic fibers. Extensive screening for new bioactive LAB was done on growing ecologically cultivated rye, and no less than 180 different strains were identified." The same group of scientists also screened the human gut extensively and identified another 355 strains." Special attention was given to the ability of these strains to bind to porcine mucin, to express cell surface hydrophobicity, and to bind to collagen, fibronectin, and other extracellular matrix proteins. Of these 535 strains, 7 were selected for further studies (3 Lb. plantarum strains, 2 Lb. paracasei subspecies paracasei, Leuconostoc mesenteroides, and P. pentosaceus). They had the ability to survive exposure to 20% bile for 1 hour and a pH of 2.5 for 2 hours, properties that enable them to survive transport through the GI tract to the colon. All of the strains also showed the ability to utilize insulin or amylopectin in vitro as their sole carbon source. Three of the strains produced 13galactosidase, proposed to alleviate symptoms of lactose intolerance. All of the strains produced antimicrobial substance(s) with activity against Gram-positive bacteria, and 2 Lactobacillus strains also showed activity against the gastric pathogen Helicobacter pylori. During a l-hour exposure of the LAB strains to pH 5, de novo production of several proteins was induced, five of which cross-reacted with stress proteins, a type of protein suggested to protect other surface proteins and adhesins during transport through the GI tract. Four of the seven LAB strains studied caused the transport of nuclear factor (NF)-KB into the nucleus of macrophage U 937. NF-KB, known to induce both proinflammatory (interleukin [IL]-I~ and IL-8) and anti-inflammatory
cytokines (IL-10), was produced by Lb. plantarum and to a lower extent also by Leu. mesenteroides. All three Lb. plantarum and P. pentosaceus strains also produced significant amounts of antioxidants." Antioxidants produced by colonic bacteria can be expected to provide beneficial effects by scavenging free radicals in the GI tract. Four of seven bacteria were chosen, together with four fibers known for their strong bioactivities, to be further studied in a synbiotic composition. The composition, called Synbiotic 2000, consists of 1010 of each of the following four LAB (probiotics)-P. pentoseceus 5-33:3, Leu. mesenteroides 32-77:1, Lb. paracasei subsp paracasei 19, and Lb. plantarum 2362-and 2.5 g of each of four fermentable fibers (prebioticsj-e-Bglucan, inulin, pectin, and resistant starch. Lb. paracasei is of human origin; the other three originate in rye.
CLINICAL EXPERIENCE IN ACUTE DISEASES Acute Diarrhea Each year several million children die of diarrheal dehydration." In a multicenter study, 140 children with diarrhea were randomly assigned to receive oral rehydration and placebo and another 147 to receive oral rehydration and a daily supply of 1010 cfu of Lactobacillus GG (LGG). Clinical signs of diarrhea lasted 58.3 ± 27.6 hours in the LAB-treated group compared with 71.9 ± 35.8 hours (P = 0.03) in the placebo group. In rotavirus-positive children treated with LAB, diarrhea lasted 56.2 ± 16.9 hours compared with 76.6 ± 41.6 hours in the placebo group (p= 0.008).37 LGG was also used to prevent diarrhea in a placebocontrolled trial performed in 204 undernourished Peruvian children, aged 6 to 24 months." The treatment was given during 15 months. The LAB-treated children had fewer episodes of diarrhea (5.21 episodes/child and year compared with 6.02 in the placebo group, P =0.028). The therapeutic gain, as pointed out by Dul'onf" and others, must be regarded as modest. Probably the use of other, more potent LAB or combinations of pre- and probiotics could lead to more significant therapeutic success. A group of 237 newborn Colombian children with a risk of developing severe diarrhea received during 1 week or until they were discharged a daily supply of 250 million live Lactobacillus acidophilus and 250 million live Bifidobacterium intanus." With this probiotic prophylaxis, the incidence of necrotizing enterocolitis was reduced to one third (18 vs. 47, P< 0.0005) that of the previous year in the inpatient group and by half (19 vs. 38, P < 0.03) in the patients transferred from other hospitals (who most likely received treatment late)." No complications were attributed to the use of probiotic preparations even in very sick newborn children, who weighed on average 2600 g (range <1000 to >4000 g) and of whom one third had severe conditions such as sepsis, pneumonia, or meningitis. An incidental observation was that the LAB-treated children had significantly less diaper dermatitis.
SECTION IV • Principles of Enteral Nutrition
A meta-analysis on the efficacy of use of probiotics in acute diarrhea in children, based on 18 eligible studies, was recently published." The researchers concluded that coadministration of probiotics with standard rehydration reduces the duration of acute diarrhea by approximately I day. This therapeutic effect is less than that achieved with use of only prebiotics.P which may support the assumption that better results could be possible with combined use of several prebiotics and probiotics (synbiotics).
Anti biotic-Associated Diarrhea
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heat-inactivated group (P = 0.023). The only patient in the treatment group who developed infection had signs of a urinary infection on the 15th day, i.e., when he had not received treatment for 8 days. This may suggest that critically ill patients should be treated for longer periods of time. The length of stay was much shorter in the treatment group (13.7 days vs. 21.4 days), but the limited number of subjects did not allow statistical significance to be reached.
Abdominal Surgery Lb. plantarum 299 in a dose of 109 and oat fiber were
Diarrhea is a common side effect of antibiotic therapy." Up to 40% of children receiving broad-spectrum antibiotics experience diarrhea.f The efficacy of LGG in preventing diarrhea was tested in a series of 202 antibiotic-treated children; 25 placebo-treated and 7 LGG-treated children developed diarrhea." The mean duration of diarrhea was 4.7 days in the LGG group versus 5.88 days in the placebo group. Again, the efficacy of the treatment is not impressive, and "the reduction of I day two liquid stools over a 10 day period in a child might be questioned.t" A recent meta-analysis identified a total of nine trials of probiotics in the literature." Probiotics were given in combination with antibiotics, and the control subjects received placebo and antibiotics in all these studies. The odds ratio in favor of active treatment was 0.39 for Saccharomyces boulardii (P< 0.001) and 0.34 for lactobacilli (P < 0.001). No prebiotics were provided in any of the studies. The hope is that combined treatment with probiotics and prebiotics (synbiotics) might eventually lead to better efficacy in future studies.
Acute Pancreatitis Organ failure and poor outcome in severe acute pancreatitis are often the result of infected pancreatic necrosis." and the mortality rate is 5 to 10 times higher when pancreatic necrosis has become infected. 48A9lnfected pancreatic necrosis occurs in about 25% of patients after I week and in almost 75% after 3 weeks.' Thus far all treatment modalities including antibioticssG-s2 and various cytokine inhibitors'? have failed to affect outcome significantly. Patients with severe acute pancreatitis were randomly assigned to receive through a nasojejunal tube either I week's daily supply of a freeze-dried preparation containing live Lb. plantarum 299 in a dose of 109 together with a substrate of oat fiber or a similar preparation, in which the Lactobacillus had been heat-inactivated.P The study was designed to be interrupted when on repeat statistical analysis the infection rate showed significant differences in favor of one or the other group, which occurred when a total of 45 patients had entered the study. Twenty-two patients had received treatment with live Lb. plantarum 299 and 23 with the heat-inactivated Lb. plantarum 299. Infected pancreatic necrosis and abscesses occurred in I of 22 (4.5%) patients in the treatment group versus 7 of 23 (30%) patients in the
used in a trial of patients undergoing extensive abdominal surgical operations, and three groups were compared: (I) live LAB and oat fiber, (2) heat-inactivated LAB and oat fiber, and (3) standard enteral nutrition." The surgical procedures were liver resections (n = 29), pancreatic resections (n =26), gastric resections (n =22), colonic resections (n = 9), and intestinal bypass (n = 4); patients were equally distributed among the three LAB treatment groups. Each group consisted of 30 patients. The 3Q-daysepsis rate was 10% (3 of 30 patients) in the two groups receiving either live or heat-inactivated LAB compared with 30% (9 of 30 patients) in the group receiving standard enteral nutrition (P =0.0 I). The biggest difference was observed in the numbers of patients who developed pneumonia (6 patients in the enteral nutrition only group, 2 patients in the live LAB and fiber group, and I patient in the heat-inactivated LAB and fiber group). The effects were most pronounced in patients undergoing gastric and pancreatic resections; with sepsis rate in the enteral nutrition only group being 8 of 16 patients (50%) compared with 3 of 17 patients (I7%) in the heatinactivated LAB group and I of 15 patients (7%) in the live LAB group. The live LAB-treated patients received significantly less antibiotic treatment (P = 0.04): the mean length of antibiotic treatment with live LAB was 4 ± 3.7 days, with heat-inactivated LAB was 7 ± 5.2 days, and with enteral nutrition only was 8 ± 6.5 days. The numbers of patients with noninfectious complications were 9 of 30 (30%) in the enteral nutrition only group, 5 of 30 (17%) in the heat-inactivated LAB group, and 4 of 30 (13%) in the live LAB group. No significant changes were observed in hemoglobin concentration; leukocyte count; C-reactive protein, blood urea nitrogen, bilirubin, and albumin levels; total lymphocyte count; CD45RA, CD45RO, CD4, and CD8; numbers of natural killer cells, or CD4/CD8 ratio. No differences were observed in length of hospital stay. Another recent study compared the effect of a probiotic fruit-drink (Pro Viva) containing a related but not identical Lb. plantarum strain, 299V.sS The contents of LAB and oat fiber are significantly less in this drink because it contains only 5% of LABfermented oat, with the final Lb. plantarum 299V density being 5 x 107. In this study, however, supplementation was provided for longer periods than in other studies, including a minimum of I week before surgery. In this study 64 patients received PRO VIVA and 65 patients received no additional treatment. Almost all patients in
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both groups received a single dose of intravenous cefuroxime and metronidazole on entry into the study. No significant differences were observed between the groups for bacterial translocation (12%vs. 12%; P= 0.82), gastric colonization with enteric organisms (11%vs. 17%, P= 0.42), or septic morbidity (13% vs. 15%; P= 0.74). The patients in the first study were subjected to much more extensive surgical procedures than those in the second study. The risk of developing septic complications is known to be much higher in such patients, which is supported by the fact that septic complications developed in 30% of control patients (patients not receiving LAB) in the first study (50% pancreas and stomach operations) compared with 15% in the second study (mainly colorectal operations). The difference in outcome can also be explained by the low dose of probiotics and prebiotics provided in the second study. A supply of LAB in a density of 107 or lower is generally regarded as too small for significant probiotic clinical effects. In the first study a concentrated powder of LAB and fiber was supplied; in the second study a liquid formula diluted approximately 20 times was used. The fact that two different strains of Lb. plantarum were used in the two studies also cannot be disregarded.
Liver Transplantation A prospective, randomized study was performed in 95 patients undergoing liver transplantation." divided into three groups: (1) selective digestive tract decontamination (SOD) four times daily for 6 weeks (n = 32), (2) Lb. plantarum 299 (LLP) in a dose of 109 plus 15 g of fermentable fibers (n =31) for 12days postoperatively, and (3) heat-killed Lb. plantarum 299 plus 15 g of fermentable fibers for 12 days postoperatively (HLP) (n =32). Enteral nutrition was supplied to all patients from the second postoperative day: group 1 without fiber and groups 2 and 3 with nutritional fibers. There were no deaths. The numbers of postoperative infections were 23 (SOD), 17 (HLP), and 4 (LLP). Signs of infections occurred in 15 of 32 patients (47%, SOD), 11 of 32 patients (34%, HLP), and 4 of 31 patients (13%, LLP) (P= 0.017). The most common infections were cholangitis, occurring in 10 (SOD), 8 (HLP), and 2 (LLP) patients, and pneumonia, occurring in 6 (SOD), 4 (HLP), and 1 (LLP) patients. The microbes isolated most often were Enterococcus species in 8 (SOD), 8 (HLP), and 1 (LLP) patients, and Staphylococcus species in 6 (SOD), 3 (HLP), and 1 (LLP) patients. No Escherichia coli or Klebsiella infections were seen in the LLP group. Noninfectious complications occurred in 15 (SOD), 19 (HLP), and 16 (LLP) patients, and early rejection in 10 (SOD), 15 (HLP), and 10 (LLP) patients. The numbers of patients requiring hemodialysis were 8 (SOD),4 (HLP), and 2 (LLP) and the numbers of patients needing a second operation were 6 (SOD), 2 (HLP), and 4 (LLP). The C04/C08 ratio was higher in the LLP group compared with that in the other two groups (P= 0.06), and the time in an intensive care unit or in the hospital and the length of antibiotic therapy were also shorter but did not reach statistical significance.
The same investigators continued their efforts to further reduce morbidity associated with liver transplantation," this time with the combination of four LAB and four fibers (Synbiotic 2000).34.35 In a double-blind, randomized study, 33 patients received Synbiotic 2000 and another 33 patients received the four fibers in Synbiotic 2000 only. The treatment started the day before surgery and continued till the 14th day after surgery. During the first postoperative month only one patient in the group receiving Synbiotic 2000 (3%) showed any signs of infection compared with 17 of 33 (51%) patients in the group receiving the four fibers only."
CLINICAL EXPERIENCE IN CHRONIC DISEASE
Human Immunodeficiency Virus Infections Individuals, especially children, with human immunodeficiency virus (HIV) infections regularly have significant GI problems, particularly diarrhea, but also malabsorption, poor nutritional status, and sometimes lipodystrophy, a severe condition that also has manifestations similar to those of metabolic syndrome. These patients with weakened immune systems often are at risk for various infections. Supplementation with multivitamins and especially vitamin A and ~-earotenes has recently been shown to significantly reduce mortality related to pregnancy58.59 and to improve birth weight and neonatal growth and reduce anemia when given to pregnant HIVinfected women." Because these vitamins, as well as many other important antioxidants, are released by microbial fermentation in the large intestine, it is likely that synbiotics could be effective in counteracting some of the negative manifestations of HIV infection in both children and adults. HIV-infected individuals have a significantly reduced amount of LAB flora in the colon (",2 x 104 vs. 1 X 107) , and supplying LAB such as Lb. reuteris' and Lb. plantarum 299V to such individuals has also been proven to be safe. It was concluded from a study of 18 children congenitally exposed to HIV that supplying synbiotics (LAB and oat fiber) has the potential to stimulate growth and development and to restore the natural immune response.f
Inflammatory Bowel Disease Although suggested but not verified in the 1970s,the fact that patients with IBO have deranged bowel microflora was convincingly demonstrated in the early 1990s. In contrast to the early studies, we studied mucosal biopsies instead of stool samples. Our trial consisted of 30 patients with ulcerative colitis (UC), 12 with active and 18 with inactive disease, and 30 control subjects.P A significant reduction in the number of anaerobic bacteria, anaerobic Gram-negative bacteria, and Lactobacillus flora was seen in all patients with active disease, in sharp contrast to patients with inactive disease. Furthermore,
SECTION IV • Principles of Enteral Nutrition
10 of 20 patients with UC had an overgrowth of Proteus mirabilis in contrast to 0 of 20 control subjects. A more recent study described a significant reduction in the numbers of LAB subspecies in patients with UC versus control subjects (average 18 vs. 32).64 In this study, Bacteroides thetaiotaomicron was more commonly observed in the patients with UC (8 of 10) than in the control subjects (4 of 10). The reduction in density of endogenous lactobacilli and bifidobacteria has been well documented in both experimental and clinical UC and also in pouchitis and Crohn disease. 65,66 A recent study suggested that in UC the mucosa has lost its ability to hold back the fecal flora and prevent close contact between resident microflora and the epithelial surface." The microbial density at the epithelial surface increases significantly with increased severity of disease. Patients with more than 10,000 cfu/mL have a thick bacterial "band" attached to the mucosa, and patients with more than 50,000 cfu/mL band show in addition inclusions of polymorphic bacteria within some enterocytes close to the lamina propria. In the early 1990swe were also able to show that supplying animals with induced colitis a synbiotic composition of LAB and oat fiber prevented further development of colitis and promoted healing. Morphologic scores, myeloperoxidase activity, and mucosal permeability became quickly normalized as the synbiotic formula was supplied." A whole series of studies in normal, ILlQ-deficient, and transgenic animals later verified the efficacy of probiotics for both prevention and healing of experimental colitis (for review see reference 69). A few human studies have also been conducted in recent years. 7()"'72 In most of the studies one specific LAB was tried, but in almost no study was a combination of several LAB or a combination of several LAB and several bioactive fibers tried. Future studies certainly will focus on combinations, which include fibers, because these offer the best hope for dramatic improvement in treatment results. A probiotic cocktail called VSL#3, consisting of four Lactobacillus strains, three Bifidobacterium strains and Streptococcus saliuarius species thermophilus (5 x lOll cells/g) but no fibers, was reported to be effective in both active UC73 and pouchitis." This report did not state whether these LAB were chosen after extensive molecular/immunologic studies to prove their strong bioactivity or if they just were chosen at random. Patients with UC were given 3 g/day for 1 year; in 15 of 20 patients UC remained in remission, 1 patient was lost to follow-up, and 4 of 20 had signs of relapse." Twenty patients with pouchitis were treated with the formula, and all showed remission after 9 months." A recent review suggested that "metronidazole is an effective treatment for active chronic disease" (odds ratio of 12.34), but that "oral probiotic therapy with VSL#3 for maintaining remission" is effective (odds ratio of 15.33).75 Although the scientific basis for treatment of IBO with synbiotics seems reasonable and attractive and the treatment has no side effects, it must be emphasized that far too few studies have yet been performed for the routine use of synbiotics outside trials to be recommended. The use of prebiotics, without additional probiotics, is
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sometimes enough to alleviate symptoms of colitis.P:" It is tempting to anticipate that a cocktail consisting of several LAB and several fibers could provide both better protection against and better treatment in IBO. However, the selection of both LAB and fibers must be made on the basis of detailed studies of their metabolic and immunologic effects. A pilot study with such a preparation (Synbiotic 2000, see earlier34,35) was recently conducted in 10 patients with distal colitis." The patients were given enemas containing the LAB and fibers twice daily for 2 weeks. Significant reductions in degree of diarrhea (before treatment: 2.5 ± 0.38) were observed on day 7 (1.13 ± 0.13, P < 0.05), on day 14 (1.13 ± 0.23, P < 0.05), and on day 21, e.g., 1 week after conclusion of treatment, (0.75 ± 0.25, P< 0.01).44 The occurrence of visible blood in the stool also decreased significantly from an initial value of 2 ± 0.27 to 1 ± 0.38 (P < 0.05) and 1.12 ± 0.35 (P < 0.05) on days 14 and 21, respectively. Similarly, the occurrences of nocturnal diarrhea, urgency, and consistency were significantly reduced during the whole study periods. Except for increased bloating and flatus in two patients, no adverse events or side effects were observed. The ideal treatment for IBO will probably be complex. A combination of other biologic treatments and synbiotic treatment may be shown to be effective. The disadvantages of biologic treatments, such as cytokine inhibitors, are considerable morbidity and high price. The complications seen, when such drugs are used, are very similar to those seen after various types of transplantation. Because use of synbiotics in connection with liver transplantation seems to lessen such cornplications,56.57 it is likely that use of synbiotics in combination with cytokine inhibitors might considerably reduce morbidity. Synbiotic treatment seems to represent the best alternative for long-term (permanent) use to maintain remission and prevent relapse in the foreseeable future. Attractive advantages, in addition to the expected efficacy, are the absence of serious side effects and the low price of treatment, which is especially important when treatment is needed for longer periods of time.
Progressive Liver Disease Nonalcoholic steatohepatitis (NASH), is becoming increasingly common in Western societies, owing to the presence of obesity associated with increasing affluence." A conservative estimate is that more than 10% of North Americans have NASH. Almost one half of the patients are obese and one third also have type 2 diabetes, hyperlipidemia, or both." The entity is no longer only seen in adults, but is also common among American adolescents." NASH is generally regarded as a precursor stage of cryptogenic cirrhosis, the incidence of which is also rapidly increasing. About 35 years ago, I demonstrated that the presence of steatosis increased considerably the risk for poor outcome in extensive liver resections." Similar observations are seen today after liver transplantation." Furthermore, without considerable changes in lifestyle, steatosis rapidly recurs after liver transplantation/"
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The grade of NASH correlates well with the grade of obesity," especially visceral obesity. Fat cells, in particular, visceral adipocytes, are known to have increased expression of cytokines, especially tumor necrosis factor-a. (TNF-a). The amount of fat in the abdomen is known to vary from a few milliliters to 6 L,82 which explains the increased exposure to TNF-a. in obese individuals, which together with overexpression of y-interferon and underexpression of (L-I0 sensitizes the liver to both endotoxins and to the toxic effects of TNF-a..83 Activation of macrophages by gut-elerived endotoxin has been assumed to be responsible for the raised levels of TNF-a and probably is a key factor in the progressive liver damage seen in patients with cirrhosis. Probiotics and prebiotics not only will significantly reduce the production and absorption of endotoxin in the intestine but also will down-regulate production of proinflammatory cytokines, including TNF-a. A long-term supply of synbiotics can be expected to reduce both the inflammation of the liver and the steatosis. Expression of toll-like receptors 4 is critically involved in TNF-a. production in response to endotoxin and Gram-positive microbial stimuli. If synbiotics are able to down-regulate the expression of toll-like receptors and reduce the production of TNF-a., synbiotics could represent a cheap and powerful tool without side effects for long-term treatment of patients with liver disease. A recent observation that in vitro TNF-a. production by peripheral blood mononuclear cells in response to stimulation by endotoxin or Staphylococcus aureus enterotoxin B is reduced by a median 46% (range: 8% to 67%) in comparison to presupplementation levels in 8 of 11 (72.7%) patients with cirrhosis given Synbiotic 2000 is of considerable interest.f Use of synbiotics in patients with chronic liver disease was well tolerated, and no adverse events or changes in their general clinical state could be observed. The effects of Synbiotic 2000 have also been investigated in a double-blind, controlled study of 55 patients with chronic liver disease, divided into three groups: (1) Synbiotic 2000 (n = 20), (2) only the fibers of Synbiotic 2000 (n = 20), and (3) placebo (nonfermentable, nonabsorbable fiber) (n = 15).85 Administration for 1 month led to a significant increase in LAB flora from 7.37 ± 047 to 9.64 ± 0.34 10glO CFUg dry/eces (P< 0.05) in the Synbiotic 2000 group, but not in the other two groups. The pH was significantly reduced from a level between 6.5 and 7 in the placebo group to 5 to 5.5 in both treatment groups. Significant decreases were observed in both treatment groups but not in the placebo group in E. coli, Staphylococcus, and Fusobacterium organisms (P< 0.001, P< 0.01, and P< 0.05, respectively) but not in Pseudomonas and Enterococcus organisms. Significant decreases were also observed in the ammonia level both in the Synbiotic 200o-treated group (60.5 ± 2.9 to 38.6 ± 3.9 umol/L) and in the fiber-only group (63.6 ± 3.9 to 41.5 ± 5.2 urnol/L), but not in the placebo group (60.5 ± 2.9 to 58.6 ± 3.9 urnol/L). The levels of endotoxin fell significantly in the two treatment groups but not in the placebo-treated group. Also the serum levels of
bilirubin and alanine aminotransferase decreased significantly from 252 ± 182 to 84 ± 65 umol/L (P< 0.01) in the Synbiotic 200o-treated group and to 110 ± 86 (P < 0.05) in the fiber-only group, but not in the placebo group. Improvements in psychometric tests and in degree of encephalopathy were also observed in both the treatment groups.
Renal Failure Bacterial overgrowth usually occurs in end-stage kidney failure when the serum creatinine level reaches approximately 6 mg/dL and the glomerular filtration rate decreases to less than 20 ml/rnin." This overgrowth usually leads to increased production of potentially toxic and carcinogenic compounds and manifests itself in poor appetite, reduced caloric intake, and increased malabsorbtion." A statistically significant decrease in the serum levels of carcinogens and toxins was observed with administration of two strains of Lb. acidophilus'" as well as with a mixture of LAB consisting of B. infantis, Lb. acidophilus and Enterococcus faecalis to uremic patients." Modest increases in appetite, caloric intake, body weight, mid-arm muscle circumference, and serum albumin level were also observed." The numbers of patients studied was small, consisting of 888 and 12 patients." respectively. The LAB strain tried was probably not the most powerful, and the dose supplied appeared to be low. However, long-term administration of probiotics or synbiotics, which, in contrast to antibiotics, have no side effects, seems to be an attractive option in all patients undergoing hemodialysis or peritoneal dialysis. Future attempts should be made with the use of LAB with well-elocumented bioactivities, at higher doses and combined with well-elocumented bioactive prebiotics.
CONCLUSION Fundamental differences exist among various LAB, and significant clinical effects can only be expected when specific LAB with well-elocumented bioactivities are used. Such beneficial effects will almost never be obtained with milk-derived LAB or bacteria in yogun.?' This was illustrated by a recent study." A standard commercial product, containing Lactobacillus acidophilus
LAS, Bifidobacterium lactis BP12, Streptococcus thermophilus, and Lactobacillus bulgaricus was mixed with 7.5 g oligofructose in a controlled study supplied to critically ill patients. Although significant reductions in the number of potentially pathogenic organisms (PPMs) could be observed in the stomach of the treated patients, no influence on intestinal permeability could be demonstrated, nor could any clinical benefits be demonstrated, when this particular formula was supplied to a mixed group of critically ill patients. Thus far most of the more significant clinical effects have been seen when LAB known for their excellent ability
SECTION IV • Principles of Enteral Nutrition
to ferment plant fibers are used. Among, these are Lb. plan/arum, Lb. paracasei, and Lb. casei, but many more remain to be identified and studed. The majority of the clinical studies thus far have been performed with Lb. rhamnosus GG, sometimes with excellent results but often with rather modest clinical effects (for more information, see reference 93). The clinical efficacy of LAB such as Lb. casei Shirota and Lb. plan/arum appears thus far to be the most pronounced, but stronger clinical effects will hopefully be obtained from mixtures of several well-documented probiotic LABs and several prebiotic fibers, chosen for their documented strong bioactivities. REFERENCES I. Delzenne NM: Oligosaccharides: state of the art. Proc Nutr soc 2003;62: 177-182. 2. Aldercreutz H: Evolution, nutrition, intestinal microflora, and prevention of cancer: a hypothesis. Proc Soc Exp Bioi Med 1998;217:241-246. 3. Cummings JH: Macfarlane GT: Role of intestinal bacteria in nutrient metabolism. J Parenter Enternal Nutr 1997;21: 357-365. 4. Hooper LV, Midtvedt T, Gordon JI: How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 2002;22:283-307. 5. Gnoth MJ, Kunz C, Kinne-Saffran E, Rudloff S: Human milk oligosaccharides are minimally digested in vitro. J Nutr 2000;130: 3014-3020. 6. Bengrnark, Prospect for a new and rediscovered form of therapy: Probiotic and phage. In Andrew PW, Oystron P, Smith GL, StewartTull De (eds): Fighting Infection in the 21st Century. Oxford, UK, Blackwell Publishing, 2000, pp 97-132. 7. Bengmark S: Gut and the immune system: Enteral nutrition and immunonutrients. In Baue AE, Faist E,Fry D (eds): SIRS, MODS and MOF-Systemic Inflammatory Response Syndrome, Multiple Organ Dysfunction Syndrome, Multiple Organ Failure-Pathophysiology, Prevention and Therapy. New York, Springer, 2000, pp 408-424. 8. Bengmark S: Refunctionalization of the gut. In Baue AE, Faist E, Fry D (eds): SIRS, MODS and MOF-Systemic Inflammatory Response Syndrome, Multiple Organ Dysfunction Syndrome, Multiple Organ Failure-Pathophysiology, Prevention and Therapy. New York, Springer, 2000, pp 435-446. 9. Cummings JH, Roberfroid MB, Anderson H, et al: A new look at dietary carbohydrate: Chemistry, physiology and health. Eur J Clin Nutr 1997;51 :417-423. 10. Loo lV, Cummings J, Delzenne N, et al: Functional food properties of nondigestible oligosacccharides: A consensus report from the ENDO project (DGXlI AIRlI-CT94-1095). Br J Nutr 1999;81: 121-132. II. Muller M, Lier D: Fermentation of fructans by epiphytic lactic acid bacteria. J Appl Bacteriol 1994;76:406-411. 12. Buddington RK, Buddington KK, Sunvold GD: Influence of fermentable fiber on small intestinal dimensions and transport of glucose and proline in dogs. Am J Vet Res 1999;60: 354-358. 13. Oyofo BA, Droleskey RE, Norman JO, et al: Inhibition by mannose of in vitro colonization of chicken small intestine by Salmonella typhimurium. Poult Sci 1989;68: 1351-1356. 14. de Felippe J Jr, da Rocha e Silva M Jr, Maciel FMB, et al: Infection prevention in patients with severe multiple trauma with the immunomodulator beta 1-3 polyglucose (glucan). Surg Gynecol Obstet 1993; 177:383-388. 15. Wang X, Brown IL, Evans AJ, Conway PL: The protective effects of high amylose maize (amylomaize) starch granules on the survival of Bifidobacterium spp in mouse intestinal tract. J Appl Microbiol 1999;87:631-639. 16. Umemoto Y, et al: Gastroenterology 1998;114:Al102.
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17. Hallert C, Kaldma M, PeterssonBG: lspaghula husk may relieve gastrointestinal symptoms in ulcerative colitis in remission. Scand J GastroenteroI1991;26:747-750. 18. Fernandez BF, Hinojosa J. Sanchez UL, et al: Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared to mesalamine in maintaining remission in ulcerative colitis. Am J Gastroenterol 1999;94:427-433. 19. Fukuda M, Kanauchi 0, Araki Y, et al: Prebiotic treatment of experimental colitis with germinated barley foodstuff: A comparison with probiotic and antibiotic treatment. Int J Mol Med 2002;9: 65-70. 20. Best R, Lewis DA, Nasser N: The anti-ulcerogenic activity of the unripe banana (Musa species) Br J Pharmacol 1984;82:107-116. 21. Hills BA, Kirwood CA: Surfactant approach to the gastric mucosal barrier protection of rats by banana even when acidified. Gastroenterology 1989;97:294-303. 22. Dunjic BS,SvenssonI, Axelsson J, Adlercreutz P, et al: Is resistance to phospholipase important to gastric mucosal protective capacity of exogenous phosphatidylcholine? Eur J Gastroenterol Hepatol 1994;6:593-598. 23. Dunjic BS, Svensson I, Axelsson J, et al: Green banana protection of gastric mucosa against experimentally induced injuries in ratsA multicomponent mechanism? Scand J Gastroenterol 1993;28: 894-898. 24. Rabbani GH, Teka T, Zaman B, et al: Clinical studies in persistent diarrhea: Dietary management with green banana or pectin in Bangladesh children. Gastroenterology 2001 ;121:554-560. 25. Foster-Powell K, Brand Miller J: International tables of glycemic index. Am J Clin Nutr 1995;62(suppl):S871-S893. 26. Bj6rck I, Liljeberg H: Dietary fiber, resistant starch and other food factors as moderators of acute glycemia and second meal tolerance. In Guillon F, Abraham G, Andersson H, et al (eds): Plant Polysaccharides in Human Nutrition: Structure, Function, Digestive Fate and Metabolic Effects. Nantes, Imprimerie Parentheses, 1997, pp 79-85. 27. Andreasen MF, Landbo A-K, Christensen LP, et al: Antioxidant effects of phenolic rye (Secale cereale L) extracts. monomeric hydrocinnamates and ferulic acid dihydrodimers on human lowdensity lipoproteins. J Agric Food Chern 2001;49:4090-4096. 28. Middleton E Jr, Kandaswami C, Theoharides TC: The effects of plant flavonoids on mammalian cells; implications for inflammation, heart disease and cancer. Pharmacol Rev 2000;52: 673-751. 29. Olasupo NA, Olukoya DK, Odunfa SA: Studies on bacteriocinogenic Lactobacillus isolates from selected Nigerian fermented foods. J Basic Microbiol 1995;35:319-324. 30. Finegold SM,Sutter VL, Mathisen GE: Normal indigenous intestinal flora. In Hentges DJ (ed): Human Intestinal Microflora in Health and Disease. London, Academic Press, 1983, pp 3-31. 31. Ahrne S, Nobaek S, Jeppsson BG, et al: The normal Lactobacillus flora of healthy human rectal and oral mucosa. J Appl Microbiol 1998;85:88-94. 32. Bennet R, Nord CE: Development of the faecal anaerobic microflora after caesarean section and treatment with antibiotics in newborn infants. Infection 1987;15:332-336. 33. Johansson ML, Molin G, Jeppsson B, et al: Administration of different Lactobacillus strains in fermented oatmeal soup: In vivo colonization of human intestinal mucosa and effect on the indigenous flora. Appl Environ Microbiol 1993;59:15-20. 34. Kruszewska K, Lan J, Lorca G, et al: Selection of lactic acid bacteria as probiotic strains by in vitro tests. Microecology and Therapy 2002;29:37-51. 35. Ljungh A, Lan J-G, Yamagisawa N: Isolation, selection and characteristics of Lactobacillus paracasei ssp paracasei isolate F19.Microb Ecol Health Dis 2002;suppl 3:4-6. 36. Rhoads M. Management of acute diarrhea in infants. JPEN J Parent Enteral Nutr 1999;23:S18-S19. 37. Guandalini S,PensabeneL, Zikri MA, et al: Lactobacillus GGadministered in oral rehydration solution to children with acute diarrhea: A multicenter European study. J Pediatr Gastroenterol Nutr 2000;30:54-60. 38. Oberhelman RA, Gilman RH, Sheen P, et al: A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J Pediatr 1999;134:15-20.
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39. DuPont HL: Prevention of diarrhea by the probiotic Lactobacillus GG. J Pediatr 1999;134:1-2. 40. Hoyos AB: Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int J Infect Dis 1999;3:197-202. 41. Huang JS, Bousvaros A, Lee JE, et al: Efficacy of probiotic use in acute diarrhea in children. A meta-analysis. Dig Dis Sci 2002;47: 2625-2634. 42. Bartlett JG: Antibiotic-associated diarrhea. Clin Infect Dis 1992;15: 573-581. 43. Elstner CL, Lindsay AN, Book LS, et al: Lack of relationship of Clostridium difflcile to antibiotic-associated diarrhea in children. Pediatr Infect Dis 1983;2:364-366. 44. Vanderhoof JA, Whitney DB, Antonson DL, et al: Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J Pediatr 1999;135:564-568. 45. Saavendra JM: Probiotics plus antibiotics; regulating our bacterial environment. J Pediatr 1999;135:535-537. 46. D'Souza AL, Rajkumar C, Cooke J, Bulpitt C: Probiotics in prevention of antibiotic associated diarrhoea: Meta-analysis. BMJ 2002; 324:1361-1364. 47. Isenmann R, Rau B, Beger HG: Bacterial infection and extent of necrosis are determinants of organ failure in patients with acute necrotizing pancreatitis. Br J Surg 1999;86:1020--1024. 48. Beger HG, Bittner R, Buchler M: Bacterial contamination of pancreatic necrosis-A prospective clinical study. Gastroenterology 1986;91:433-438. 49. Buchler MW, Gloor B, Muller CA, et al: Acute necrotizing pancreatitis: Treatment strategy according to the status of infection. Ann Surg 2000;232:619-626. 50. Kingsnorth A: Role of cytokines and their inhibitors in acute pancreatitis. Gut 1997;40:1-4. 51. Qamruddin AO, Chadwick PR: Preventing pancreatic infection in acute pancreatitis. J Hosp Infect 2000;44:243-253. 52. Golub R, Siddiqi F, Pohl D: Role of antibiotics in acute pancreatitis: A meta-analysis. J Gastrointest Surg 1998;2:496--503. 53. Olah A, Belagyi T, lssekutz A, et a1: Early enteral nutrition with specific Lactobacillus and fibre reduces sepsis in severe acute pancreatitis. Br J Surg 2002:89:1103-1107. 54. Rayes N, Hansen S, Boucsein K, et al: Early enteral supply of fibre and lactobacilli vs parenteral nutrition-A controlled trial in major abdominal surgery patients. Nutrition 2002;18:609-615. 55. McNaught CE,Woodcock NP, MacFie J, Mitchell CJ: A prospective randomized study of the probiotic Lactobacillus plantarum 299Von indices of gut barrier function in elective surgical patients. Gut 2002;51:827-831. 56. Rayes N, Hansen S, Seehofer D, et al: Early enteral supply of Lactobacillus and fibre vs selective bowel decontamination (SBD)-A controlled trial in liver transplant recipients. Transplantation 2002;74:123-127. 57. Rayes N, Seehofer D, Theruvath T, et al: Combined perioperative enteral supply of bioactive pre- and probiotics abolishes postoperative bacterial infections in human liver transplantation-A randomised, double blind clinical trial. In press. 58. West KP, Katz J, Khatry SK,et al: Double blind, cluster randomized trial of low dose supplementation with vitamin A and ~ carotene on mortality related to pregnancy in Nepal. BMJ 1999;318: 570--575. 59. Semba RD. The vitamin A and mortality paradigm: Past, present and future. Scand J Nutr 2001;45:4&-50. 60. Kimwenda N, Miotti PG, Taha TE, et al: Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi. Clin Infect Dis 2002;35:611kl24. 61. Wolf BW,Wheeler KB,Ataya DG, Garleb KA: Safety and tolerance of Lactobacillus reuten supplementation to a population infected with the human immunodeficiency virus. Food Chem Toxicol 1998;36: 1085-1094. 62. Cunningham-Rundles S, Ahrne S, Bengmark S, et al: Probiotics and immune response. Am J GastroenteroI2000;95(supp 1):S22-S25. 63. Fabia R, ArRajab A, Johansson ML, et al: Impairment of bacterial flora in human ulcerative colitis and in experimental colitis in the rat. Digestion 1993;54:248-255.
64. Pathmakanthan S: Mucosally associated bacterial flora of the human colon: Quantitative and species-specific differences between normal and inflamed colonic biopsies. Microb Ecol Health Dis 1999;11:169-174. 65. Favier C, Neut C, Mizon C, et al: Fecal j}o-galactosidase and bifidobacteria are decreased in Crohns disease. Dig Dis Sci 1997;42: 817-822. 66. Sartor RB: Microbial factors in the pathogenesis of Crohn's disease, ulcerative colitis and experimental intestinal inflammation. In Kirsner JG (ed): Inflammatory Bowel Diseases, 5th ed. Philadelphia, Saunders, 1999, pp 153-178. 67. Swidsinsky A, Ladhoff A, Pernthaler A, et al: Mucosal flora in inflammatory bowel disease. Gastroenterology 2002;122:44-54. 68. Fabia R, ArRajab A, Johansson ML, et al: The effect of exogenous administration of Lactobacillus reuteri R2LC and oat fibre on acetic acid-induced colitis in the rat. Scand J Gastroenterol 1993;28: 155-162. 69. Guarner F, Malagelada JT: Role of bacterial in experimental colitis. Best Pract Res Clin Gastroenterol 2003;17:793-804. 70. Hamilton-Miller JMT: A review of clinical trials of probiotics in the management of inflammatory bowel disease. Infect Dis Rev 2001; 3:83-87. 71. Shanahan F: Probiotics and inflammatory bowel disease: From fads and fantasy to facts and future. Br J Nutr 2002;88 (suppl 1): S5-S9. 72. Marteau P, Seksik P, Jian R: Probiotics and intestinal effects: A clinical perspective. Br J Nutr 2002;88 (suppI1):S51-S57. 73. Venturi A, Gionchetti P, Rizzello F, et al: Impact on the composition of the faecal flora by a new probiotic preparation: Preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther 1999;13:1103-1108. 74. Gionchetti P, Rizello F, Venturi A, et al: Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: A double-blind, placebo-controlled trial. Gastroenterology 2000; 119:305-309. 75. Sandborn WJ, Mcleod R, Jewell DP: Medical therapy for induction and maintenance of remission in pouchitis: A systemic review. Inflamm Bowel Dis 1999;5:33-39. 76. Pathmakanthan S, Walsh M, Bengmark S: Efficacy and tolerability treating acute distal ulcerative colitis with symbiotic enema's: A pilot trial [abstract]. Presented at United European Gastroenterology Week, Geneva, 2003. 77. James 0, Day Ch: Non-alcoholic steatohepatitis: Another disease of affluence. Lancet 1999;353:1634-1636. 78. Bengmark S: Liver steatosis and liver resection. Digestion 1969;2: 304-311. 79. Marchesini G, Forlani G: NASH: From liver diseases to metabolic disorders and back to clinical hepatology. Hepatology 2002;35: 497-499. 80. Kim WR, Poterucha JJ, Porayko MK, et al: Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation 1996;62: 1802-1805. 81. Wanless IR, Lentz JS: Fatty liver hepatitis (steatohepatitis) and obesity: An autopsy study with analysis of risk factors. Hepatology 1990;12:1106--1110. 82. Thomas EL,Saeed N, Hajnal JV, et al: Magnetic resonance imaging of total body fat. J Appl Physiol 1998;85:1778--1785. 83. Yang S, Lin HZ, Lane MD, et al: Obesity increases sensitivity to endotoxin liver injury: Implications for the pathogenesis of steatohepatitis. Proc Nat! Acad Sci 1997;94:2557-2562. 84. Riordan SM,Skinner N, Nagree A, et al: Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Hepatology 2003;37:1154-1164. 85. Simenhoff ML, Saukkonen JJ, Burke JF, et al: Bacterial population in the small bowel in uremia. Nephron 1978;22:63-68. 86. Qing L, duan ZP, Ha OK, et al: Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with liver cirrhosis. Hepatology (in press). 87. Simenhoff ML, Saukkonen JJ, Burke JF, et al: Amine metabolism and the small bowel in uremia. Lancet 1976;2:818-821. 88. Zimenhoff ML, Dunn SR, Zollner G, et al: Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus. Miner Electrolyte Metab 1996;22:92-96.
SECTION IV • Principles of Enteral Nutrition 89. Hida M, Aiba Y, Sawamura S, et al: Inhibition of the accumulation of uremic toxins in the blood and their precursors in feces after oral administration of Lebenin", a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis. Nephron 1996;
74:349-355.
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90. Jain PK, McNaught CE, Anderson ADG, et al: Influence of synbiotic containing Lactobacillus acidophilus LAS, Bifidobacterium factis BPf2, Streptococcus thermophilus, Lactobacillus bufgaricus and oligofructose on gut barrier function and sepsis in critically ill patients: a randomized controlled trial. Clinical Nutrition (in press).
Monitoring for Efficacy, Complications, and Toxicity Ainsley M. Malone, MS, RD, LD, CNSD Connie K. Brewer, RPh, BCNSP
CHAPTER OUTLINE Introduction Evaluation and Treatment of Enteral Feeding Complications Gastrointestinal Complications Delayed Gastric Emptying Gastric Residual Volumes Treatment of Delayed Gastric Emptying Gastroesophageal Regurgitation and Aspiration Risk Factors Clinical Monitors for Detection Methods to Minimize Aspiration Risk Diarrhea Incidence and Etiology Treatment Constipation Metabolic Complications The Refeeding Syndrome Definition and Incidence Prevention and Treatment Hyperglycemia Monitoring for Efficacy and Complications Summary
INTRODUCTION In its most basic sense, the purpose of enteral nutrition is to provide nutrients via the gastrointestinal (GI) system to sustain life. The successful use of enteral nutrition to achieve this purpose depends on many variables including feeding tube location, the clinical state of the patient, and other treatment decisions. Successful delivery of enteral nutrition requires ongoing monitoring to assess the treatment regimen and identify those factors indicative of therapeutic benefit as well as inadequate delivery 276
of nutrients. Most importantly, monitoring is critical to identify adverse outcomes and prevent complications. In addition, monitoring of enteral nutrition is necessary to evaluate the efficacy of the nutritional care plan and its relationship to desired outcomes. In this chapter we will focus on two areas: first, the complications most commonly encountered by patients receiving enteral tube feedings will be addressed with emphasis on their treatment and prevention, and second, the importance of evaluating enteral nutrition with regard to efficacy will be discussed.
EVALUATION AND TREATMENT OF ENTERAL FEEDING COMPLICATIONS Complications with the use of enteral tube feedings can be classified in many ways. Most commonly they are categorized as mechanical, GI, and metabolic.' In this chapter GI and metabolic complications will be addressed. Mechanical complications associated with feeding tubes and problems related to tube feeding delivery are fully discussed in Chapter 17.
GASTROINTESTINAL COMPLICATIONS The most common complications observed with enteral feedings involve GIfunction. GI complications most often occurring with enteral feeding include nausea, vomiting, delayed gastric emptying, abdominal distention, constipation, and diarrhea,"! Additional complications include aspiration and nonocclusive bowel necrosis, both associated with high mortality.v-" Aspiration is often described as either a GI or mechanical complication.v' Montejo and colleagues- prospectively evaluated critically ill patients receiving enteral nutrition. In a multicenter observational study of 400 patients, the authors observed that 251 (62.8%) experienced one or more GI complications during their feeding course. These included high gastric residual volumes (GRVs), aspiration pneumonia,
SECTION IV • Principles of Enteral Nutrition
abdominal distention, vomiting, regurgitation, diarrhea, or constipation. In a subsequent study, Montejo and associates" evaluated the incidence of GI complications in gastrically or jejunally fed patients. Both groups experienced GI complications as defined above, with 24% of the patients in the jejunal group experiencing GI complications compared with 57% in the gastric group. Identification and treatment of these complications are essential to the successful use of enteral nutrition. In addition, for aspiration, this effort may have a direct impact on patient outcome.
DELAYED GASTRIC EMPTYING Nausea, vomiting, and increased GRVs are complications associated with delayed gastric emptying. Nausea and vomiting occur in approximately 12% to 20%of all patients receiving enteral feedings." whereas, in the critically ill patient, increased GRV is the reason cited most often for the discontinuation of enteral feedings." The incidence of regurgitation or vomiting with aspiration and subsequent pneumonia increases with the presence of delayed gastric emptying. Gastric emptying is a complex mechanism requiring coordinated actions of the stomach and small intestine," Many nutritional factors are involved in the variability of gastric emptying including caloric density, osmolarity, and nutrient content. Liquids with high caloric density and higher osmolality empty more slowly than those with lower caloric densities or isotonicity." Liquids with increased fat content are known to delay gastric emptying. In healthy volunteers, Sidery and colleagues" demonstrated that ingestion of high-fatliquid meals delays gastric emptying compared with ingestion of high-earbohydrate meals. In a study of ambulatory patients with chronic obstructive lung disease, Akrabawi and co-workers'? demonstrated significantly longer gastric emptying with a high-fat liquid formula. The type of fat ingested may also have a role in gastric emptying. Medium-ehain fatty acids delay gastric emptying more than short- or longchain fatty acids." The presence of fiber in a liquid meal has been implicated in altered gastric emptying; however, evaluation in healthy subjects did not substantiate this theory. II Disorders of gastric emptying are common in patients receiving enteral feedings, especially those who are critically il1. 12 Many clinical variables result in altered gastric emptying including diabetes mellitus, neurologic and rheumatologic disorders, surgical intervention, and use of selected medications. 13 The incidence of gastroparesis in diabetes mellitus ranges from 27% to as much as 58%, depending on the population studied. Its incidence is greater in those who have type 1 diabetes and/or disease duration of longer than 10 years. Patients with neurologic disorders such as stroke, brain tumors, and seizures often experience delayed gastric emptying and/or nausea and vomiting." In addition, patients with moderate to severe head injury may demonstrate altered gastric emptying as may those with chronic renal failure.s,14
BmI!II
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Drugs That Delay Gastric Emptying
Alcohol (high concentration) Aluminum hydroxide antacids Atropine f3-Agonists Calcitonin Calcium channel blockers Dexfenfluramine Diphenhydramine Glucagon Interleukin-l Levodopa Lithium Omeprazole Ondansetron Opiates Phenothiazine Progesterone Propofol Sucralfate Tetrahydrocannabinol Tobacco Tricyclic antidepressants From Lin HC, Hasler WL: Disorders of gastric emptying, In Yamada T (ed): Textbook of Gastroenterology, 2nd ed. Philadelphia, JB Lippincott, 1995,vol I, p 1318.
Surgical procedures such as vagotomy, pyloroplasty, and fundoplication have been associated with delayed gastric emptying." Gastric atony associated with critical illness alters gastric emptying and is thought to be caused by several variables including hyperglycemia, electrolyte imbalance, and medications. IS In sepsis, the presence of endotoxin, through a variety of mechanisms, impairs gastric emptying." Table 23-1 lists medications that are known to delay gastric emptying. The use of opiates for pain management is commonly known to be a cause of gastroparesis owing in part to its effect on GI motility. Propofol has also been suggested to contribute to delayed gastric emptying.l':" The use of dopamine has been shown to alter gastric emptying. In a study by Tarling and associates," those who received dopamine demonstrated slower gastric emptying compared with those who did not receive the medication.
Gastric Residual Volumes The measurement of GRVin the patient receiving enteral tube feeding has long been recommended as a determinant of enteral tolerance. The rationale for this practice has been the belief that GRV indirectly assesses gastric emptying and can ultimately be used to assess the risk of regurgitation and subsequent aspiration.F:" According to McClave and Snider," there are inherent flaws in this rationale and practice. The argument for using GRV does not account for the 1500 to 3000 mL of combined salivary and gastric secretions that are generated daily. In addition, studies have shown that GRVs do not correlate with altered gastric emptying.F" Studies evaluating the use of GRV to assess enteral feeding intolerance have yielded conflicting results. McClave and colleagues'? compared GRVwith physical and radiographic assessment of GI function and found
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no correlation between GRV and objective scores of physical or radiographic examination. The authors concluded that GRV should not be used alone as an indicator of enteral feeding intolerance; rather it should alert the practitioner to the possibility that altered GI function may be present. Conversely, Mentec and co-workers" studied the use of GRV as a measure of upper digestive intolerance in patients receiving enteral tube feedings in an intensive care unit (lCU). Upper digestive intolerance as defined by GRV of greater than 150 mL or the presence of vomiting occurred in 46% of the patients studied and was associated with a longer ICU stay and higher ICU mortality. The authors concluded that GRV is a useful marker of upper digestive intolerance and should be used to monitor enteral feedings in the ICU setting. Despite conflicting data, GRVs will most likely continue to be used as a measure to assess enteral feeding tolerance." The practice of measuring and assessing GRV should focus not on single measurements but rather on serial trends and in correlation with clinical assessment.l-ls ln a recent summit on aspiration in the critically ill patient, recommendations were made for the interpretation and use of GRVs in monitoring enteral tube feeding." Table 23-2 outlines these recommendations. The importance of rational interpretation of GRVs in relation to patient clinical status cannot be overemphasized. The development and use of an algorithm or clinical pathway in interpreting and managing GRVs has been suggested",
Treatment of Delayed Gastric Emptying Methods to treat delayed gastric emptying involve pharmacologic and/or non pharmacologic approaches. Nonpharmacologic methods include altering the nutrient formulation and/or feeding method. Because formulas with increased caloric density and hypertonicity are associated with delayed gastric emptying, use of an isotonic formula with moderate caloric density (1.0 to ' . •
Recommendations for Interpretation and Response to Gastric Residual Volumes (GRVs)
• Abrupt cessation should occur for overt regurgitation or aspiration • GRVs should always be used with clinical assessment • Feeds should not be stopped for GRVs <400-500 ml • GRVs >500 ml should result in withholding of feeds and reassessment of tolerance • GRVs <500 ml should be returned to the patient • GRVs between 200-500 ml should prompt careful bedside evaluation • GRVS <200 ml should prompt ongoing evaluation of aspiration risk Adaped from McClaveSA, Snider HL. Clinical use of gastric residual volumes as a monitor for patients on entemaltube feeding. J Parent Ent Nutr 2002; 26;543-S50 and McClave SA, Snider HL, Lowen CC, et al: Use of residual volume as a maker for entemal feeding intolerance: prospective blinded comparison with physical examination and radiographic findings. JPEN J Parenter Enteral Nutr 1992;16:99-105.
1.2 kcal/mL) is suggested.i-" In addition, the use of a lower-fat formula may be beneficial.4.9,I0,13 Alterations in the method of enteral feeding delivery that may improve gastric emptying include administering the formula at room temperature, reducing the rate of infusion by 20 to 25 mUhr, and providing a smaller bolus feeding, if this is the method most appropriate for the patient.v" Before use of pharmacologic agents to improve gastric emptying, a review of the patient's medication profile is critical. Consideration should be given to altering the amounts and use of opiate analgesics and other medications known to alter gastric emptylng.-v" The current choices for prokinetic agents to treat gastrointestinal dysmotility in enterally fed patients are limited. Prokinetic agents such as metoclopramide, cisapride, and erythromycin have different mechanisms of action to increase both the number and strength of gastrointestinal muscle contractions, thereby accelerating gastric emptying. Metoclopramide is a cholinergic agonist and a selective dopamine D2 receptor antagonist that is thought to promote contraction of the esophagus, gastric antrum, jejunum, and ileum." Unlike other prokinetic agents, metoclopramide is absorbed through the blood-brain barrier and can cause undesirable side effects such as drowsiness and restlessness. Erythromycin is a macrolide antibiotic, the side effect profile of which includes local release of motilin from the gastroduodenum. Motilin, a powerful stimulant of gastric antral and duodenal contractions, increases gastric motility. The gastrointestinal prokinetic effect seen with erythromycin is dose dependent. The dosage of erythromycin required to increase gastric emptying is less than that required for an antibiotic effect.23 Cisapride, another promotility agent, has been used successfully in the past; unfortunately it was removed from the U.S. market in August 2000 because its use was associated with cardiac arrhythmias, particularly torsade de pointes, in patients with prolonged QT intervals." Cisapride enhances cholinergic motor activity throughout the entire gastrointestinal tract and does not have the neurologic side effects seen with metoclopramide. Placebo-controlled studies have demonstrated that cisapride, metoclopramide, and intravenous erythromycin all promote gastric emptying in critically ill patients.23,25,26 Maclaren and colleagues in 20002 7 compared the efficacy of single doses of enteral forms of cisapride, metoclopramide, and erythromycin in critically ill patients intolerant to enteral nutrition. These researchers demonstrated that this single dose of enteral cisapride or metoclopramide promoted gastric emptying, with metoclopramide showing a quicker onset of action. Enteral erythromycin was found not to be effective as a gastric promotility agent, which was attributed to interference in the drug's absorption due to the study methodology. Two singledose studies in critically ill patients, one of which included patients with gastric motility dysfunction, showed that intravenous erythromycin was highly effective compared with placebo in accelerating gastric emptying.23,28It should also be noted that several single- and repeated-dose studies with both intravenous and enteral erythromycin showed significant improvement in gastric
SECTION IV • Principles of Enteral Nutrition
emptying compared with the effects of placebo in studies involving healthy adults and patients with diabetic gastroparesis or bowel resection." Additional studies are needed to compare multiple doses of erythromycin and metocloprarnide.P The most recent double-blind study in critically ill adults with gastric dysmotility, conducted by Maclaren and colleagues in 2001,29 compared repeated dose therapy with cisapride and metoclopramide. Both promotility agents enhanced gastric motility and improved tolerance to intragastric feedings. Metoclopramide accelerated gastric emptying and reduced GRV to a significantly greater extent than did cisapride.P The unequal efficacy between metoclopramide and cisapride may be due to differing mechanisms of action. Cisapride enhances motor activity throughout the entire gastrointestinal tract whereas metoclopramide selectively increases peristaltic contractility of the esophagus, gastric antrum, duodenum, and jejunum.P
GASTROESOPHAGEAL REGURGITATION AND ASPIRATION Aspiration pneumonia is the most serious complication of enteral tube feedings." The reported incidence of aspiration in patients receiving enteral feedings is quite varied owing to differences in the definitions used. Aspiration is defined as the inhalation of material into the airway and can include, among others, saliva and nasopharyngeal secretions and liquids, including enteral feeding formulas. Aspiration does not always lead to clinically evident pneumonia. Aspiration pneumonia is defined as parenchymal inflammation from the aspirated material, resulting in radiographic evidence of pulmonary infiltrate." Gastroesophageal reflux (GER) is often the primary event in the aspiration of gastric contents. Distention of the fundus of the stomach may result in an increased incidence of transient lower esophageal relaxations, lending to the increased likelihood of GER events.P A reduced incidence of aspiration has been reported in patients receiving jejunal versus gastric feedings although the data conflict. In patients with head injuries, Spain and co-workers" reported equal aspiration rates in patients receiving gastric versus transpyloric feedings (6% vs. 7%, not significantj.P Esparza and associates" also documented the lack of a clinically significant difference in aspiration rates between gastric versus transpylorically fed patients (7% vs. 13%, not significant)." The final placement of the feeding tube tip was not described in either study, a piece of information that is essential to drawing any conclusions. As recently described by Heyland and colleagues." a trend toward reduced aspiration occurred when feeding tubes were placed more distally in the small bowel.
Risk Factors Several factors have been associated with an increased incidence of GER including type and size of feeding tube, feeding method, body position, and the presence
279
of neurologic dystunction.Y" Ibanez and co-workers" compared the incidence of GER in critically ill patients receiving enteral nutrition through a small-bore nasogastric feeding tube with that in patients who did not receive enteral nutrition. Neither group experienced GER, and the authors concluded that the use of a small-bore nasogastric feeding tube does not increase the risk of GER. In a subsequent study," Ibanez and co-workers evaluated the effects of both a nasogastric tube (NGT) and body position on GER incidence in orotracheally intubated patients. A significantly higher incidence of GER occurred in patients with NGTs compared with those with no NGTs. GER was higher in patients placed in the supine position compared with those in the semirecumbent position, but this finding was not statistically significant. Coben and colleagues" evaluated the effects of bolus versus continuous feedings on lower esophageal sphincter (LES) relaxation and GER. Bolus feedings were associated with increased LES relaxation and an associated increase in GER whereas continuous feedings had no effect on LES or GER. Two studies have demonstrated increased incidence of GER in those with cerebrovascular accidents or other neurologic dysfunctions.F'" These variables are important considerations in assessment of the risk of GERwith enteral feedings. Multiple risk factors for aspiration exist in patients receiving enteral tube feeding. Risk factors for aspiration in critically ill patients include a documented previous episode of aspiration, decreased level of consciousness (sedation and increased intracranial pressure), neuromuscular disease and structural abnormalities of the aerodigestive tract, endotracheal intubation, vomiting, and persistently high GRVs. Additional risk factors in other populations such as long-term care patients include the presence of neurologic dysfunction and use of gastrostomy tubes. 38,39 Metheny" recently conducted an extensive review and analysis of the literature summarizing risk factors for aspiration in critically ill tube-fed patients. Her analysis identified decreased level of consciousness and a sustained supine position as major risk factors for aspiration, despite significant variability among studies.
Clinical Monitors for Detection Several monitoring tools have been proposed to detect the presence of aspiration in patients receiving enteral feedings, but none has been found to be effective." The practice of coloring enteral feedings with blue dye became prevalent because of inherent assumptions of both its high sensitivity to detect aspiration and reduced risks associated with its use. Eightysix percent of ICU nurses surveyed in 1999 reported routinely using blue dye to color enteral feedings in patients who were also receiving mechanical ventilation." Concerns regarding the risk of using blue dye emerged in the mid-1990s as case reports of urine and skin discoloration appeared in the literature." Maloney and associates'" reported the death of a patient who
280
23 • Monitoring for Efficacy, Complications, and Toxicity
had been receiving blue-eolored enteral feedings and subsequently developed skin and urine discoloration. Additional deaths have been reported, raising concern that blue dye may be absorbed in those with increased intestinal permeability." Because blue dye is a known mitochondrial toxin, the potential for adverse outcome with blue dye use is significant. McClave and co-workers," in their consensus statement, suggested that the use of blue dye for detecting aspiration in patients receiving enteral feedings should be abandoned. Additional proposed methods to detect aspiration include testing of tracheobronchial secretions for glucose or the gastric enzyme pepsin. Glucose testing of tracheal aspirates has limited sensitivity and specificity and is invalid when blood is present. In addition, the accuracy of this testing method has not been studied.f It has been suggested that the use of this method to detect aspiration should be abandoned." Metheny and colleagues" recently examined the rate at which the gastric enzyme pepsin in suctioned tracheal secretions could be detected. Test results for 14 sputum specimens were positive for pepsin, which strongly suggested that aspiration occurred in 5 of the 30 patients studied. The authors concluded that an immunoassay for pepsin in tracheal secretions may be useful for detecting pulmonary aspiration. This method is currently undergoing further study.
Methods to Minimize Aspiration Risk
associated with a higher incidence of either pulmonary aspiration, nosocomial pneumonia, or both compared with a semirecumbent position. 40,48 Elevating the head of the bed, along with ensuring that the patient does not slide down to a supine position, is a simple and safe method to minimize aspiration risk and has no associated cost. In addition to head of bed elevation, providing enteral feedings via continuous rather than bolus or intermittent infusion is suggested as is the use of prokinetic agents." Measures not recommended to reduce aspiration risk include changing to a nasoenteric tube with a smaller diameter or from a NGT to a percutaneous endoscopic gastrostomy tube. These methods have not been found to reduce aspiration risk." The North American Summit Consensus Statement recommends assessment of all critically ill patients receiving tube feedings for the presence or absence of aspiration risk factors. With the initiation of enteral feedings, the following steps should be taken to reduce aspiration risk: elevation of the head of the bed more that 30 to 45 degrees, good oral care, and regular assessment of tolerance and tube placement/position. Additional steps should be taken in critically ill patients. These include tight glycemic control, correction of electrolyte abnormalities, avoidance of narcotics, and continuous enteral feeding infusion. The use of prokinetic agents and small bowel feeding distal to the ligament of Treitz should be considered prophylactically in patients with known risks for aspiration."
DIARRHEA With the absence of sensitive methods for detecting aspiration, attention should thereby focus on both prevention and on methods to minimize its risk. One such method is the infusion of enteral feedings into the small bowel. Data documenting reduced incidence of pulmonary aspiration in patients fed into the small bowel are conflicting." Studies have often been conducted with small sample sizes, and therefore it may not have been possible to detect a clinically significant difference. In a recent meta-analysis of studies comparing gastric with small bowel feeding, Heyland and associates" demonstrated a statistically significant reduction in pneumonia with the use of small bowel feedings. They concluded that small bowel feeding might be associated with a reduction in GER and a lower rate of ventilator-associated pneumonia. One question in the use of small bowel feedings to minimize aspiration risk is where specifically should the feeding tube be placed? Heyland and associates" demonstrated that the further down the small bowel the tip is located, the greater the reduction in GER and pulmonary aspiration. Therefore, it would be prudent to focus efforts on placing a feeding tube at or beyond the ligament of Treitz rather than in the duodenal region." Additional methods for minimizing aspiration risk should be used. Most important is elevation of the head of the bed to more than 30 to 45 degrees for patients who are recumbent during the infusion. Several studies have documented that a supine position is
Diarrhea is the most commonly reported GI side effect in patients receiving enteral tube feedings.' Its cause is often thought to be the enteral feeding itself rather than other factors. Thus, alterations are often made in the enteral formula, its infusion rate, and method of administration, which ultimately result in inadequate nutrient intake. Diarrhea is a serious issue, because, if left uncontrolled, it can lead to a multitude of problems including fluid and electrolyte imbalance, perianal pain, skin breakdown, and malnutrition. In some patients, enteral feedings may need to be stopped and parenteral nutrition initiated.
Incidence and Etiology The reported incidence of diarrhea in patients receiving enteral feedings varies widely owing to the broad variation in how diarrhea is defined. Definitions range from "increased stool frequency and liquidity'r? to a specific definition of "three liquid stools per day" or "more than 500 mUhr stool volume for 2 consecutive days."4.50 The incidence of diarrhea ranges from 2% to 63% with the higher incidence reported in the critically ill patient population.?' In addition, higher incidences have been reported in studies in which a wide definition of diarrhea has been utilized, i.e., "more than 1 loose stool per day."52
..
SECTION IV • Principles of Enteral Nutrition
The occurrence of diarrhea in enterally fed patients can be due to a multitude of causes. Unfortunately, tube feedings are thought to be the primary reason patients develop diarrhea and are often altered or discontinued as a result. Several studies evaluating causes of diarrhea in patients receiving tube feedings have not confirmed these results.P An excessively rapid infusion rate such as that seen with bolus or intermittent feedings has been associated with the development of diarrhea. 54,55 In addition, feeding into the stomach rather than the intestine may be a factor in the development of diarrhea. Gastric feedings may lead to increased secretion of water and electrolytes in the colon, resulting in diarrhea" Studies of the causes of diarrhea related to the enteral formula have often focused on its osmolality. Historically, the use of hypertonic enteral formulas was thought to increase the risk of osmotic diarrhea, and the risk could be minimized by diluting the formula at initiation of feeding/" Pesola and colleagues'" demonstrated that the use of hypertonic formulas does not lead to diarrhea in normal volunteers or postoperatively in patients with head or neck cancer. Other investigators have confirmed these results, refuting osmolality of the formula as a causative factor in the development of diarrhea.v" although one study demonstrated a positive association with formula osmolalities greater than 590 mOsm/kg. 51 Other aspects of enteral formulas known to be associated with the development of diarrhea include lack of fiber, increased fat content, and microbial contamination of the formula. I,5,53 In addition, colonic motility is increased with higher-fat enteral formulas, leading to rapid movement of stool through the colon.P Microbial contamination of enteral formulas is common in the hospital setting, primarily from the introduction of microbes via handling and administration. 30,53,58 The increased usage of closed enteral feeding systems has the potential for minimizing this risk because with longer hanging times, less manipulation of the feeding system is necessary. Mickschl and colleagues'? and Wagner and co-workers" both demonstrated in patients in the ICU a reduced incidence of formula contamination with a closed versus an open enteral feeding system. Of those factors unrelated to the enteral formula or administration method, the use of antibiotics and/or specific medications is the most common reason for the development of diarrhea.' The medication itself or the form in which it is delivered can lead to the development of diarrhea. Table 23-3 listsspecific medications with diarrhea as a known side effect. Mechanisms causing diarrhea vary, but most often involve bacterial overgrowth, mucosa damage, or impairment of fluid transport or absorption." Certain drugs can cause diarrhea due to an osmotic effect of the active drug itself or to a component of the product (e.g., sorbitol). As little as a 10 to 20 g of sorbitol can lead to GI side effects including diarrhea. Sorbitol is often an underappreciated contributor to diarrhea" and should be one of the first to consider in patients receiving enteral nutrition who develop diarrhea.f The contribution of antibiotic usage to diarrhea can be quite significant. Antibiotics can alter normal colonic bacterial flora, resulting in overgrowth of abnormal
281
Medications with Increased Incidence of Diarrhea
Ampicillin Bisacodyl Caffeine Clindamycin Colchicine Digoxin Erythromycin Hydralazine Lactulose Magnesium-containing preparations Metoclopramide Methotrexate Neomycin Penicillamine Procainamide Quinidine Theophylline
From Ratnaike RN,JonesTE: Mechanisms of drug-induced diarrhea in the elderly. DrugsAging 1998;13:245-253.
bacteria and subsequent diarrhea. In addition, the reduced level of normal flora can impair normal carbohydrate/ fiber metabolism, leading to an osmotic diarrhea." One of the most common nosocomial pathogens, Clostridium difficile, is associated with use of broad spectrum antibiotic, specifically ampicillin, amoxicilIin, c1indamycin,
cephalosporins.f The presence of hypoalbuminemia has long been considered to be a cause of diarrhea in patients receiving enteral feedings. 4.5,53 It has been suggested that patients with albumin levels of less than 2.5 mg/dL develop diarrhea due to malabsorption as a result of intestinal ederna.P Studies confirming increased incidence of diarrhea in those with hypoalbuminemia have yielded conflicting results,5,53 leading to the current view that no relationship exists between albumin level and the incidence of diarrhea.P The effects of existing medical conditions on the development of diarrhea must be considered. Obviously those patients with known GI impairment such as short-bowel syndrome, pancreatic insufficiency, inflammatory bowel disease, or acquired immunodeficiency syndrome may have diarrhea related to their primary disease.' In addition, an increased incidence of diarrhea is associated with diabetes. The proposed mechanisms are reduced absorption of electrolytes by the enterocyte as well as increased colonic motllity.f Selected surgical procedures can impair intestinal transit and lead to diarrhea. Diarrhea is a recognized complication in as many as 25% of patients undergoing a truncal vagotomy." Patients with ileal and/or colonic resections have an increased risk of diarrhea due to a combination of bile salt malabsorption and a loss of the capacity to handle the transport of sodium and chloride, a significant source of diarrhea."
Treatment It has been suggested that the treatment of diarrhea follow an organized approach with the use of a pathway or algorithm. Figure 23-1 illustrates such an algorithrn.P
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23 • Monitoring for Efficacy, Complications, and Toxicity
11. Provide adequate fluids to maintain hydration and electrolyte balance 2. Reduce fluid and electrolyte losses b. Change to continuous duodenal infusion
a. Provide soluble fiber
c. Reduce rate of infusion
Enteric pathogen or inflammation or disease process?
I Pharmacological I
I Treat accordingly I Enteric pathogen
Disease/ inflammation
C. difficile Salmonella Shigella Campylobacter Yersinia E. coli
Malabsorption syndromes Diabetes Pancreatic insufficiency Bile salt malabsorption Fecal impaction
If possible, change offending medication Antibiotics Sorbitol containing medications H2 blockers Lactu lose/laxatives Magnesium-containing antacids Potassium and phosphorus supplements Antineoplastics Quinidine
I
I
.. : Diarrhea continues :
I Antimotility medication I Loperamide HCI or diphenoxylate HCI, atropine sulfate Codeine Paregoric Deodorized tincture of opium
[2reatment worked
I
Treatment didn't work
Gradually increase tube feeding rate to goal as diarrhea resolves
Change to peptide-based or elemental enteral formula
Treatment worked Increased rate as tolerated to goal
Treatment didn't work D/C tube feeding Provide PN until diarrhea resolved Os 0.2 NS via feeding tube
FIGURE 23-1. Algorithm for treatment of diarrhea. Reprinted from Fuhrman MP: Diarrhea and tube feeding: The treatment of diarrhea in tube-fed patients. Nutr Clin Pract 1999; 14:84-87.
SECTION IV • Principles of Enteral Nutrition
Williams and associates" identified significant variations in the diagnosis and management of diarrhea in enterally fed patients in an ICU and recommended the development of a structured protocol for management. Before initiation of treatment, it is essential that the etiology of the diarrhea be determined. Diarrhea can be described as being either osmotic or secretory. Osmotic diarrhea is characterized by the presence of unusual amounts of osmotically active solutes in the gut lumen.f Sorbitol, hypertonic medications, such as magnesium, or undigested macronutrients are potential sources of such solutes." Increased secretion of electrolyte and water by the gut describes secretory diarrhea, which is associated with a number of diseases or syndromes. (For a listing of sorbitol-containing products, see Chapter 24.) Secretory diarrhea will not respond to fasting the way that osmotic diarrhea will and can be considered the type of diarrhea if discontinuation of enteral feeding does not result in resolution.v" Calculating the stool osmotic gap can further assist in identifying the type of diarrhea. This can be accomplished by using the following formula: 290 - 2([stool Na"] + [stool K+]). An osmotic gap of more than 125 mOsm/kg describes osmotic diarrhea whereas a gap of less than 50 mOsm/kg describes secretory diarrhea." While the source of diarrhea is being evaluated, several adjustments in a patient's enteral feeding can be made to minimize contributing factors. Changing to a continuous duodenal or jejunal infusion may be beneficial to minimize the effects of bolus and/or gastric feedings on development of diarrhea. s6•6s Changing to a lower-fat enteral formula is also suggested, as is the introduction of fiber. Efficacy of the use of fiber either from an enteral formula or as a supplement in management of diarrhea has been mixed, in part depending on the type of fiber and on the prevailing flora," For a more thorough review of dietary fiber and its role in diarrhea management, see Chapter 14. Both soluble and insoluble fibers have been studied in the management of diarrhea. An insoluble fiber such as soy polysaccharide is a common component of enteral formulas and has not been shown to improve diarrhea consistently, especially in the acutely ill patient. 69.71 Soy polysaccharide-containing enteral formulas may be more beneficial in patients receiving chronic long-term enteral feeding. Bass and associates'" demonstrated a significant reduction in diarrhea in chronically ill patients requiring tube feedings for more than 25 days who received a soy polysaccharide-containing enteral formula compared with a fiber-free formula. Wong" reviewed the use of fiber in diarrhea management and suggested that insoluble fiber may be more effective in treating the patient receiving long-term tube feeding whereas soluble fiber may be beneficial in the critically ill patient. Forms of soluble fiber include, among others, guar, pectin, and psyllium mucilloid. In a recent evaluation, Schultz and colleagues" demonstrated a trend toward diarrhea reduction when pectin was combined with an insoluble fiber formula compared with an insoluble fiber formula alone. Enteral formulas contain various forms of fiber and often have combined sources of
283
• . . Diseases or Syndromes Associated . . with Secretory Diarrhea Infection with enterotoxic organisms such as Clostridium difficile Abuse of stimulant laxatives Intestinal resection Inflammatory bowel disease Bile acid malabsorption Fatty acid malabsorption Chronic infections Celiac sprue Small intestinal lymphoma Villous adenoma of the rectum Zollinger-Ellison syndrome Collagen vascular diseases Congenital defects Malignant carcinoid syndrome From Fine KD, Krejs GJ, Fordtran JS: Diarrhea. In GI Disease: Pathophysiology/Diagnosis/Management, 5th ed. Philadelphia, WBSaunders, 1995,vol II, p 1043.
both soluble and insoluble fibers. For a listing of enteral formulas and their fiber sources see Chapter 14. Stool specimens should be analyzed for the presence of enteric pathogens, especially C. difficile. In addition the presence of certain diseases (fable 23-4) should be evaluated, and they should be treated accordingly. Medications should be reviewed, and those that are hypertonic or contribute high amounts of sorbitol should be evaluated for causality. Consideration should be made to altering the form as well as the type of medications to minimize their contribution to diarrhea. If diarrhea continues despite enteral feeding changes, ruling out of infectious causes, and removal of diarrheacausing medications, antidiarrheal medications may be provided. It is suggested that medications not be used for diarrhea management unless stool culture results are negative for bacteria." Table 23-5 provides doses of commonly used medications for the treatment of diarrhea. Medication doses at scheduled intervals has been shown to be more effective than intermittent doses." The
-
Selected Doses of Antidiarrheal Medications
Medication
Adult Dose
Antimotility Lomotil Loperamide Paregoric Opium tincture
5 mg qld, do not exceed 20 rug/day Initially 4 mg, then 2 mg after each loose stool; do not exceed 16 rng/day 5-10 mL 1-4 times daily 0.6 mL qld
Adsorbents Kaolin and pectin Antlsecretory Bismuth
Octreotlde
30-120 mL after each loose stool Two tablets or 30 mL every 30 min to 1 hr as needed; up to 8 doses/day Initial: 100 J.lg subcutaneously tid
Adapted from Spruill WJ, Wade WE: GI disorders. In DiPiroIT. Talbert RL, Yee GC, et al (eds): Pharmacotherapy: A Pathological Approach, 5th ed. New York, McGraw-Hill, 2002. p 660.
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23 • Monitoring for Efficacy, Complications, and Toxicity
use of probiotics has recently been suggested for the treatment of diarrhea." See Chapter 22 for greater detail. If diarrhea continues despite use of antidiarrheal medications, consideration may be given to use of an elemental formula. The use of peptide-based enteral formulas has been shown to improve diarrhea in hypoalbuminemic patients.v" Despite all of the above treatment approaches, if diarrhea continues and is severe, enteral feedings should be discontinued for bowel rest and parenteral nutrition should be initiated. 65,75
CONSTIPATION Constipation can be difficult to define because normal stool habits vary significantly among individuals. A general definition of constipation is the accumulation of excess waste within the colon.' Constipation is more prevalent in patients requiring long-term enteral feedings, although it can occur in acutely ill patients requiring tube feedings, especially in those who become dehydrated.i-" The most commonly cited reasons that enterally fed patients develop constipation are lack of fiber, insufficient water, fecal impaction, and slowing of peristalsis by drugs or hormonal or electrolyte derangements.P The primary goal in managing constipation in the tube-fed patient is prevention. It is important to ensure adequate fluid intake either by providing additional boluses of water or by formula dilution. If a concentrated formula is being used, consider a change to a 1 kcallmL
IEImIJII
concentration if the patient's clinical status permits. Use of a fiber-eontaining formula can be helpful in preventing constipation. Fiber propels waste through the colon, increasing fecal bulk, which promotes increased stooling." Shankardass and co-workers" compared use of a fiber formula with a fiber-free formula in long-term tube-fed patients. They found that constipation rate was equal with or without fiber; however, a reduction in laxative use was observed in those who received the fiber formula. If a fiber formula is being provided, a minimum of 1 mUkcal is suggested to prevent constipation," If, despite the use of fiber or administration of increased fluids, constipation is not resolved, the use of stool softeners, laxatives, or enemas may be necessary. It is important to recognize and treat constipation to avoid the development of impaction or bowel obstruction.P
METABOLIC COMPLICATIONS A major advantage of enteral nutrition over parenteral nutrition is a reduced overall complication rate." Several of the factors responsible for the metabolic complications seen among patients receiving enteral nutrition are similar to those seen with parenteral nutrition." See Table 23-6 for a detailed listing of potential metabolic complications. Metabolic complications such as altered hydration status and electrolyte and glucose control occur more often in patients with underlying illnesses and resultant organ dysfunction.P
Metabolic Complications of Tube Feeding
Problem
Possible Causes
Prevention or Therapy
Glucose intolerance
Refeeding syndrome in malnourished patient Specific disease states or condition such as diabetes mellitus, sepsis or trauma Metabolic stress Inadequate fluid intake
Monitor serum glucose daily until stable «200 mg/dl.) at goal TF rate. Maintain last tolerated TF rate, then gradually increase as tolerated.
Hypertonic dehydration
Excessive Iluld losses Administration of hypertonic, highprotein formula in patient unable to express thirst Overhydratlon
Excessive fluid intake Rapid refeeding In malnourished patient Increased extracellular mass catabolism causing loss of body cell mass with subsequent potassium loss Elevated aldosterone levels causing sodium retention Altered sodium pump causing excessive intracellular sodium retention Cardiac, hepatic, or renal insufficiency
Provide 30%-50% total kcal as fat; may need modular formula. Monitor daily fluid intake and output; monitor body weight daily; weight change >0.2 kg/day reflects decrease or increase of extracellular fluid. Monitor serum electrolyte values, serum osmolality, urine specific gravity, and BUN and Cr levels daily. (BUN/Cr ratio is usually 10:1 in patients with normal hydration status.) Assess fluid status; estimate fluid loss (mild loss, n, body weight decrease; moderate loss, 6% body weight decrease; severe loss, 10% body weight decrease); replace fluid loss in addition to maintenance fluid needs enterally or parenterally. Assess fluid status; monitor daily fluid intake and output. Monitor serum electrolyte values daily, Monitor body weight; weight change >0.2 kg/day reflects decrease or increase of extracellular fluid. Administer diuretic therapy. Use formula with lower free-water content if necessary,
Continued
SECTION IV • Principles of Enteral Nutrition
285
_ _ Metabolic Complications of Tube Feeding-cont'd
Problem
Possible Causes
Prevention or Therapy
Hypokalemia
Refeeding syndrome in malnourished patients Depleted body cell mass Effect of antidiuretic hormone and aldosterone Diuretic therapy Excessive losses (e.g., from diarrhea or nasogastric drainage) May induce or be the result of metabolic acidosis Insulin therapy Dilutional state Refeeding syndrome in malnourished patients Insulin therapy Phosphate-binding antacids Refeeding syndrome in malnourished patients Excessive losses from urine, skin, or stool Metabolic acidosis
Monitor serum potassium level daily until stable within normal limits at goal TF rate. Supplement potassium and chloride.
Hypophosphatemia
Hypomagnesemia
Hyperkalemia
Hypoglycemia
Hypernatremia
Hypernatremia
Poor perfusion (e.g., congestive heart failure) Renal failure Excessive potassium intake from oral diet and/or TF formula Sudden cessation of TF for patient receiving oral hypoglycemic agents or insulin therapy Fluid overload Dilutional state due to elevated antidiuretic hormone level with subsequent parenteral infusion of saline solutions Cardiac, hepatic, or renal insufficiency Inadequate fluid intake with excessive losses Depletion of total body sodium, extracellular mass, and extracellular fluid
Hyperphosphatemia
Renal insufficiency
Hypercapnia
Overfeeding
Essential fatty acid deficiency Hypozincemia
Excessive carbohydrate load in patient with respiratory dysfunction Inadequate linoleic acid intake (e.g., prolonged used of low-fat enteral formula) Excessive losses from diarrhea, wound, or GI losses (Note: serum zinc level may not accurately reflect total body zinc stores.)
Monitor serum phosphorus level daily or every other day until stable within normal limits at goal TF rate. Supplement phosphorus enterally or parenterally. Adjust antacid dose if necessary. Monitor serum magnesium level daily or every other day until stable within normal limits at goal TF rate. Supplement magnesium enterally or parenterally. Monitor serum potassium level daily or every other day until stable within normal limits at goal TF rate. Treat cause of poor perfusion. Kayexalate, glucose, and/or insulin therapy. Decrease potassium intake; use formula with lower potassium content. Monitor serum glucose level daily until stable within normal limits at goal TF rate; taper TF gradually. Monitor serum sodium level daily until stable within normal limits at goal TF rate. Assess fluid status. Administer diuretic therapy, if required. Restrict fluids. Restrict sodium. Monitor dally fluid intake and output; monitor body weight daily; weight change >0.2 kg/day reflects decrease or increase of extracellular fluid. Monitor serum electrolyte values, serum osmolality, urine specific gravity, and BUN and CR levels daily. (BUN/Cr ratio is usually 10:1 in patients with normal hydration status.) Assess fluid status; estimate fluid loss (mild loss, 3r., body weight decrease; moderate loss, 6% body weight decrease; severe loss, 10% body weight decrease); replace fluid loss in addition to maintenance fluid needs enterally or parenterally for the repletion of extracellular fluid space. Administer phosphate binder therapy. Use formula with lower phosphorus content if necessary. Provide maintenance calorie and protein needs without overfeeding. Use enteral formula with balanced distribution of carbohydrate, protein, and fat. Provide 30%-50% of total kcal as fat. Include at least 4% kcal needs as essential fatty acids (linoleic acid); add modular fat formula to diet regimen; administer 5 mL of enteral safflower oil daily. Supplement zinc enterally or parenterally.
BUN, blood urea nitrogen; CR, creatinine; GI, gastrointestinal;TF,tube feeding. Adapted from Ideno KT: Enteral nutrition. In Gottschlich MM, Matarese LE, Shronts EP (eds): NutritionSupport Dietetics Core Curriculum, 2nd ed. SilverSpring, MD, American Society for Parenteral and Enteral Nutrition, 1993, pp 98--99.
286
23 • Monitoring for Efficacy, Complications, and Toxicity
BED
Monitoring Parameters of Enteral Nutrition (EN) to Prevent Complications
Parameter Abdominal examination Weight Fluid Intakes/outputs Stool frequency, consistency, and volume Gastric residual checks Enterostomy tube site assessment for leakage and/or skin Irritation/redness Blood glucose (nondiabetic) Serum electrolytes, blood urea nitrogen/creatinine, glucose, calcium, magnesium, and phosphorus Liver function tests
During Initiation of EN or for a Critically III Patient
During Stable EN Therapy or for a Rehabilitating Patient
Every 4-6 hours Daily Every 4-6 hours Dally Every 4-6 hours Dally
Every 12-24 hours Weekly Daily Daily Variable Variable
Every 4-6 hours Daily
Weekly Weekly
Weekly
Weekly
Careful monitoring by nutrition support professionals can minimize or prevent metabolic complications related to enteral feeding therapy." Standardized protocols for enteral nutrition administration and monitoring should be used." Table 23-7 details specific monitoring parameters and suggested frequency of use based on the patient's level of care. With initiation of enteral nutrition, monitoring frequency depends on correction of baseline fluid, glucose, and electrolyte abnormalities, the preexisting degree of malnutrition, and the continuing level of metabolic stress. To promote a standardized monitoring regimen, monitoring guidelines are often delineated on formalized tubefeeding orders." Additional fluids and electrolytes may be required beyond the fixed amounts supplied in enteral formulas." The need for fluid and electrolyte restriction may necessitate a change to a fluid- and/or electrolyterestricted formula.
THE REFEEDING SYNDROME
Definition and Incidence Refeeding syndrome is the term used to describe severe electrolyte and fluid shifts that may result from therapeutic refeeding after severe weight loss (severe advanced protein-ealorie malnutritionj.f It is more common in the elderly, although mortality figures are difficult to establish accurately because patients often have other underlying disease states." Anorexia nervosa and alcoholism are the two most common clinical presentations of the refeeding syndrome, but the disorder has also been described in oncology patients undergoing chemotherapy, malnourished elderly individuals, and selected postoperative patients. The total incidence of refeeding syndrome has been estimated to be as high as 25% in patients with cancer who receive nutritional support.f Other patients at risk include stressed and nutritionally depleted patients, those who have not been fed for 7 to 10days, patients with morbid obesity who are consuming restrictive diets, and elderly individuals with chronic medical conditions and poor nutrient intake."
Patients with severe weight loss have adapted largely to the use of free fatty acids and ketone bodies as energy sources, which do not require phosphate-containing intermediates.' Complications may result if refeeding is initiated using an excessively rapid repletion of carbohydrate or if nutrient requirements of the expanding body cell mass are not anticipated. Asudden shift to glucose as the predominant fuel will be associated with a high demand for production of phosphorylated glycolytic intermediates as well as a shift away from fat metabolism, a process to which these patients would have adapted/" Refeeding with dextrose as a fuel source also stimulates insulin secretion and is followed by an intracellular shift of glucose along with the electrolytes necessary for glucose oxidation. The rapid reintroduction of large amounts of carbohydrate feedings can result in fluid and electrolyte abnormalities, including hypophosphatemia, hypokalemia, and hypomagnesemia. Hypophosphatemia is the hallmark of the refeeding syndrome and has been reported in patients receiving repletion both parenterally and enterally. Severe hypophosphatemia is associated with hematologic, neuromuscular, cardiac, and respiratory dysfunction.' Another common manifestation of the refeeding syndrome is fluid retention, due primarily to the antinatriuretic effect of increased insulin concentrations. Sudden expansion of extracellular fluid can lead to cardiac decompensation in patients with severe marasmus.' Alternatively, administration of dextrose may cause significant hyperglycemia, which may in tum result in osmotic diuresis and dehydration." Table 23-8 further outlines the physiologic and metabolic sequelae of the refeeding syndrome. Close monitoring of serum phosphate, magnesium, potassium, and glucose are imperative when any form of specialized nutrition support is initiated, particularly in undernourished patients."
Prevention and Treatment Screening by an interdisciplinary team to identify patients at risk for refeeding complications is the best approach to prevention. Electrolyte disturbances can occur within the first few days of refeeding, cardiac complications
SECTION IV • Principles of Enteral Nutrition ~
~
287
Physiologic and Metabolic Sequelae of I.feedlng Syndrome
Organ System
Effects of Hypophosphatemia
Effects of Hypokalemia
Cardiovascular
Changes in myocardial function, arrhythmia, congestive heart failure (CHF), sudden death Changes in red blood cell morphology, white blood cell dysfunction, hemolytic anemia, thrombocytopenia, platelet dysfunction Liver dysfunction Confusion, coma, weakness, lethargy, parasthesia cranial nerve palsy, siezures, Gullian-Barre-like syndrome, rhabdomylosis Acute respiratory failure
Orthostatic hypotension, altered sensitivity to digoxin, arrhythmia, electrocardiogram (EKG) changes, cardiac arrest
Hematologic Hepatic Neuromuscular Respiratory Gastrointestinal Metabolic Renal
Arreflexia, hyporeflexia, parathesia, rhabdomylosis, weakness, paralysis parasthesias, respiratory depression Constipation, ileus, increased hepatic encephalopathy Glucose intolerance, hypokalemic metabolic acidosis Reduced urinary concentrating ability, polyuria, polydypsia, nephropathy with reduced urinary concentrating ability, myoglobinuria due to rhabdomylosis
Organ System
Effects of Hypomagnesemia
Effects of Glucose/fluid Intolerance
Cardiovascular Hemodynamic Neuromuscular
Arrhythmia, tachcardia, torsade de pointes
Congestive heart failure, sudden death Dehydration, fluid overload, hypotension Hyperosmolar nonketotic coma
Pulmonary Gastrointestinal Metabolic
Ataxia, confusion, hyporeflexia, irritability muscular tremors, parasthesias, personality changes, seizures, tetany, weakness, vertigo Abdominal pain, anorexia, diarrhea, constipation
Renal
Carbon dioxide retention, respiratory depression Fatty liver Hyperglycemia, hypernatremla, ketoacidosis, metabolic acidosis Osmotic diuresis, prerenal azotemia
Reprinted with permission: Russell M, Cromer M, Grant J: Complications of enteral nutrition therapy. In Gotlschlich MM (ed): The Science and Practice of Nutrition Support: A Case-Based Core Curriculum. Dubuque, IA. Kendall-Hunt Publishers, 2001, p 189.
occur within the first week, and delirium and other neurologic features generally follow afterward." The refeeding syndrome can be life threatening if not treated promptly. Although enteral feeding formulas contain generous amounts of electrolytes, additional supplementation may be necessary to maintain serum potassium, phosphorus, and magnesium levels in normal ranges early in a malnourished patient's enteral therapy regimen. Several recommendations have been made to minimize the risk of refeeding syndrome. In addition to close monitoring of electrolyte levels, use of conservative calorie estimation and gradual introduction of dextrose should be considered to be the standard approach in patients at risk for refeeding syndrome.~6 After electrolyte levels have stabilized and fluid status is stable, consideration can be given to advancing the energy intake to promote nutritional repletion as warranted."
HYPERGLYCEMIA Hyperglycemia is rare in patients receiving continuous enteral feedings who do not have diabetes mellitus." Insulin secretion is greater after enteral ingestion of either dextrose or protein than after intravenous infusion and is due to the incretin effect,88 Incretin, produced in the GI tract, enhances insulin secretion, making hyperglycemia
less likely. Most hyperglycemia due to enteral feeding is probably the result of a combination of factors commonly seen in the acute care setting including diabetes mellitus, insulin resistance (precipitated by illness), medications (notably steroids), and physiologic stress." Hyperglycemia requires treatment because it impairs immune function, increases the risk of infection, increases postischemic neuronal damage, and can result in fluid and electrolyte losses. 1 Therefore, measures taken to monitor and control blood glucose during enteral nutrition support are important." Glucose should be monitored at periodic intervals in all patients who receive enteral feeding. Treatment of hyperglycemia includes evaluating the appropriateness of caloric delivery as well as the rate of enteral feeding infusion." It is important to treat the underlying disease, adjust any medications responsible for hyperglycemia, maintain intravascular volume, and prevent electrolyte disturbances. If randomly measured, blood glucose concentrations remain elevated (>180 mg/dL) at the carbohydrate level needed by the patient, insulin or an oral hypoglycemic agent should be administered (if at the goal rate of continuous feedings) and the amount should be titrated to reduce the blood glucose concentration into the desired range. I The frequency and composition of the enteral feedings should be tailored to fit the profile of the hypoglycemic agent, and administration of excess calories
288
23 • Monitoring for Efficacy, Complications, and Toxicity
should be avoided." For a more thorough discussion of enteral formula selection in hyperglycemia refer to Chapter 43.
MONITORING FOR EFFICACY AND. COMPLICATIONS Monitoring for complications during enteral feeding is essential to minimize potential adverse effects as described earlier and to optimize nutrient delivery. Additional monitoring is necessary to evaluate the efficacy of a patient's enteral feeding in relationship to the desired outcomes. How effective has the enteral feeding regimen been in achieving specific patient goals such as weight gain or increased strength? Specific goals and outcomes should be developed early in the assessment process and should be based on a variety of patient-specific factors including disease, current condition, care setting, and overall wtshes." Table 23-9 describes several parameters that may be useful in monitoring and assessing efficacy in patients receiving both acute care and long-term enteral feeding. Although many of these involve nutritional end points that are often influenced by ongoing illness, they often are readily available and may be useful as intermediate markers of efficacy.so Monitoring for nutritional efficacy includes serial evaluation of parameters often included in the initial nutrition assessment and care plan. Serum
proteins are often used and may be best suited for use after the patient has recovered from the acute injury or inflammatory process. Until this time, nitrogen balance may be a useful monitoring parameter to assess nutritional adequacy.P A common and essential component of nutritional monitoring includes evaluating the adequacy of enteral intake." Without an accurate assessment of actual nutrient intake, evaluation of specific goals and whether they have been achieved is not possible. It is well known that ordered intake does not equate to actual intake. McClave and associates" compared actual enteral intake to that ordered in critically ill patients and found that, on average, only 78% of ordered enteral volume was actually received. Selected procedures, tube displacement, and routine nursing care activities are common reasons for disruption of enteral feeding and can result in a significant decrease in actual nutrient intake. Enteral intake monitoring can be performed without difficulty and should be considered a primary parameter for assessing the efficacy of enteral nutrition." The frequency of monitoring to evaluate efficacy will vary with the patient's overall nutrition goals and objectives as well as the patient's clinical state." Monitored parameters should be compared with the initial goals and objectives with subsequent adjustments made to the nutritional care plan. Overall monitoring frequency should be evaluated and adjusted as clinical status and prognosis change."
. . . Suggelted Monitoring of Entera~ Nutrition (EN) to Promote Nutritional Efficacy During Initiation of EN
During Stable EN Therapy
During Long-Term Home ENTherapy
Daily N/A N/A
Weekly N/A N/A
Weekly Every 1-2 months Every 1-2 months
N/A
Weekly
Weekly to monthly
Albumin
Monthly
Monthly
Transferrin
Weekly
Weekly
Prealbumln
Weekly
Weekly
24-hour urine urea nitrogen
Weekly
Once or twice monthly
Monthly, then frequency tailored to the patient situation Monthly, then frequency tailored to the patient situation Monthly, then frequency tailored to the patient situation Frequency tailored to patient-specific situations
Daily Daily
2-3 times weekly 2-3 times weekly
Weekly, then tailored to the patient situation Monthly, then frequency tailored to the patient situation
Daily
Dally
Weekly
Parameter
Anthropometric Weight Triceps skinfold Mldarm muscle circumference Muscle function Level of physical endurance
Metabolic
Nutritional Intake Calories Protein, fluid, electrolytes, trace elements, vitamins Skin integrity Wound healing, pressure sore(s)
Adapted from Janson DD, Chessman KH: Enteral nutrition. In Depiro IT, Talbert RL, Yee GC, et al (eds): Pharmacotherapy: A Pathological Approach, 5th ed. New York, McGraw-Hill, 2002, p 2513.
SECTION IV • Principles of Enteral Nutrition
SUMMARY In summary, the most effective administration of enteral feedings requires care to prevent and treat GI and metabolic complications, including refeeding syndrome. The team approach to enteral administration includes careful evaluation of outcomes to monitor and optimize efficacy. REFERENCES I. Lord L, Trumbore L, Zaloga G: Enteral nutrition implementation and management. In Merritt RJ (ed): A.S.P.E.N. Nutrition Support PracticeManual. Silver Spring, MD, American Societyof Parenteral and Enteral Nutrition, 1998, p 189. 2. Montejo JC: Enteral nutrition-related GI complications in critically ill patients: A multicenterstudy. Crit Care Med 1999;27:1447-1453. 3. Montejo JC, Grau T, Acosta J, et al: Multicenter, prospective, randomized, single-blind study comparing the efficacy and GI complicationsof early jejunal feeding with early gastric feeding in critically ill patients.CritCare Med 2002;30:796-800. 4. Russell M, Cromer M, Grant J: Complications of enteral nutrition therapy. In Gottschlich MM (ed): The Science and Practice of Nutrition Support: A Case-Based Core Curriculum. Dubuque, lA, Kendall-Hunt Publishers, 2001, p 189. 5. Lefton J: Management of common GI complications in tube-fed patients. Support Line 2002;24:19-25. 6. Marvin RG, McKinely BA, McQuiggan, et al: Nonocclusive bowel necrosisoccurring in critically ill trauma patients receivingenteral nutrition manifestno reliable clinical signs forearly detection. Am J Surg2000;179:7-12. 7. McClave SA, Sexton LK, Spain DA, et al: Enteral tube feeding delivery in the intensive care unit: Factors impeding adequate delivery. Crit Care Med 1999;27:1252-1256. 8. HaslerWL: The physiology of gastricmotility and gastricemptying. In Yamada T (ed): Textbook of Gastroenterology, 2nd ed. Philadelphia, JB Lippincott, 1995, Vol I, p 191. 9. Sidery MB, Macdonald lA, Blackshaw PE: Superior mesenteric artery blood flow and gastric emptying in humans and the differential effectsof high fatand high carbohydrate meals. Gut 1994;35: 186-190. 10. Akrabawi SS, Mobarhan S, Stoltz RR, et al: Gastric emptying, pulmonary function, gas exchange and respiratory quotient after feeding a moderate versushigh fat enteral formula meal in chronic obstructive pulmonary disease patients. Nutrition 1996;12:260-265. II. Bouin M, Savoye G, Hellot HS, et al: Does the supplementation of the formula with fiber increase the risk of gastro-esophageal reflux duringenteral nutrition? Ahuman study.ClinNutr2001;20:307-312. 12. Ritz MA, Fraser R, Tam W, et al: Impacts and patterns of disturbed GI function in critically ill patients. Am J Gastroenterol 2000;95: 3044-3052. 13. Lin HC, Hasler WL: Disorders of gastric emptying. In Yamada T (ed): Textbook of Gastroenterology, 2nd ed. Philadelphia, JB Lippincott, 1995, vol I, p 1318. 14. DeMeo MT, Bruninga K: Physiology of the aerodigestive systemand aberrations in that systemresulting in aspiration.J Parenter Enteral Nutr2002;26:S9-S18. 15. Frost P, EdwardsN, Bihari D: Gastric emptyingin the critically illThe way forward? Intensive Care Med 1997;23:243-245. 16. Tarling MM, Toner CC, Withington PS, et al: A model of gastric emptying using paracetamol absorption in intensivecare patients. Intensive Care Med 1997;23:256-260. 17. Mallampalli A,McClave SA, Snider HL: Defining tolerance to enteral feeding in the intensivecare unit. ClinNutr2000;19:213-215. 18. McClave SA, Snider HL: Clinical use of gastric residual volumesas a monitor for patients on enteral tube feeding. J Parenter Enteral Nutr2002;26:543-S50. 19. McClave SA, Snider HL, Lowen CC, et al: Use of residual volume as a marker for enteral feeding intolerance: Prospective blinded comparison with physical examination and radiographic findings. J Parenter EnteralNutr1992;16:99-105. 20. Mentec H, Dupont H, Bocchetti M, et al: Upper digestive intolerance during enteral nutrition in critically ill patients: Frequency, riskfactors and complications. CritCare Med2001;29:1955-1961.
289
21. McClave SA, DeMeo MT, DeLegge MH, et al: North American Summit on Aspiration in the Critically 111 Patient consensus statement. J Parenter Enteral Nutr2OO2;26:58O-S85. 22. Maclaren R. Intolerance to intragastric enternal nutrition in critically ill patients: complications and management. Pharmacotherapy 2000;20(12):1486-1498. 23. Chapman MJ, Fraser RJ, Kluger MT, et al: Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. CritCare Med 2000;28(7):2334-2337. 24. Wysowski DK, Corken A, Gallo-Torres H, et al: Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisipride and Food and Drug Administration regulatory actions. Am J Gastroenterol 2001;24:1690-1694. 25. Heyland DK, Tougas G, Cook DJ, Guyatt GH: Cisapride improves gastricemptyingin mechanicallyventilated,criticallyillpatients:A randomized, double blind trial. Am J Respir Crit Care Med 1996; 154:1678-1683. 26. Calcroft RM, Joynt G, Gomersall CD, Hung V: Gastric emptying in criticallyill patients:A randomized, blinded, prospective comparison of metoclopramide with placebo. Intensive Care Med. 1997; 23(Suppl 1):SI38. 27. Maclaren R,Kuhl DA, Gervasio JM, et al: Sequential singledoses of cisipride, erythromycin, and metoclopradmide in critically ill patients intolerant to enteral nutrition: A randomized, placebocontrolled, crossoverstudy. CritCare Med 2000;28(2):438-444. 28. Dive A, Miesse C, Galanti L, et al: Effect of erythromycin on gastric motility in mechanically ventilated critically ill patients: A doubleblind, randomized, placebo-controlled study. CritCare Med 1995; 23:1356-1362. 29. Maclaren R, Patrick WD, Hall RI, et al: Comparison of cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastic enteral nutrition in critically ill, mechanically ventilated adults. Clinical Therapeutics 2001;23(11): 1855-1866. 30. Beyer PL: Complications of enteral nutrition. In Matarese LE, Gottschlich MM (eds): Contemporary Nutrition Support Practice, A Clinical Guide, 1sted. Philadelphia, WB Saunders, 1998, p 216. 31. ZalogaGP: Aspiration-related illnesses: Definitions and diagnosis.J Parenter Enteral Nutr2002;26:S2-58. 32. Spain DA, DeWeese RC, Reynolds MA, et al: Transpyloric passage of feeding tubes in patients with head injuries does not decrease complications.J Trauma 1995;39:1100-1102. 33. Esparza J, Boivin MA, Hartshorne MF, et al: Equal aspiration rates in gastrically and transpylorically fed criticallyillpatients. Intensive Care Med 2001;27:660-664. 34. Heyland DK, DroverJW, MacDonald S, et al: Effect of post-pyloric feeding on gastroesophageal regurgitation and pulmonary microaspiration: Results of a randomized controlled trial. CritCare Med2001;29:1495-1500. 35. DeLegge MH: Aspiration pneumonia: Incidence, mortality and at-risk populations.J Parenter EnteralNutr2002;26: SI9-S25. 36. Ibanez J, Penafiel A, Marse P, et al: Incidence of gastroesophageal reflux and aspiration in mechanically ventilated patients using small bore nasogastric tubes. J Parenter Enteral Nutr 2000;24: 103-106. 37. Ibanez J, Penafiel A, Raurich JM, et al. Gastroesophageal reflux in intubated patients receivingenteral nutrition: Effect of supine and semi-recumbent positions. J Parenter Enteral Nutr 1992;16: 419-422. 38. Coben RM, Weintraub A, DiMarino Al, et al: Gastroesophageal reflux during gastrostomy feeding. Gastroenterology 1994;106: 13-16. 39. Lucas CE, Yu P, Vlahos A, et al: Lower esophageal sphincter dysfunction often precludes safe gastric feeding in stroke patients. ArchSurg 1999;134:55-58. 40. Metheny NA: Risk factors for aspiration. J Parenter Enteral Nutr 2002;26:S26-S33. 41. Maloney JP, Ryan TA: Detection of aspiration in enterally fed patients: A requiem for bedside monitors of aspiration. J Parenter EnteralNutr2002;26: S34-542. 42. Metheny NA, Aud MA, Wunderlich RJ: A survey of bedside methods used to detect pulmonary aspiration of enteral formula in intubated tube-fed patients. Am J CritCare 1999;8:160-169. 43. Maloney JP, Halbower,FoutyBF, et al: Systemic absorption of food dye in patients with sepsis. N Engl J Med2000;343:1047-1048.
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44. Maloney JP, Ryan TA, Brasel KJ, et al: Food dye use in enteral feedings: A review and a call for a moratorium. Nutr Clin Pract 2002;17:169-181. 45. Metheny NA, Chang YH, Ye JS, et al: Pepsin as a marker for pulmonary aspiration.AmJ CritCare 2002;11:150-154. 46. Heyland DK, DroverJW, Dhaliwal R, et al: Optimizing the benefits and minimizing the risksof enteral feeding in the criticallyill:Role of small bowel feeding. J Parenter Enteral Nutr2002;26:S51-S57. 47. Heyland DK, DroverJW, MacDonald S, et al: Effect of post-pyloric feeding on gastroesophageal regurgitation and pulmonary microaspiration: Results of a randomized controlled trial.CritCare Med 2001;29:1495-1501. 48. ScolapioJS: Methods fordecreasingriskof aspirationpneumonia in critically ill patients.J Parenter EnteralNutr2002;26:S58--S61. 49. Fine KD, Krejs GJ, Fordtran JS: Diarrhea. In GI Disease: PathophysiologylDiagnosis/Management, 5th ed. Philadelphia, WB Saunders, 1995, vol II, p 1043. 50. Williams MS, Harper R, Magnuson B, et al: Diarrhea management in enterallyfed patients. NutrClin Pract 1998;13:225-229. 51. SmithCE, Marien L,BrogdonC,et al: Diarrheaassociated with tube feeding in mechanically ventilated critically ill patients. NuTS Res 1990;39:148--152. 52. Bliss DZ, Guenter PA, Settle RG: Defining and reportingdiarrhea in tube-fed patients-What a mess! AmJ Clin Nutr 1992;16:488--489. 53. Eisenberg P: An overview of diarrhea in the patient receiving enteral nutrition.Gastroenterol Nurs 2002;25:95-104. 54. Ciocon JO, Galindo-Ciocon DJ, Tiesses C, et al: Continuous compared with intermittenttube feeding in the elderly. J Parenter Enteral Nutr 1993;16:525-528. 55. HeitkemperME, Martin DL, Hansen BC et al: Rate and volume of intermittententeral feeding. J Parenter EnteralNutr1981;5:125-129. 56. Bowling TE: Enteralfeeding-related diarrhea: Proposed causes and possiblesolutions. Proc NutrSoc 1995;54:579-590. 57. PesolaGR, Hogg JE, Eissa N,et al: Hypertonic nasogastric tube feedings: Do they cause diarrhea?CritCare Med 1990;18: 1378--1382. 58. Okuma T, Nakamura M, Totake H, et al: Microbial contamination of enteral feeding formulas and diarrhea. Nutrition 2000;16:719-722. 59. Mickschl DB, Davidson LJ, Flournoy DJ, et al: Contamination of enteral feedings and diarrhea in patients in intensive care units. HeartLung1990;19:362-370. 60. Wagner DR, Elmore MF, Knoll DM: Evaluation of "closed" vs "open" systems for the delivery of peptide-based enteral diets. J Parenter EnteralNutr 1994;18:453-457. 61. Ratnaike RN, Jones TE: Mechanisms of drug-induced diarrhea in the elderly. Drugs Aging 1998;13:245-253. 62. McMarthy MS, Fabling JC, Bell DE: Drug-nutrient interactions. In Shikora SA, Martindale RG, Schwaitzberg SO (eds): Nutritional Considerations in the Intensive Care Unit: Science, Rationale and Practice. Dubuque, IA, Kendall-Hunt Publishing, 2002, p 153. 63. Bartlett JG: Antibiotic associated diarrhea. N Engl J Med 2002;346: 334-339. 64. Kelly CP, Pothoulakis C, laMont IT: Clostridium difficile colitis. N Engl J Med 1994;330:257-262. 65. FuhrmanMP: Diarrheaand tube feeding: The treatment of diarrhea in tube-fedpatients. NutrClin Pract 1999;14:84-87. 66. Powell DW: Approach to the patient with diarrhea.InYamadaT (ed): Textbookof Gastroenterology, 2nd ed. Philadelphia,JB Lippincott, 1995, vol 1, p 830. 67. American Gastroenterological Association Clinical Practice and Practice EconomicsCommittee: AGA technical reviewon the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116: 1464-1486. 68. Dobb GJ, Towler SC: Diarrhea during enteral feeding in the critically ill: A comparison of feeds with and without fiber. Intensive Care Med 1990;16:252-255.
69. BassOJ, Forman LP, AbramsSE, et al: The effect of dietary fiber in tube-fed elderly patients. J Gerontol Nurs 1996;22:37-44. 70. Belknap D, Davidson LJ, Smith CR: The effects of psyllium hydrophilic mucilloid on diarrhea in enterally fed patients. Heart Lung 1997;26:229-237. 71. Nakao M, Ogura Y, Satake S, et al: Usefulness of soluble dietary fiber forthe treatment of diarrhea during enteral nutrition in elderly patients. Nutrition 2002;18:35-39. 72. Wong K: The role of fiber in diarrhea management. Support Line 1998;20:16-20. 73. Schultz AA, Ashby-Hughes B, Taylor R, et al: Effects of pectin on diarrhea in critically ill tube-fed patients receiving antibiotics. Am J CritCare 2000;9:403-411. 74. Cresci G: The use of probiotics with the treatment of diarrhea. NutrClin Pract 2001;16:30-34. 75. Clinical Pathways and Algorithms for Delivery of Parenteral and Enteral Nutrition Support in Adults. Silver Spring, MD, American Society for Parenteral and Enteral Nutrition, 1998. 76. Position of the American DieteticAssociation: Health implications of dietary fiber. J Am Diet Assoc 2002;102:1316-1323. 77. Shankardass K, Chuchmuch S, Chelswick K, et al: Bowel function of long-term tube-fed patients consuming formulae with and without dietary fiber. J Parenter Enteral Nutr 1990;14: 508-512. 78. Cabre E, Gassull MA: Complications of enteral feeding. Nutrition 1993;9:1-9. 79. Janson DO, Chessman KH: Enteral nutrition. In Dipiro IT, et al (eds): Pharmacotherapy: A Pathophysiologic Approach, 5th ed. NewYork, McGraw-Hill, 2002, pp 2495-2517. 80. A.S.P.E.N. Board of Directors and Task Force on Standards for Specialized Nutrition Support for Hospitalized Adult Patients: Standards for specialized nutrition support: Adult hospitalized patients. Nutr Clin Pract 2002;17:384-391. 81. Ideno KT: Enteral Nutrition. In Gottschlich MM, Materese LE, Shonts EP(eds): Nutrition Support Dietetics: Core Curriculum, 2nd ed. Silver Spring, MD, 1993, American Society of Parenteral and Enteral Nutrition, pp 71-104. 82. Knochel JP: The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 1977;137:203-220. 83. Crook MA, Hally V, Panteli N: The importance of the refeeding syndrome. Nutrition 2001;17:632-637. 84. Brooks MJ, Melnik G: The refeeding syndrome: An approach to understanding its complications and preventing its occurrence. Pharmacotherapy 1995;15:713-726. 85. WeinsierRL, KrumdieckCL: Death resultingfrom overzealous total parenteral nutrition: The refeeding syndrome revisited. Am J Clin Nutr 1981;34:393-399. 86. Soloman SM, Kirby DF: The refeeding syndrome: A review. JPEN J Parenter Enteral Nutr.1990;14:90-97. 87. Charney P: Diabetes mellitus. In Lysen L (ed): Quick Reference to Clinical Dietetics. Gaithersburg, MD, Aspen Publishers, 1997, pp 38-43. 88. Creutzfeldt W: The incretin concept today. Diabetologia 1979;16:75-85. 89. A.S.P.E.N. Board of Directors and Clinical Guidelines Task Force: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002 ;26: 1SA-138SA. 90. Cresci GA: Nutrition Assessment and Monitoring. In Shikora SA, MartindaleRG, SchwaitzbergSD (eds): Nutritional Considerations in the Intensive Care Unit: Science, Rationale and Practice. Dubuque, lA, Kendall-Hunt Publishing, 2002, p 121. 91. McClave SA, Sexton LK, Spain DA: Enteral tube feeding in the intensive care unit: Factors impeding adequate delivery. CritCare Med 1999;27:1252-1256.
Pharmacotherapeutic Issues Carol Rollins, MS, RD, PharmD .Cynthia Thomson, PhD, RD Tracy Crane, RD
CHAPTER OUTLINE Introduction Types of Drug-Nutrient Interactions Physical Incompatibility Pharmaceutical Incompatibility Pharmacologic Incompatibility Physiologic Incompatibility Pharmacokinetic Incompatibility Correcting Vitamin, Mineral, and Electrolyte Deficiencies Avoiding Drug-Enteral Feeding Incompatibilities Drug Administration Through Enteral Feeding Tubes Conclusion
INTRODUCTION As the role of enteral feeding in the care of patients evolves, it has become evident that drug-nutrient interactions can affect the quality and the cost effectiveness of health care. A drug-nutrient interaction is defined as an alteration of the kinetics or dynamics of a drug or a nutritional element or a compromise in nutritional status as a result of the addition of a drug.' Although drug-nutrient interactions can occur in any patient, those with decreased immunity and physiologic reserve (e.g., critically ill, immunocompromised, and elderly patients) have the highest risk of experiencing an adverse outcome due to drug-nutrient interactions. Undesired events are even more likely to occur in patients who rely on an enteral delivery mechanism to provide both nutrients and drugs," Detection and early recognition of these interactions may assist the clinician in preventing metabolic complications while the desired therapeutic outcome is achieved. Clearly, drug-nutrient interactions can result in a variety of clinically significant problems with nutrients and drugs including inadequate absorption, altered tolerance to enteral feeding, altered metabolism, physical
incompatibilities resulting in occluded feeding tubes, altered elimination, and antagonistic activity between nutrients and drugs.'
TYPES OF DRUG-NUTRIENT INTERACTIONS To classify drug-nutrient interactions, specific incompatibilities have been described in the literature" and consist of physical, pharmaceutical, pharmacologic, physiologic, and pharmacokinetic incompatibilities or interactions. Each will be discussed separately in subsequent sections of the chapter. Most drugs appear to be compatible with enteral nutrition regimens when recommended drug administration protocols are followed. However, only a handful of studies have evaluated the kinetics or dynamics of drugs or nutritional elements in patients receiving enteral nutrition therapy, and relatively few drugs and enteral formulas have been formally evaluated for physical compatibility. When present, incompatibilities can result in noticeable problems. Keep in mind that most drug-nutrient interactions involve a single incompatibility that can be effectively resolved; the exception may be pharmacokinetic interactions involving altered absorption as the result of another type of interaction.
Physical Incompatibility Physical incompatibility occurs when mixing of a drug and enteral formula results in a change in formula texture (granulation, precipitation, or gel formation), flow characteristics, viscosity, or homogeneity (e.g., separation or breaking of an emulsion). A major complication of physical incompatibility is occlusion of enteral feeding tubes. The formula, drugs administered through the tube, and the fluid used to flush the tube may all contribute to physical incompatibility and loss of tube patency. Table 24-1 provides examples of the types of physical incompatibility that occur when selected drugs are administered with enteral feeding formulas." Limited 291
292
24 • Pharmacotherapeutic Issues
-
Physical Incompatibilities between Drugs and Enteral Formulas
Type
Drug(s)
Granulation
Cibalith-S syrup, Mellarll oral solution, Thorazine concentrate, Organidln elixir Feosol elixir, Neo-Calglucon syrup, Dimetane elixir Sudafed syrup, Klorvess Syrup Kaopectate Robitussin expectorant
Gel formation Separation Precipitation
Adapted from Cutie AJ, Altman E, Lenkel L:Compatibility of enteral products with commonly employed drug additives. JPEN J Parenter Enteral Nutr 1983;7:186-191.
data are currently available on the physical compatibility of drugs with enteral formulas, particularly with enteral products and drugs developed within the past 15 years. Based on reported studies, formulas with intact protein are more prone to physical incompatibility with drugs than are peptide or free amino acid enteral products.r" However, all intact protein formulas tested for physical compatibility with drugs have contained casein or caseinates as the protein source.v'? Results may differ with formulas containing other protein sources. In an in vitro study using pharmaceutical vehicles (i.e., syrups, elixirs, and water) without active drug it was found that formulas containing casein or caseinates were likely to form large clumps and curds with acidic or neutral pH syrups and acidic elixirs." Soy protein formulas formed finer precipitates with the same vehicles whereas whey protein formulas did not show signs of physical incompatibility even with acidic syrups and elixirs. The most likely explanation for these observations is that such incompatibilities result from changes in the tertiary structure of proteins as bonds break and the proteins "unfold" with exposure to acid or alcohol. Dilution of formula and high protein content do not influence the risk of physical incompatibility, as is expected with changes in the tertiary structure of proteins."! Incompatibility between oil-base pharmaceutical products and enteral formulas appears to involve a mechanism different from a change in protein structure because formulas containing peptides and free amino acids, which lack tertiary structure, are involved." However, both intact protein and peptide or amino acid enteral formulas are oil-in-water emulsions that require an appropriate balance between emulsifiers and oils to prevent separation of the oil and water phases. Addition of an oil-base pharmaceutical product could disrupt this balance, resulting in loss of formula homogeneity as the oil and water phases separate. The contribution of fiber to physical compatibility between enteral formulas and drugs has not been adequately studied. In an in vitro study 11 of 39 pharmaceutical preparations were found to be incompatible with both fiber-containing and low-residue (i.e., nonfiber) intact protein formulas." Only one preparation, metaclopramide (Reglan) syrup, was physically compatible with the low-residue formula but not compatible with the formula containing fiber. This suggests that soy
polysaccharide, the source of fiber in the study formula (Enrich), has minimal influence on physical incompatibility. Soy polysaccharide is primarily insoluble fiber and could exhibit compatibilities different from those of soluble fibers. Compatibility of drugs with formulas containing soluble fiber has not been evaluated. However, differences in physiochemical properties and compatibility of soluble fiber are suggested by experience with psyllium hydrophilic mucilloid. In one small study, 33% of patients receiving psyllium hydrophilic mucilloid to prevent diarrhea required tube replacement due to feeding tube occlusion.'! Use of a fiber-containing formula rather than addition of psyllium to the feeding regimen is recommended. Fluids used to flush the feeding tube may contribute to physical incompatibility and tube occlusion. Water is the fluid of choice for flushing feeding tubes and should be the only fluid used to clear the tube of formula or drugs. Cranberry juice is acidic and can cause tube occlusion.'! The mechanism is probably the same as that with acidic syrups and elixirs, i.e., changes in the tertiary structure of proteins. Carbonated beverages are no better than water as a tube irrigant and may present some risk of tube occlusion from interactions with enteral formulas or drugs. Avoidance of acidic or neutral pH pharmaceutical syrups and acidic elixirs reduces the risk of physical incompatibilities as does adherence to protocols that include flushing the tube with water before and after drug administration. Use of a peptide or amino acid formula reduces the risk of some physical incompatibilities, but selecting these formulas for the purpose of managing physical interactions is rarely cost effective. Table 24-2 summarizes methods for avoiding or minimizing the various types of incompatibilities discussed in this chapter, including physical incompatibility.
Pharmaceutical Incompatibility Pharmaceutical incompatibility is a change in drug dosage form that results in altered enteral formula or drug potency, efficacy, or tolerance. The classic examples of pharmaceutical incompatibility are crushing of enteric-coated tablets and crushing of the contents from slow-release capsules for administration through enteral feeding tubes. A list of oral drug dosage forms that should not be crushed is published periodically in Hospital Pharmacy and American Drug Index.14,15 However, such lists are difficult to maintain and are not exhaustive. Nutrition support clinicians should recognize terms commonly associated with dosage forms that are not to be crushed and collaborate with a knowledgeable pharmacist when the advisability of crushing for administration through a feeding tube is uncertain. Table 24-3 provides a list of common terms indicating that crushing is not advised. An interdisciplinary approach with dietitians, nursing staff, and pharmacists working together to determine the most effective drug and formula administration regimen is advised. Issues to be addressed include the appropriate route for the drug (by mouth, through the feeding tube,
SECTION IV • Principles of Enteral Nutrition
293
_ _ Clinical Alternatives to Avoid Drug-Enteral Nutrition Incompatibilities Types of Incompatibility
Action
Physical
Do not mix medication with enteral formula Try another enteral formula Use alternate dosage form Use alternate route for administration Use a therapeutic equivalent Check dosing for appropriateness Use adjunct medication to treat adverse effect Dilute medication
Pharmaceutical
Pharmacologic
Physiologic
Phannacokinetic
x
X
x X X
X X
X
X
X X X
X
X X X
X X X
X X X
X X
X
Reprinted from Thomson CA, Rollins CJ: Enteral feeding and medication incompatibilities. Support Line 1991;8(3):9-11.
,
rectal, transdermal, or parenteral), dosage form (oral solution, suspension, crushed tablet, or capsule contents), and drug and formula administration schedules (continuous formula vs. hold for a period of time or adjustment for immediate release drug vs. sustained release taken by mouth). Occasionally, crushing or opening a capsule is not advised because of unacceptable taste. In this case, opening the capsule or crushing the tablet for administration through an enteral feeding tube is permissible. For patients with a large-bore feeding tube (i.e., 14 F or larger enterostomy), it may be possible to remove the individuallycoated beads or granules (i.e., enteric-eoated or sustained-release) from some microencapsulated dosage forms and administer them through the feeding tube without crushing." This includes some slow release products (Cardizem CD, Cardizem SR, Fergon, Thea-Our Sprinkle, and various theophylline brands) and certain enteric-eoated products (Creon, Pancrease, Pancrease MT, Prevacid, Prilosec, Prozac, and Verelan). For products designed with enteric-coated drug granules in a delayed-release capsule (e.g., omeprazole or lansoprazole) particular attention must be paid to tube location when the granules are administered through the tube. After uncrushed granules are poured down a gastric tube and before the usual flush with water, the tube must
IDmlIJII
be flushed with an acidic fruitjuice (e.g., apple, cranberry, grape, orange, pineapple, or tomato) to prevent loss of the enteric coating. Water should be used to flush the tube after the microencapsulated pellets, beads, or granules are administered through a postpyloric feeding tube. Administration of microencapsulated dosage forms should not be attempted with small-bore nasogastric or nasoenteric tubes or with a tube that requires surgical replacement if an occlusion occurs. Microformulations that should not be administered through a feeding tube, per the manufacturers, include ciprofloxacin suspension (a microcapsular formulation), c1arithromycin suspension (a microgranular formulation) and erythromycin suspension (a microscapular formulation). Risk of tube occlusion is high with these products.
Pharmacologic Incompatibility Pharmacologic incompatibility is a commonly encountered drug-nutrient interaction in clinical practice. This incompatibility centers around a drug's mechanism of action, leading to enteral feeding intolerance, as manifested by diarrhea, gastrointestinal (GI) distension,
Terms Associated with Dosage Forms That Should Not be Crushed
Definition
Abbreviation or Term Used
Examples
Controlled dosing Controlled release Extended release
CD CR ER,XL, XR LA SR, Extentab, Repetab, Sequel, Spansule, Sprinkle, Timecap, 12,24 or 12 hour after the product name, Slo- or Slow in product name SA SR TR Entab, Enseal, EC
Ceclor CD DynaClrc CR, Norpace CR, Sinemet CR Ditropan XL, Glucotrol XL, Procardia XL Dllacor XR, Tegretol XR Entex LA, Inderal LA Dimetane Exentab, Proventil Repetab, Pathllon Sequel, Feosol Spansule, Feverall Sprinkle, Nitrocine Timecap, Triaminic 12, The0-24, Sudafed 12 Hour, Sio-Niacin, Sio-Phyllin GG, Slow-Mag Choledyl SA, Tedral SA Calan SR, Isoptln SR, Pronestyl SR, Wellbutrin SR Rondec TR, Triaminic TR AzuIfidine Entab, ASAEnseal, EC-Naprosyn
Long acting Slow release
Sustained action Sustained release Time release Enteric-coated
294
24 • Pharmacotherapeutic Issues
_ _ Examples of Pharmacologic Incompatibilities between Enteral Formulas and Drugs Symptoms or Problem
Drugs with Mechanisms of Action Causing the Symptom(s) or Activity Antagonistic to the Nutrient in Enteral Formula
Emesis or severe nausea
Antiparkinson agents, chemotherapy agents, erythromycin, nonsteroidal anti-Inflammatory agents (NSAIDs), opiates Antibiotics, chemotherapy agents (e.g., Camptosar doxorublctn, etoposide), cholinergic agents, stimulant laxatives (e.g., cascara sagrada), metoclopramide
Diarrhea Antagonistic activity Vitamin K antagonist Folate antagonist
Warfarin Methotrexate, trlmethoprlm, pyrimethamine
nausea, emesis, altered taste perceptions, altered biochemical concentrations, or antagonistic activity. Nutrients can also induce a pharmacologic incompatibility or interaction by interfering with a drug's mechanism of action. Examples of pharmacologic incompatibilities are presented in Table 2~. One of the more recognized pharmacologic interactions is that between vitamin K and warfarin." To avoid interference with warfarin activity, the vitamin K content of products on the enteral formulary must be carefully evaluated by the nutrition support clinician. Table 24-5 provides a brief list of enteral formulas and the vitamin K content per 1000 Kcal of formula. Oral anticoagulant therapy can be stabilized for a given level of vitamin K intake (within reason), but significant changes in vitamin K intake, ascan occur when an enteral formula is started or
stopped, can have a significant effect on anticoagulation. Therefore, formulas containing greater than 75 to 100 Ilg of vitamin K per 1000 Kcal or supplying more than 200 to 300Ilg of vitamin K daily should be used with caution or avoided in patients receiving warfarin therapy. The vitamin K content of most enteral formulas was reduced to modest amounts by the mid-I 980s, yet reports of warfarin resistance in patients receiving enteral nutrition continued to appear. Unlike the pharmacologic antagonism of warfarin by vitamin K, this warfarin resistance responded when warfarin administration was separated from formula administration by a period of time. 18,19 Binding of warfarin to an enteral formula component is likely, and this presumption is supported by a small in vitro study in which warfarin loss to a filterable component of formula, most likely protein, was
BEll Vitamin K Content of selected Adult Enteral Formulas· Vitamin Kper 1000 Cal 35 to 40
Hydrolyzed and
IntactProMn Fonnulu
Specialized Formulae
Ensure Plus NuBasics, NuBasics Plus, NuBasics VHP Vivonex T.E.N. Respalor
41 to 45 50 to 55
56 to 60 65 to 70
80 to 85
Boost Plus Osmolite, TwoCal HN NovaSource 2.0 Perative NuBasics 20, Nutren 1.0 with fiber Nutren Products: 1.0, 1.5, 2.0 Replete with or without fiber Ensure Plus HN, Jevity, Osmolite HN IsoSource 1.5 Jevity Plus, Osmolite HN Plus FiberSource HN, IsoSource HN IsoSource Standard ProBalance Ensure Carnation Instant Breakfast with 2% Milk
Nepro Tolerex, Vivonex Plus Crucial, Glytrol NutriVent, Reabilan Peptamen VHP Impact 1.5 Glucerna, Pulmocare NovaSource Pulmonary Oxepa DiabetiSource, Impact Impact with fiber Optimental
Subdue, TraumaCal
100 to 105
120 to 125 238
Carnation Instant Breakfast: Ready to Drink, No Sugar Added with 2% Milk Isocal HN Deliver 2.0 Isocal Boost High Protein
Protain XL, Choice dm
Manufacturer Ross Nestle Novartis Mead Johnson Mead Johnson Ross Novartis Ross Nestle Nestle Nestle Novartis Ross Novartis Ross Novartis Novartis Nestle Ross Nestle Mead Johnson Nestle
Mead Johnson Ross Mead Johnson Mead Johnson
*Compiled from manufacturers' information. Confirm vitamin K content with the product label and current manufacturer's data because vitamin K content of enteral formulas can change.Vitamin K content is listed in micrograms,
SECTION IV • Principles of Enteral Nutrition
demonstrated.'? This pharmacokinetic interaction should be suspected when warfarin resistance occurs despite intake of 250 Ilg or less of vitamin K daily in a patient receiving enteral nutrition. Formula administration should be held for at least 1 hour before and after warfarin administration to avoid drug binding to a component of the formula. Biochemical alterations associated with drug use, some of which are classified as pharmacologic interactions, are another common clinical problem, although not specifically associated with enteral nutrition therapy. Table 24-6 lists several of the most commonly diagnosed biochemical alterations and the drug(s) that are often associated with them.
Physiologic Incompatibility Physiologic incompatibility involves the nonpharmacologic actions of a drug that result in reduced tolerance to enteral nutrition and are often referred to as side effects or adverse effects rather than incompatibilities or interactions. Diarrhea related to increased osmolality is the most common physiologic incornpatibility.W' Many physiologic incompatibilities can be avoided by changing the administration route (i.e., changing to a sublingual, transdermal, rectal, intravenous, or intramuscular route) or by diluting high-osmolality drugs with water before administration through the feeding tube. Lowering the dosage to the minimum necessary for the desired therapeutic response or changing to a therapeutically
BEll
295
equivalent drug, if medically feasible, can also reduce symptoms. Finally, symptoms such as diarrhea can be treated or prevented with other drugs. Table 24-7 provides a list of hypertonic medications often prescribed for enterally fed patients. Excipients, nondrug components necessary to make a tablet or other dosage form, are another cause of diarrhea in enterally fed patients. Sorbitol, which is used widely as a sweetener and solubilizing agent, is the most common diarrhea-inducing excipient,22-25 Mannitol, lactose, saccharin, and sucrose can also contribute to diarrhea either through increased osmolality or GIsensitivity (e.g., lactose intolerance). Most nonprescription drugs list excipients as "inactive ingredients" on the package, but this information is seldom included on labels or in product information for prescription drugs. Published data on excipient content may be imprecise and must be used cautiously because excipients often change based on availability or price. In addition, excipient content is product specific and cannot be extrapolated between manufacturers. For example, the sorbitol content of liquid theophylline products (80 mg/IS mL) ranges from oto 0.8 g/mL, as noted in Table 24-8. Currently available liquid antimicrobial agents that contain no sorbitol are listed in Table 24-9, although they may contain other sweeteners that have been associated with diarrhea. Table 24-10 summarizes the prevalence of sweeteners in some commonly prescribed liquid antimicrobial agents." When excipients are considered to be a possible cause for diarrhea of unknown etiology in a patient, clinicians must contact the manufacturer to determine the current
Common Biochemical Abnormalities Associated with Drugs Prescribed for Enterally Fed Patients
Biochemical Abnonnality
Serum Glucose Hyperglycemia Hypoglycemia
Serum Potassium Hyperkalemia
Drugs
Corticosteroids, estrogen, octreotide, pentamidine, phenytoin, tacrolimus, thiazide diuretics, triamterene Pentamidine, sulfonylureas
Hypokalemia
Amiloride, angiotensin-converting enzyme Inhibitors, cyclosporln, penicillin G potassium, potassium salts, spironolactone, tacrolimus, triamterene Amphotericin B, carbenicillin, foscarnet, loop diuretics, piperacillin, thiazide diuretics, ticarcillin
Serum Sodium Hypernatremia Hyponatremia
Penicillin G sodium Loop and thiazide diuretics, probenecid, spironolactone
Serum Magnesium Hypermagnesemia Hypomagnesemia
Antacids containing magnesium (in patients with renal dysfunction), magnesium salts Amphotericin B. cisplatin, cyciosporin, foscarnet, loop and thiazide diuretics, pentamidine
Serum Phosphorus Hyperphosphatemia Hypophosphatemia
Chemotherapy agents causing tumor lysis syndrome, foscarnet, sirolimus Bisphosphonates, corticosteroids, foscarnet, loop and thiazide diuretics, sucralfate
Calcium Hypercalcemia Hypocalcemia
Calcitonin Bisphosphonates, corticosteroids, foscarnet, indomethacin, loop diuretics, probenecid, triamterene
Serum Lipids Hypertriglyceridemia
Chlorpromazine, corticosteroids, cyciosporin, loop diuretics, sirolimus, thiouracil
296
24 • Pharmacotherapeutic Issues
_ _ Frequently Prescribed Hypenonlc Medications Product
Manufacturer
Acetaminophen elixir, 65 mg/rnl, Acetaminophen with codeine elixir Aminophylline liquid, 21 mg/rnl, Amoxacillin suspension, 50 rng/rnl, Ampicillin suspension, 50 mg/ml, Ampicillin suspension, 100 mg/rnl, Calcium glubionate syrup, 0.36 g/rnl, Cephalexin suspension, 50 rng/rnl, Cimetidine solution, 60 mg/ml, Cotrimoxazole suspension Dexamethasone elixir, 0.1 mg/rnl, Dexamethasone solution, 1 mg/rnl, Dextromethorphan hydrobromide syrup, 2 mg/ml, Digoxin elixir, 50 Ilg/ml Diphenydramine hydrochloride elixir, 2.5 rng/rnl, Diphenoxylate hydrochloride-atropine sulfate Docusate sodium syrup, 3.3 mg/ml, Erythromycin ethylsuccinate suspension, 40 mg/ml, Ferrous sulfate liquid, 60 rng/ml, Fluphenazine hydrochloride elixir, 0.5 mg/ml, Furosemide solution, 10 mg/rnl, Kaolin-pectin suspension Haloperidol concentrate, 2 rng/ml, Hydroxyline hydrochloride syrup, 2 mg/ml, lactulose syrup, 0.67 rng/ml, Lithium citrate syrup, 1.6 mEq/ml Methyldopa suspension, 50 rng/ml, Metoclopramide hydrochloride syrup, 1 mg/ml, Multivitamin liquid Nystatin suspension, 100,000 unlts/ml, Paregoric tincture Phenytoin sodium suspension, 6 rng/rnl, Phenytoin sodium suspension, 25 mg/rnl, Potassium chloride liquid, 10% Potassium chloride liquid, 10% Potassium iodide saturated solution, 1 g/ml Prochlorperazine syrup, 1 mg/ml, Promethazine hydrochloride syrup, 1.25 mg/ml, Sodium citrate liquid Sodium phosphate liquid, 0.5 g/ml Theophylline solution, 5.33 mg/ml, Thiabendazole suspension, 100 mg/rnl, Thioridazine suspension, 20 mg/rnl, Trace element Injection
Roxane Wyeth Flsons
Squibb Squibb Bristol Sandoz Dista Smith Kline & French Burroughs Organon Roxane Parke-Davis Burroughs Roxane Roxane Roxane Abbott Roxane Squibb Hoechts-Roussel Roxane McNeil Roerig Roerig Roxane Merck, Sharp & Dohme Robins Upjohn Squibb Roxane Parke-Davis Parke-Davis Adria Roxane Upsher Smith Smith Kline & French Wyeth Willen Fleet Berlex Merck, Sharp & Dohme Sandoz lyphomed
Average O8IDolailty (mOamfkg) 5400 4700 450 2250 2250 1850 2550 1950 5550 2200 3350 3100 5950 1350 850 8800 3900 1750 4700 1750 2050 900 500 4450 3600 6850 2050 8350 5700 3300 1350 2000 1500 3000 3300 10,950 3250 3500 2050 7250 800 2150 2050 500
Adapted from Dickerson RN, Melnick G: Osmolality of oral drug solutions and suspensions. Am J Hosp Pharm 1988;45:832-834. Copyright 1988, American Society of Hospital Pharmacists, Inc. Reprinted with permission. (R9634) ASHPassumes no responsibility for the accuracy of the translation.
excipient content of the specific drug products being administered. Patients with food allergies (e.g., gluten sensitivity) or severe lactose intolerance are particularly susceptible to excipient-induced diarrhea and need close monitoring. Other adverse reactions including urticaria, asthma, belching, nausea, or even anaphylactic shock can also occur in patients with a sensitivity to sweeteners, flavorings, or dyes that may be added to drugs during the manufacturing process. 22,24 Administration of intravenous drugs by mouth or through a feeding tube does not preclude excipient sensitivity and is not generally recommended because of stability concerns. Although intravenous products do not contain sweeteners and flavorings, they often do contain preservatives and solubilizing agents that can cause adverse reactions in sensitive individuals.
Pharmacokinetic Incompatibility The final type of incompatibility between drugs and nutrients occurs when the enteral feeding formula alters bioavailability, distribution, metabolism, or elimination of the drug, or the reverse, when the drug alters nutrient function. Pharmacokinetic interactions are influenced by multiple factors, as listed in Table 24-11, that often occur as the result of another type of incompatibility. For instance, pharmaceutical incompatibilities such as administration of crushed enteric-eoated tablets or sublingual tablets through gastric tubes typically result in reduced drug bioavailability. Pharmacologic actions of drugs also contribute to pharmacokinetic interactions. For example, drugs that modify gastric motility (e.g., erythromycin, metoclopramide, morphine, and anticholinergic agents) can alter nutrient bioavailability.
--
SECTION IV • Principles of Enteral Nutrition
297
Sorbitol Content of Selected Liquid Dosage Forms Brand and Dosage Fono
Concentration (mgfS mL)
Manufacturer*
Ibuprofen
Tylenol Infant's drops Tylenol Children's elixir Tylenol Children's suspension Tylenol Extra Strength liquid Pedia-Profen suspension
500 160 160 167 100
McNeil McNeil McNeil McNeil McNeil
None 0.2 0.2 0.2 0.3
Naproxen
Naprosyn suspension
125
Roche
0.1
Furadantin suspension Sumycin suspension Bactrim pediatric suspension Septra suspension TMP/SMZ
25 125 (TMP 40
0.14 0.3 0.07 0.45
Biocraft
PG Apothecon Roche GW 0.07
Tegretol suspension Phenobarbital elixir Dilantin-30 suspension Dilantin-125 suspension Mysoline suspension Depakene syrup
100 15 and 20 30 125 mg 250 250
Novartls Lilly Parke-Davis Parke-Davis WA Abbott
0.12 None None None None 0.15
McNeil Roxane
None None
Roxane Forest RPR Central 3M Pharmaceuticals Roxane Forest
0.14 None 0.58 0.8 0.1 0.46 0.46
RPR
0.12
CI888If1cation
Sorbitol (gfmL)t
Analgesics Acetaminophen
Antibiotics Nitrofurantoin Tetracycline Trimethoprimj sulfamethoxazole
+
SMZ 200)
Anticonvulsants Carbamazepine Phenobarbital Phenytoin Primadone Valproic acid
Antidiarrheals Loperamide Loperamide oral solution
Imodium A-D
Bronchodilators Aminophylline Theophylline (80 mg/15 mL)
Theophylline/gualfenesln
Aminophylline oral liquid Elixophyllin elixir Slo-Phyllin 80 syrup Theoclear-80 syrup Theolair liquid Theophylline solution Elixophyllin-GG elixir
105 27 27 27 27 27 27 theophylline + 100 gualfenesin
Slo-PhylJin GG syrup
Diuretics Chlorothiazide Furosemide
Hydrochlorothiazide
Diuril oral suspension Furosemide solution Furosemide solution Lasix oral solution Hydrochlorothiazide solution
250 10 40 10 50
Merck Roxane Roxane HMR Roxane
None 0.48 0.48 None None
Metoclopramide syrup Metoclopramide oral solution Metoclopramide Intensol
5 5 10
Biocraft Roxane Roxane
0.4 0.25 0.25
Tagarnet liquid Pepcid oral suspension Zantac syrup
300 40 75
SKB Merck GW
0.56 None 0.1
Diazepam oral solution Diazepam lntensol Benadryl elixir (cherry) Benadryl elixir, diet Lorazepam Intensol
5 10 12.5 12.5 10
Roxane Roxane Warner Lambert Warner Lambert Roxane
None None None 0.45 None
GJStimulants Metoclopramide
Histamine H2 Antagonists Cimetidine Famotidine Ranitidine
Sedatives/Hypnotics Diazepam Diphenhydramine Lorazepam
*GW, Glaxo Wellcome; HMR, Hoechst-Marion Roussel; PG, Procter&Gamble; RPR, Rhone-Poulenc Rorer; SKB, SmithKline Beecham;WA, Wyeth-Ayers!. 'Determine daily sorbitol dose by calculating the total milliliters per day of drug, then multiply by the grams of sorbitol per milliliter.For example, the calculation for a patient receiving 10 mg of metoclopramide four times daily using Biocraft metoclopramide syrup (5 mg/5 mL concentration) is as follows: 10mUdose x 4 doses/day x 0.4 g/mL = 16g/day. Data obtained from manufacturers between 1999 and 2003.
298
24 • Pharmacotherapeutic Issues
_ _ Liquid Antibiotic Preparations Reported to Contain No Sorbitol Generic Name
Brand and Dosage Form
Concentration (per 5 mL)
Manufacturer*
Amoxicillin
Various brands of suspension
125 mg and 250 mg
Amoxicillin Ampicillin Azithromycin
Amoxll and Trlmox pediatric drops Various brands of suspension Zithromax 100 suspension Zithromax 100 suspension Ceclor suspension Durlcef suspension Ceftin suspension Cephalexin suspension Keflex oral suspension Velosef suspension Cipro oral suspension Biaxin suspension Cleocln pediatric oral solution Dynapen and Pathocil suspensions Vibramycin monohydrate suspension Vlbramycin calcium syrup EES:!OO EES 400 EryPed suspension drops EES/sulfisoxazole suspension Pediazole Lorabid suspension Various brands of suspension Veetids oral suspension Gantrisin pediatric suspension Vancocin oral solution
250 mg (50 mg/mL) 125 mg and 250 mg 100 mg 200 mg 125 mg, 187 mg, and 250 mg 125 mg and 250 mg 125 mg and 250 mg 125 mg and 250 mg 125 mg and 250 mg 125 mg and 250 mg 250 mg and 500 mg 125 mg and 250 mg 75 mg 62.5 mg 25mg 50mg 200 rng 400 mg 200 mg and 400 mg 200 mg/600 mg 200 mg/600 mg 100 mg and 200 mg 125 mg 125 rng and 250 mg 500 mg 1 g bottle
Apothecon, Biocraft, Lederle, SKB, WA SKB, Apothecon Apothecon, Biocraft, Lederle Pfizer Pfizer Lilly BMS GW Lederle, Biocraft Dista BMS Bayer Abbott Upjohn Apothecon, WA Pfizer Pfizer Abbott Abbott Abbott Lederle Ross Lilly Biocraft, SKB, WA Apothecon Roche Lilly
Cefaclor Cefadroxil Cefuroxime Cephalexin Cephradine Ciprofloxacin Clarithromycin Clindamycin Dicloxacillin Doxycycline Erythromycin ethylsuccinate Erythromycin/sulfisoxazole Loracarbef Penicillin VK Sulfisoxazole Vancomycin
*BMS, Bristol-Myers Squibb; GW,Glaxo Wellcome; RPR, Rhone-Pouienc Rorer; SKB, SmithKlein Beecham; WA, Wyeth-Ayerst. Data obtained from manufacturers between 1999 and 2003.
Nutrients that must be released from the food matrix while in the stomach are most effectively absorbed with slower emptying and poorly absorbed when gastric emptying is rapid. Examples include riboflavin, iron, and cobalamin. Enteral formula characteristics that slow gastric emptying, likewise, alter bioavailability of certain drugs as shown in Table 24-11. The site of feeding (i.e., gastric, duodenal, or jejunal) determines the pH and the portions of the GI tract to which a drug administered through the feeding tube is exposed. Stability of drugs and, to some extent, absorbability are influenced by pH. Unfortunately, relatively few studies have explored the effect of delivery site on drug
_
bioavailability. This leaves the nutrition support clinician with a few small studies, case reports, and extrapolation from pharmacokinetic principles as the basis for decisions about drug administration through postpyloric feeding tubes. Drugs that require an acid environment to go into solution, such as ketoconazole or tetracycline, are likely to have reduced absorption when delivered via a jejunal feeding tube. The same is true when a significant percentage of drug absorption occurs in the duodenum. Ciprofloxacin exemplifies a drug in the later situation with approximately 40% of a dose absorbed from the duodenum." Absorption of ciprofloxacin is best with duodenal administration, lowest with jejunal administration, and
Sweetner Content of Selected Antimicrobials Antimicrobials
Sweetner
Mannitol Lactose Saccharin Sorbitol Sucrose Unspecified
Amox
Amp
Pen
Ceph
Eryth
Sulf
Other
(11) 5 0 5 0 8 0
(10) 1 0 4 0 9 0
(12) 0 0 11 0 12 0
(19) 0 1 0 0 18 0
(18) 1 2 1 1 14 3
(10) 0 1 4
(11) 0 3 5
3
3
7 1
6 0
Total
7 7 30 7 74 4
Amox =amoxicillin; Amp =ampicillin; Pen =penicillin; Ceph =cephaiosporins; Eryth =erythromycin; Sulf =sulfonamides. Numer of preparations for which data were collected are listed in parentheses. Reproduced by permission from Kumar A, Weatherly MR, Beaman DC:Sweetners, flavorings, and dyes in antibiotic preparations. Pediatrics 1991;87:352-360. Copyright 1991.
SECTION IV • Principles of Enteral Nutrition
intermediate with gastric administration because there is some drug loss from acid exposure but improved absorption in the duodenum.Pr" On the other hand, digoxin is well absorbed from the jejunum and is more bioavailable when delivered to the jejunum compared with passage through the stomach where it is susceptible to acid hydrolysis." The administration schedule for tube feeding can influence drug absorption through physiologic effects on the GI tract. Slower gastric emptying and an increased presence of digestive enzymes and GI
299
secretions characterize the fed state. Some drugs demonstrate improved bioavailability when administered during a fed state (i.e., with food) whereas others are best administered during a fasted state, which is usually interpreted as at least 1 hour before meals or 2 hours after meals. Few studies have been conducted to determine whether tube feeding regimens have the same effect on drug absorption as oral intake. However, results of one small study of hydralazine pharmacokinetics suggested that continuous gastric infusion of enteral formula is associated with a fasted condition
. . . Factors Influencing Pharmacokinetic Interactions
Factor
Contributing Factors
Effect on Drugs and Nutrients
Drug dosage forms: solid. suspension, or solution; specific design (e.g., buccal, sublingual, enteric coated, long acting)
Solids and suspensions require dissolution; solutions do not
Dissolution is pH dependent for most drugs and requires time; therefore, solutions may be more readily absorbed under some conditions Buccal and sublingual dosage forms Bioavailability decreased by gastric acid and hepatic metabolism Doses inadequate when given by tube Most enteric-coated drugs are acid labile Decrease bioavallability if crushed before gastric administration Mechanisms for long action are destroyed by crushing Erratic dosing with too much drug initially but inadequate drug later results in altered response to therapy Potential for overdose symptoms Increased time for release of nutrients from food before nutrients entering duodenum Increases absorption of high-fiber nutrients absorbed by active process in calorically dense duodenum (e.g., riboflavin) Improved binding of cobalamine with intrinsic factor for active absorption Increased exposure to acid Bioavailability decreased for acid labile drugs (e.g., ampicillin, digoxin) Increased bioavailability for nutrients best absorbed in a reduced state (e.g., iron) Increased time for dissolution of drugs Increased bioavailability of acid-soluble, acid-stabile drugs (e.g., ketoconazole, itraconazole, tetracycline); poorly soluble, acid stabile drugs (e.g., griseofulvin, carbamazepine) Drug dissolution depends on pH of stomach, duodenum, or jejunum Acid-soluble drugs may be poorly absorbed without gastric acid Drug stability may be pH dependent Chemical decomposition of acid-labile drugs in stomach: therefore, bioavailability is reduced Significant absorption in the duodenum Decreased absorption with jejunal administration (e.g., ciprofloxacin) Fed state associated with slower gastric emptying and increased gastric enzymes See comments above on gastric emptying Decreased bioavailability of bound drug protein Subtherapeutic concentration Slow gastric emptying; see comments above
Dosage forms with a specific design may not be effective if crushed or administered through a feeding tube
Slow gastric emptying
Formula components: High-fat content Viscous consistency High or low osmolarity >800 mosm/l, <250 rnOsm/L
Drugs: Anticholinergic agents, e.g., atropine, belladonna, benztropine, scopolamine Narcotic agents
Site of feeding
pH of site
Site of drug or nutrient absorption
Administration schedule: continuous vs. bolus
Influences fed vs. fasting state of the GI tract
Formula components: protein; fat
Drug binding to formula component, most likely protein Influences gastric emptying
300
24 • Pharmacotherapeutic Issues
in terms of gastric emptying and drug absorption whereas bolus feeding produces a fed state." It is unclear if this holds true for other drugs or for all types of enteral formulas. Nonetheless, it is reasonable to assume that bolus and intermittent feeding regimens produce effects on drug absorption that are similar to those of a meal. The real dilemma is whether to assume that continuous infusion regimens always produce a fasted state for drug absorption. Without more data, the judicious approach is to hold feedings for 1 hour before and 1 to 2 hours after administration of critical drugs that are to be taken on an empty stomach (e.g., azithromycin for a serious infection). In addition, specific recommendations exist to hold enteral formula before and after administration of some drugs that are normally taken with food or without regard to food. For these drugs, including phenytoin, carbamazepine, fluoroquinolones (e.g., ciprofloxacin), theophylline, and warfarin, potentially significant alterations in drug bioavailability are seen when they are administered concomitantly with enteral formula. The impact on nutrient provision can be minimized by only stopping formula infusion briefly during actual drug administration for drug with a wide therapeutic range when response can be monitored and the drug regimen adjusted if necessary.
Phenytoin In many reports in the literature, administration of phenytoin concurrent with enteral feeding resulted in reduced bioavailability of phenytoin. In a recent review an interaction was found in 25 case reports, letters, and nonrandomized, retrospective studies, and no interaction was reported in 4 randomized, prospective, controlled trials.32 In three of the four controlled trials, formula and phenytoin were consumed orally; in one, continuous nasogastric feeding was given. Allfour trials in which no interaction was reported were conducted in 10 or fewer healthy subjects. No one has clearly delineated the mechanism for a phenytoin-enteral formula interaction, although numerous theories exist. The mechanism usually suggested is binding or complexation with a component of the enteral formula that results in physical incompatibility and reduced bioavailability.P Other explanations are related to pH or binding to the feeding tubing. Various methods have been suggested to minimize the risk of interaction, but therapeutic concentrations with relatively "normal" oral phenytoin doses appear to occur most consistently when formula administration is held for 1 to 2 hours before and after the phenytoin dose. Clamping of the gastrostomy tube for 1 hour after phenytoin administration through the tube resulted in higher serum phenytoin concentrations than continuous feeding in a retrospective review of patients with brain injuries.P However, holding formula administration for 2 hours before and after the drug dose has also been suggested. Nonetheless, holding formula administration even for as long as 2 hours has not always been shown to be
effective, and other methods may need to be considered. Use of phenytoin capsules or a meat-based formula cannot be recommended as a reliable approach. Diluting the phenytoin suspension threefold with water before administration does appear to improve drug delivery and should be done routinely." Increasing the phenytoin dose until therapeutic drug concentrations are achieved and maintained can be considered, and changing to intravenous phenytoin administration may be reasonable if problems with interaction persist. Regardless of the steps taken to minimize the interaction between phenytoin and enteral formula, serum phenytoin concentrations must be monitored closely to avoid subtherapeutic concentrations with tube feeding. Monitoring serum concentrations once to twice weekly when tube feeding is started or discontinued or until the patient's dose of phenytoin is therapeutically stable is reasonable, as is close observation for signs and symptoms of poor disease control and drug toxicity throughout tube feeding.
Carbamazepine Clinical observation and in vitro studies have raised concern that administration of carbamazepine concurrent with enteral formula results in subtherapeutic drug concentrations. Carbamazepine absorption is limited by the rate of dissolution; thus, anything that reduces the time available for carbamazepine to go into solution or alters exposure to the most effective pH for dissolution, including administration through a postpyloric tube, decreases absorption. Data supporting an interaction between carbamazepine and enteral formula are not overwhelming, but there is enough concern that recommendations are published to hold formula for 2 hours both before and after administration of carbamazepine.F" Although limited, available data suggest that an interaction is most likely to be clinically significant when carbamazepine is administered through a postpyloric tube. Because serious complications are associated with subtherapeutic carbamazepine concentrations, it is reasonable to hold formula for 2 hours before and after drug administration in this population. However, it may be best to monitor serum carbamazepine concentrations in patients receiving drug through a gastric tube and hold formula on a patient-by-patient basis when maintaining a therapeutic concentration is difficult. Carbamazepine suspension is viscous and should be diluted with an equal volume of water." Further documentation and studies in patients receiving carbamazepine and enteral feeding are needed to determine the incidence of interactions in patients and to identify the best method of managing the interaction when it occurs.
Fluoroquinolones In most studies evaluating fluoroquinolone bioavailability with enteral formula, ciprofloxacin has been used.
SECTION IV • Principles of Enteral Nutrition
Decreases in bioavailability of 27% to 67% were reported for hospitalized patients receiving ciprofloxacin through a feeding tube, and the greatest decrease was seen with jejunal admlnistration.e-? Continuous nasogastric enteral feeding has also been noted to result in decreased ciprofloxacin bioavailability in critically ill patients. 38.39 However, the clinical significance of decreased ciprofloxacin bioavailability is uncertain because drug concentrations above the mean inhibitory concentration (MIC) for many pathogens have been reported." Untiladequate drug concentrations (AUC 2/MIC ratio) for treatment of major pathogens are contirmed in larger studies, caution must be used when enteral ciprofloxacin is selected for patients receiving tube feeding. Researchers evaluating the interaction between other fluoroquinolones and enteral formula suggested that it is influenced by drug hydrophilicity and may not be related to drug binding to divalent cations (i.e., calcium and magnesium) in the formula. In an in vitro study, ofloxacin recovery was about 54%, levofloxacin recovery was about 39%, and ciprofloxacin recovery was about 17.5% when the drug was mixed with an intact protein formula." The loss of unbound antibiotic occurred immediately on mixing and did not correlate with the cation content of the formula. However, the amount of drug loss did appear to increase as the hydrophilicity of the drug increased. Binding to the feeding tube itself does not seem to occur with the fluoroquinolones." No specific component of enteral formula that binds fluoroquinolones has been identified, and it is unclear if drug loss occurs to the same extent with a hydrolyzed protein formula as with an intact protein formula. The recommended method to minimize the interaction between enteral formula and ciprofloxacin or norfloxacin is to hold formula for at least 1 hour before and 2 hours after the drug dose. 35.36 Because subtherapeutic antibiotic concentrations could have serious effects on morbidity and mortality, holding formula before and after administration of all fluoroquinolones is a reasonable measure until further data are available to confirm the effects of an interaction on the MIC of specific organisms. Selecting a different antibiotic with appropriate coverage for the infectious agent would also avoid the interaction. The commercially available 5% and 10% Cipro oral suspensions (ciprofloxacin from Bayer Corporation) are not to be administered through feeding tubes; thus ciprofloxacin tablets should be crushed if this drug is to be administered by feeding tube.
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theophylline preparations with an intact protein formula taken by mouth compared with fasting. 44,45 Studies are needed to determine whether holding formula administration before and after theophylline administration provides any clinical benefit. Unless erratic theophylline serum concentrations or inadequate disease control are noted after initiation of tube feeding, it is difficult to justify holding formula in most patients.
Warfarin The interaction between warfarin and some filterable component of enteral formula was discussed earlier in the chapter. This mechanism of warfarin resistance requires further study to determine the formula component involved and the significance and prevalence of the interaction. Holding formula administration for 1 hour before and after warfarin administration is recommended when warfarin resistance occurs with modest (~250 Ilg) vitamin K intake. Whenever enteral feeding is initiated or changed in a patient receiving warfarin therapy, careful monitoring for an alteration in anticoagulant response is appropriate to assure patient safety. Pharmacokinetic interactions involve alterations in metabolism, distribution, and elimination as well as changes in absorption. Nutrient composition of enteral formulas can significantly affect drug metabolism, primarily by altering enzyme activity or by inducing changes in splanchnic-hepatic blood f1ow.3.46,47 Drugs that are extensively metabolized by the liver are particularly susceptible to changes in hepatic blood flow and renally excreted drugs are affected by renal blood flow and glomerular filtration rate. Theophylline elimination is increased with high protein intake, which stimulates splanchnic-hepatic blood flow, and decreased by a high-earbohydrate, low-protein diet. For other drugs, such as quinidine, low protein intake may increase renal tubular reabsorption and decrease urinary elimination of the drug. To date, available clinical data on the impact of enteral formulas on drug pharmacokinetic parameters, including bioavailability, remain limited; however, if drug efficacy appears to be reduced during enteral feeding, the clinician should consider altering the formula, feeding route, or feeding regimen to resolve the problem. In addition, absorption of nutrients can be altered by administering specific drugs. Table 24-12 lists some of the common drug-induced nutrient defects, including alterations in absorption."
Theophylline Holding enteral formula administration for 1 hour before and 2 hours after theophylline administration is recommended despite relatively few data to support this practice.P-" In one small study, continuous nasogastric feeding was reported to interfere with theophylline absorption." Food intake is reported to result in rapid release of some sustained-release preparations, but in two single dose studies in healthy volunteers no effect on extent of absorption was found for sustained-release
CORRECTING VITAMIN, MINERAL, AND ELECTROLYTE DEFICIENCIES When deficiencies in vitamins, minerals, or electrolytes are diagnosed, replacement therapy should be initiated. Replacement therapies known to be compatible with enteral feedings include liquid multivitamin preparations, most potassium acetate, chloride, or phosphorous injections, potassium phosphate preparations (e.g.,
302
24 • Pharmacotherapeutic Issues
Neutra-Phos and Phosphosoda), magnesium oxide, sodium chloride, acetate or phosphate injections, and water-based fat-soluble vitamins."
AVOIDING DRUG-ENTERAL FEEDING INCOMPATIBILITIES Possible solutions to common drug-enteral feeding incompatibilities are summarized in Table 24-2, and practice guidelines related to drug-nutrient interactions in enteral nutrition patients are listed in Table 24-13.50 The clinician should keep in mind that preventing these incompatibilities results in the most cost-effective care and may reduce iatrogenic morbidity for patients. A multidiscipllnary approach to reviewing drugs before initiation of enteral feeding and reevaluating the patient's
_
drugs on a regular basis should be used to avoid incompatibilities whenever possible.
DRUG ADMINISTRATION THROUGH ENTERAL FEEDING TUBES Administration of drugs through feeding tubes should be avoided whenever possible. Many patients receiving enteral nutrition are allowed some oral intake, and this is the preferred route for drug administration if not contraindicated. Some drugs are available in instant dissolving tablets, sublingual or buccal tablets, or liquid dosage forms that may be alternatives when a patient cannot swallow tablets. Liquid preparations compounded extemporaneously from available solid dosage forms may be considered, if compatible with enteral feeding. For
Nutrient Defects Induced by Drugs· Nutrient Altered
Mechanism
Notes on NutrlUonai Care
Numerous
Riboflavin
Increased pH alters absorption
Recommend a multivitamin products or B-complex vitamin with up to 200% of OR! for riboflavin if antacids used regularly (>3 days/wk)
Antlconuulsants Phenytoin, prlmidone, phenobarbital
Folate, Vitamins BI2 and 0
Accelerates vitamin 0 metabolism In liver; mechanism in folate absorption unclear
Monitor nutrient levels in patients on long-term therapy (>3 to 6 months); supplement as necessary
Folate, iron, vitamin BI2
Autoimmune
Monitor nutrient levels; supplement as necessary
Nitrogen, fat, Ca, Na, K, Mg, vitamins A and BI2, folate
Structural defect; bile acid sequestration
Monitor nutrient levels; supplement as necessary
Folate
Mucosal block Dl- and trivalent cations (effect on iron absorption not clinically significant)
Monitor for anemia (uncommon) Forms chelates
Drng
Antacids
Antihypertensive Methyldopa
Anti-infectives Neomycin, cycloserine, erythromycin, kanamycin
Irritable Bowel Therapy Sulfasalazine, tetracyclines
Hold tube feeding for 1 and 2 hours after drug administration Take drug 1 hour before or 2 hours after meal
Anti-innammatory Colchicine
Fat, carotene, vitamin BI2
Mitotic arrest; structural (for gout) damage
Monitor vitamins A and B12; Na, K defect; enzyme and electrolyte status; supplement as necessary
Folate. vitamin BI2, Ca
Mucosal damage
Monitor folate and vitamin B12 status; supplement as necessary
Antineoplastic Methotrexate
Continued
SECTION IV • Principles of Enteral Nutrition
303
_ _ Nutrient Defects Induced by Drugs*--cont'd Drug
Nutrient Altered
Mechanism
Notes on Nutritional Care
Fat, Ca, Mg, iron, folate, vitamin BIZ
Mucosal block in vitamin BIZ uptake can cause megaloblastic anemia; mechanism of absorption unclear
Monitor nutrient levels; supplement as necessary
Vitamins C, folate, vitamin B6
Altered metabolism
Recommend multivitamin or B complex plus C vitamin with up to 200% of ROl; folate especially critical if pregnancy planned when drug stopped
Antitubercular p-Aminosalicylic acid
Contraceptive Estrogen-containing
Glucocorticoids Dexamethasone, prednisone
Folate
Monitor folate level and for megaloblastic anemia
Vitamin BIZ
Monitor vitamin BIZstatus
Glucose-lowering Metformin
Hypocholesterolemla Cholestyramine
Fat, fat-soluble vitamins, carotene
Binding of bile acids, salts, and nutrients
Clofibrate
Vitamins A, D, E, and BIZ
Unknown action on liver
Colestipol
Fat, fat-soluble vitamins
Binds and promotes excretion of bile acids
Castor oil
Ca,K
Malabsorption of fat-soluble vitamin
Mineral oil
Carotene, vitamins A, D, and K
Physical barrier; nutrients dissolve in oil and are lost
Vitamin B I2
Change in ileal pH inhibit vitamin BIZabsorption
Monitor vitamin B 12, A, and D long-term therapy (>3 months) or recommend multivitamin that includes fat-soluble vitamins at 100% ROI; monitor iron status; supplement as necessary Monitor nutrients and/or recommend multivitamin as with cholestyramine Monitor nutrients and/or recommend multivitamin as with cholestyramine
Laxatives Monitor Ca and K; supplement as necessary; recommend multivitamin as with cholestyramine Avoid use near meal times
Potassium Repletion KCl
Monitor vitamin BIZstatus
"Only drugs that alter vitamin status are included in this table. The reader should seek alternate sources of information for the many drugs that alter electrolyte status.
_
Practice Ciuldellnes Related to Drug·Nutrlent Interactions
Drug profiles of patients receiving nutrition support should be reviewed for potential effects on nutrition and metabolic status. Drugs coadministered with enteral nutrition formula should be reviewed periodically for potential incompatibilities. When drugs are administered via an enteral feeding tube, the tube should be flushed before and after each drug is administered. Liquid drug formulations should be used, when available, for administration via enteral feeding tubes. Patients receiving enteral nutrition who develop diarrhea should be evaluated for antibiotic-associated causes, including Clostridium difficile. In the absence of reliable information concerning compatibility of a specific drug with a nutrition support formula, the drug should be administered separately from the formula. Modified from A.S.P.E.N. Board of Directors and The Clinical Guidelines Task Force: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. Section IX: Drug-nutrient interactions. JPEN J Parenter Enteral Nutr 2002;26(1 suppl):42SA.
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24 • Pharmacotherapeutic Issues
patients in whom use of the GI tract is contraindicated, drugs may be available in rectal or transdermal dosage forms (e.g., patches, pastes, and ointments). Because of administration issues and cost, intravenous and intramuscular routes of drug administration are the least desirable alternatives but can be used when necessary. Reducing the frequency and duration of drug administration through the enteral feeding tube results in reduced risk for tube occlusion. When drugs must be administered through the feeding tube, the following guidelines should serve to reduce the incidence of occluded feeding tubes.3.16.35.36 1. Flush the feeding tube with 15 to 30 mL of warm tap water before and after administration of any single drug. 2. If a drug is to be given on an empty stomach, check gastric residual volumes before drug administration when feeding into the stomach. 3. Use only water to flush feeding tubes; other liquids (e.g., cranberry juice or colas) significantly increase osmolality and may contribute to tube occlusion. 4. When ordering drugs for administration via a feeding tube, provide specific information on the tube and the location of its distal tip to the dispensing pharmacist so that the most appropriate dosage form can be used. 5. Administer medications as liquid, crushed tablets, or opened capsules diluted in 10 to 15 mL of room temperature tap water. Know which drugs should not be crushed or opened. 6. Administer each drug separately. 7. Dilute hypertonic drugs with water. 8. Administer drugs known to cause GI irritation when formula remains in the GI tract. 9. Avoid potential drug-nutrient interactions by seeking multidisciplinary team input and using alternate administration routes, alternate formulas or drugs, or altered feeding or drug schedules as indicated. 10. Monitor regularly to allow early diagnosis and effective treatment of potential drug-enteral feeding interactions.
CONCLUSION Several different types of drug-enteral feeding interactions or incompatibilities can affect the quality of care provided to enterally fed patients-physical, pharmaceutical, pharmacologic, physiologic, and pharmacokinetic incompatibilities. Unfortunately, minimal research has been done to clearly define the incidence, risk factors, and consequences associated with drug-enteral formula interactions or the best methods to treat interactions when they do occur. Prevention depends on clinician awareness of the potential for interactions to occur and adherence to protocols for drug administration in patients receiving enteral nutrition therapy. A cooperative, team approach involving the expertise of the physician, pharmacist, clinical dietitian, and nurse is essential to provide optimal care to patients receiving enteral nutrition therapy.
REFERENCES 1. Chan L-N: Redefining drug-nutrient interactions. Nutr Clin Pract 2000;15:249. 2. Chan L-N: Drug-nutrient interaction in clinical nutrition. Curr Opin Clin Nutr Metab Care 2002;5:327. 3. Lourenco R: Enteral feeding: drug/nutrient interaction. Clin Nutr 2001;20:187. 4. Thomson CA, Rollins CR: Enteral feeding and medication incompatibilities. Support Line 1991;8(3):9. 5. Cutie AI, Altman E, Lenkel L: Compatibility of enteral products with commonly employed drug additives. J Parenter Enter Nutr 1983;7: 186. 6. Bums PE, McCall L. Wirsching R: Physical compatibility of enteral formulas with various common medications. J Am Diet Assoc 1988;88:1094. 7. Fagerman KE, Ballou AE: Drug compatibilities with enteral feeding solutions co-administered by tube. Nutr Support Services 1988;8:31. 8. Altman E. Cutie AI: Compatibility of enteral products with commonly employed drug additives. Nutr Support Services 1984;4:8. 9. Holtz L, Milton J, Sturek JK: Compatibility of medications with enteral feedings. J Parenter Enter Nutr 1987;11:183. 10. Strom JG, MillerSW:Stability of drugs with enteral nutrient formulas. Drug Intell Clin Pharm 1990;24:130. 11. Rollins CJ: Tube feeding formula and medication characteristics contributing to undesirable interactions [abstract]. J Parenter Enteral Nutr 1999;21:S13. 12. Davidson W, Belknap DC, Flournoy OJ: Flow characteristics of enteral feeding with psyllium hydrophilic mucilloid added. Heart Lung 1991;20:405. 13. Metheny N, Eisenberg P, McSweeney M: Effectof feeding tube properties and three irrigants on clogging rates. Nurs Res 1988;37:165. 14. Mitchell JF: Oral dosage forms that should not be crushed or chewed. Hosp Pharm 2002;37:213. 15. Billups N, Billups SM (eds): American Drug Index 2003, 4th ed. St Louis, Facts and Comparisons. 2002. 16. Beckwith MC, Barton RG. Graves C: A guide to drug therapy in patients with enteral feeding tubes: dosage form selection and administration methods. Hosp Pharm 1997;32:57. 17. Rollins CJ: General pharmacologic issues. In Matarese LE. Gottschlich MM (eds): Contemporary Nutrition Support Practice: A Clinical Guide, 2nd ed, Philadelphia, WB Saunders, 2003, p 315. 18. Petretich DA: Reversal of Osmolite-warfarin interaction by changing warfarin administration time [letter]. Clin Pharm 1990;9:93. 19. Penrod LE, Allen JB, Cabacungan LR: Warfarin resistance and enteral feedings: 2 case reports and a supporting in vitro study. Arch Phys Med Rehabil2001;82:127G-1273. 20. Dickerson RN, Melnik G: Osmolality of oral drug solutions and suspensions. Am J Hosp Pharm 1988;45:832. 21. Miyagawa CI: Drug-nutrient interactions in critically ill patients. Crit Care Nurse 1993;13:69. 22. Feldstein TJ: Carbohydrate and alcohol content of 200 oral liquid medications for use in patients receiving ketogenic diets. Pediatrics 1996;97:506. 23. Lutomski OM, Gora ML, Wright SM, et al: Sorbitol content of selected oral liquids. Ann Pharmacother 1993;27:269. 24. Kumar A, Weatherly MR, Beaman DC: Sweeteners, flavorings and dyes in antibiotic preparations. Pediatrics 1991;87:352. 25. Edes TE, Walk BE. Austin JL: Diarrhea in tube-fed patients: Feeding formula not necessarily the cause. Am J Med 1990;88:91. 26. Staib AH, Beerman 0, Harder S, et al: Absorption differences of ciprofloxacin along the human gastrointestinal tract determined using a remote-control drug delivery device. Am J Med 1989; 87(suppl 5A):66S. 27. Yuk JH, Nightingale CH, Quintiliani R, et al: Absorption of ciprofloxacin administered through a nasogastric or a nasoduodenal tube in volunteers and patients receiving enteral nutrition. Diag Microbiol Infect Dis 1990;13:99. 28. Sahai J, Memish Z, Conway B: Ciprofloxacin pharmacokinetics after administration via a jejunostomy tube. J Antimicrob Chemother 1991;28:936. 29. Healy DP, Brodbeck MC, Clendening CE:Ciprofloxacin absorption is impaired in patients given enteral feedings orally and via gas-
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trostomy and jejunostomy tubes. Antimicrob Agents Chernother 1996;40:6. 30. Magnusson JO: Metabolism of digoxin after oral and intrajejunal administration. BrJ ClinPharmacoI1983;16:741. 31. SempleHA, KooW, TamYK et al: Interactions between hydralazine and oral nutrients in humans.Ther Drug Monit 1991;13:304. 32. Au Yeung SC, Ensom MHH: Phenytoin and enteral feedings: Does evidence support an interaction?Ann Pharmacother 2000;34:896. 33. Faraji B, Yu PP:Serum phenytoin levelsof patients on gastrostomy tube feeding. J Neurosci Nurs1998;30:55. 34. McGoodwin PE, Seifert CF, Bradberry JCet a1: Recovery of phenytoin from a percutaneous endoscopic gastrostomy Pezzer catheter following in vitro delivery of multiple doses of phenytoin suspension and phenytoincapsules [abstract].Pharmacotherapy 1990; 10:233. 35. Estoup M: Approaches and limitations of medication delivery in patientswith enteral feedingtubes. CritCare Nurse 1994;14:68. 36. Engle KK, Hannawa TE: Techniques for administering oral medications to critical care patients receiving continuous enteral nutrition. AmSoc Health-Syst Pharm 1999;56:1441. 37. Clark-Schmidt AL, Garnett WR, Lowe DR, et al: Loss of carbamazepine suspension through nasogastric feeding tubes. Am J HospPharm 1990;47:2034. 38. Mimoz 0, BinterV, Jacolot A, et al: Pharmacokinetics and absolute bioavailability of ciprofloxacin administered through a nasogastric tube with continuous enteral feeding to critically ill patients. Intensive Care Med 1998;24:1047. 39. de Marie S, VandenBergh MFQ, Buijk SL, et al: Bioavailability of ciprofloxacin after multiple enteral and intravenous doses in ICU patientswith severe gram-negative intra-abdominal infections. Intensive Care Med 1998;24:343.
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40. Cohn SM, Sawyer MD, Bums GA, et al: Enteric absorption of ciprofloxacin during tube feeding in the criticallyill.J Antimicrob Chemother 1996;38:871. 41. Wright DH, PietzSL, Konstantinides MT, et al: Decreased in vitro fluoroquinolone concentrations after admixture with an enteral feeding formulation. JPEN J Parenter EnteralNutr2000;24:42. 42. Druckenbrod RW, Healy DP: In vitro delivery of crushed ciprofloxacin through a feeding tube. Ann Pharmacother 1992; 26:494. 43. Gal P, Layson R: Interference with oral theophylline absorption by continuous nasogastricfeedings. Ther Drug Monit1986;8:421. 44. Plezia PM, Thronley SM, Kramer TH, et al: The influence of enteral feedings on sustained-release theophylline absorption. Pharmacotherapy 1990;10:356. 45. Bhargava VO, Schaaf LJ, BerlingerWG, et al: Effect of an enteral nutrient formula on sustained-release theophylline absorption. Ther DrugMonit 1989;11:515. 46. Fleischer 0, Li C, Zhou Y: Drug, meal and formulation interactions influencing drug absorption after oral administration. Clin Pharmacokinet 1999;36:233. 47. Singh BN: Effects of food on clinical pharmacokinetics. Clin Pharmacokinet 1999;37:213. 48. Zeman FJ: Drugs and nutritional care. In Clinical Nutrition and Dietetics, 2nd ed. NewYork, MacMillan, 1993, p 97. 49. PageCP,HardinTC: Nutritional Assessment and Support:APrimer. Baltimore, Wiliams & Wilkins, 1993. 50. A.S.P.E.N. Board of Directors and The Clinical Guidelines Task Force:Guidelinesfor the use of parenteral and enteral nutrition in adult and pediatric patients. Section IX: Drug-nutrient interactions. JPEN J Parenter EnteralNutr2002;26(suppl 1):42SA.
Home Enteral Nutrition Reimbursement Marion F. Winkler, MS, RO, LON, CNSO Jorge E. Albina, MO
CHAPTER OUTLINE Introduction Enteral Nutrition Suppliers Verification of Eligibility and Coverage Enteral Nutrition in Skilled Nursing Facilities Indications for Home Enteral Nutrition Medicare Coverage for Home Enteral Nutrition Medicare Product Classification Coverage Requirements for Equipment, Supplies, and Pumps Reimbursement for Professional Services Completing the Certificate of Medical Necessity Appeals Process for Denials Role of Nutrition Support Practitioners and Home Care Personnel
INTRODUCTION Growth in the number of patients receiving home enteral nutrition is due to decreased length of hospitalization, improvements in technology, and the availabilityof clinically focused home care services.v" From 1989 to 1992, the number of Medicare beneficiaries receiving enteral nutrition increased from 34,280 to 73,323. 4 The British Association of Parenteral and Enteral Nutrition reported a 20% annual increase of patients receiving home enteral nutrition, representing 10,864 persons on the home tube feeding registry in the United Kingdom in 1996 to 1997.5 Approximately one quarter of these patients were children. Chartwell Pennsylvania, a provider of home infusion services, recorded a 40% increase in enteral nutrition business between 1999 and 2002 with an average monthly census of 450 patients.! Current statistics on the volume of patients receiving home enteral nutrition are not available because there is 306
no mandatory reporting mechanism. Medicare projections suggest continued growth in home health care and parenteral and enteral nutrition through 2008.6 Home enteral nutrition is a costly therapy. Expenditures for durable medical equipment COME) under which enteral nutrition is billed increased from 2.3 billion dollars in 1992 to 3.7 billion dollars in 1997.6 Reddy and Malone? reported in 1998 that the cost of home enteral nutrition, including standard formula, supplies and care, and one hospitalization was about $18,000. The per patient annual cost of enteral feeding noted by Coram Healthcare varied from $8,000 to $12,000.8 This is comparable to information from a Rhode Island-based provider indicating an average of $550/month billed for standard formula for Medicare beneficiaries receiving home enteral nutrition in 2002. The annual growth rate for recipients of parenteral and enteral nutrition is expected to be 3% in 2003 and 4% per year from 2004 to 2008.6 In this chapter, key principles for optimizing reimbursement for home enteral nutrition will be outlined. An understanding of the indications and coverage criteria of the various insurers, particularly Medicare, is essential in this process. In-depth knowledge of the required documentation and strategies to accurately complete the certificate of medical necessity CCMN) are extremely important. Case studies and sample letters will be used to illustrate documentation for disease-specific disorders, specialty product usage, and the need for an enteral feeding pump. The role of health care practitioners involved in the home care referral process is described.
ENTERAL NUTRITION SUPPLIERS OME companies supply most home enteral nutrition as a "drop-ship" service.P' A small but growing number of home care patients purchase formula directly from a local pharmacy or grocery store. An increasing number of home care nursing agencies and home infusion companies are providing enteral supplies with the added service of clinical monitonng.P" Payment sources vary
SECTION IV • Principles of Enteral Nutrition
by region and supplier. Coram Healthcare reported that 46% of patients receiving home enteral nutrition had Medicare coverage, 17% had Medicaid, 35% had commercial insurance, and 3% had other insurance or payment mechanisrns.' Data from the past 2 years from a Rhode Island home infusion provider indicated that 34% of patients receiving home enteral nutrition had Medicare coverage, 59% had commercial insurance, 4% had Medicaid, and 3% were self-pay customers.
VERIFICATION OF ELIGIBILITY AND COVERAGE Home care agencies or DME vendors require a thorough review of eligibility and coverage criteria before they agree to accept a patient for home enteral nutrition. This is a necessary step because even with the most clear-cut clinical indication, there is still the risk of denial of payment from an insurer, resulting in a lengthy appeals process or potentially a large financial burden to the patient. It is important to identify the type of coverage held by the patient because requirements for approval vary with the type of program and individual plans. Government programs, e.g., Medicare and Medicaid, have very strict coverage criteria and require a detailed history, tests, and nutritional data to determine medical eligibility. Medicaid programs, which cover services for low-income citizens, vary by state and according to each local managed care organization or provider. Coverage policies for home enteral nutrition therapies in specific states should be verified. An informative document detailing Medicaid policy coverage by state is available on the Web site http://www.ross.com/reimbursement/ medicaid.asp. Coverage policies and reimbursement for enteral nutrition also vary with private payers and managed care organizations and often require preauthorization or precertification. The development of these precertification processes is often criticized as being arbitrary and lacking a scientific basis." Based on insurance or Medicare reimbursement, the patient may be responsible for some of the home care expenses or for a co-payment. For example, if Medicare criteria are met, patients are usually responsible for 20% of reasonable or customary charges. These charges are typically the average cost of the product based on historical data and prices in a particular geographic region. Patient charges may be higher for home enteral nutrition if it is supplied by a non-Medicare participating provider. 10 The Balanced Budget Act of 1997 authorizes The Centers for Medicare & Medicaid Services (CMS) to enter into competitive bidding for some categories of DME or to apply inherent reasonableness to align payment amounts with current market prices. This has had a substantial impact on the provision of and payment for enteral nutrition products.P-" A concern is that the average cost of a product may be based on the price in grocery and drug stores without consideration of all the elements necessary to ensure safe home enteral nutrition including costs of patient and family training, monitoring, and equipment and supplies. These issues were addressed
307
in an Institute of Medicine" report, which specifically recommended that professional nutrition services in home health care be improved and that reimbursement systems and regulations be reevaluated. Some insurance companies establish their own criteria for enteral nutrition whereas others follow the Medicare guidelines. Most private payers have contracted per diem rates for supplies in addition to formula charges. Regardless of what type of private insurance the patient has, it is important to determine that the patient has home health benefits of sufficient scope to cover a therapy that may be needed indefinitely." Some patients referred for home care have private insurance that is known to cover enteral therapy for specific clinical conditions or disease states, but their particular plan does not include this coverage. For example, a woman needed enteral nutrition because of an esophageal malignancy, but her insurance policy only covered enteral nutrition for Crohn's disease. The family had to meet with the employer providing the coverage to negotiate a change in benefits. Aside from the need for home enteral nutrition, many patients typically require additional services, equipment and supplies, or nursing assistance for wound care, ostomy care, administration of antibiotics or oxygen, tracheostomy care, pain management, diabetes education, or rehabilitation. Reimbursement specialists, case managers, and discharge planners can assist in obtaining and evaluating this intormation."
ENTERAL NUTRITION IN SKILLED NURSING FACILITIES Skilled nursing facilities have the option to provide enteral nutrition directly or through contracts with an outside supplier. Enteral nutrition when provided to a patient covered by Medicare Part A must be billed by the facility to the fiscal intermediary. In this situation, enteral nutrition therapy is classified as a routine dietary cost for reporting purposes. Medicare Part B payment is not available for beneficiaries covered for a stay under Part A. If Part A coverage is not applicable, enteral nutrition may be billed under Part B. Eligibility requirements described for home enteral nutrition also apply to the patient in a skilled nursing facility. A detailed discussion of this topic can be found in the Enteral Product Reimbursement Guide for Skilled Nursing Facilities and Homecare Providers.16
INDICATIONS FOR HOME ENTERAL NUTRITION Appropriate candidates for home enteral nutrition are patients who have a functioning gastrointestinal (Gl) tract and who have oral intake inadequate to restore or maintain nutritional status. The A.S.P.E.N. Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Pediatric Patients state that home nutrition therapy should be used in adult patients who cannot meet nutrient requirements orally and in patients who are able to
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25 • Home Enteral Nutrition Reimbursement
receive therapy safely outside an acute care setting." Home nutrition support for pediatric patients should only be given in the home if the patient has a caregiver who is willing and able to provide care in a safe environment." Most insurers that cover enteral nutrition at home will only do so when the therapy is the patient's sole source of nutrition. Sale source or total enteral nutrition usually refers to therapy that is a person's primary source of sufficient calorie and nutrient intake to achieve or maintain appropriate body weight. Insurers typically define a total daily intake of 20 to 35 cal/kg as sufficient for most adults. Patients who are making a transition to an oral diet or who require only supplemental feedings will not usually receive reimbursement for enteral nutrition at home. Some insurers specify that over-the-counter nutritional formulas are considered to be food and are noncovered health services even if provided by tube. Some restrict coverage to enteral nutrients requiring a prescription such as those for inborn errors of metabolism, malabsorption syndromes, short bowel syndrome, Crohn's disease, or severe pancreatitis. The conditions most often requiring home enteral nutrition fall into several broad categories: • Impaired nutrient ingestion • Inability to consume adequate oral nutrition • Impaired digestion and absorption • Severe wasting or growth retardation Impaired nutrient ingestion often involves dysphagia or swallowing disorders due to neurologic impairment, cognitive dysfunction, vocal cord paralysis, trauma to the head or neck, congenital anomalies in children, and shortness of breath due to cystic fibrosis or respiratory ailments when the work of breathing itself interferes with eating ability. Patients at home who are unable to consume adequate oral nutrition include those in a comatose state, pregnant women with hyperemesis gravidarum, those with cachexia due to cardiac disease or cancer, those with spinal cord injury, and those recovering from trauma and undergoing active rehabilitation and physical therapy. Conditions with impaired digestion or absorption include gastroparesis, inflammatory bowel disease, and pancreatic insufficiency. These patients often have motility or malabsorptive disorders but are able to tolerate modified enteral nutrition therapy. Conditions with severe wasting or growth retardation include cystic fibrosis, cerebral palsy, myasthenia gravis, congenital heart disease, cancer cachexia, and failure to thrive. The designation of a diagnostic code that relates directly to the need for enteral nutrition is an essential ingredient for coverage (fable 25-1). Often a home care referral is made, and the discharge planner provides the home care company or DME supplier with the hospital admission diagnosis. This is usually the case for patients who are admitted for cardiac surgery or an underlying respiratory disease and have a complication necessitating enteral nutrition support. The diagnosis, related to the need for enteral nutrition in this example, might be stroke or neurologic impairment, dysphagia, or vocal cord paralysis. The most common diagnoses associated with the reason for home enteral nutrition as reported by Coram Healthcare were GI disorders, protein-ealorie
malnutrition, nutritional or metabolic developmental syndromes, intestinal malabsorption, and esophageal diseases," Patients receiving home enteral nutrition followed by a Rhode Island home care provider in 2001 included 20% with head and neck malignancy, 15% with dysphagia, 15% with a cerebrovascular accident or neurologic impairment, 12% with malnutrition or wasting disease, 12% with respiratory failure or aspiration pneumonia, 10% with GI disease or pancreatic carcinoma, 8% with hyperemesis gravidarum, and 8% with pyloric stenosis. In 2002 the diagnoses included 24% with head and neck malignancy, 14%with GI malignancy, 14% with dysphagia, 11 % with failure to thrive, 11% with neuromuscular and degenerative disorders, 7% with gastroparesis, 7% with a CVA or neurologic impairment, 4% with esophageal disease, 4% with renal failure, and 4% with cystic fibrosis.
MEDICARE COVERAGE FOR HOME ENTERAL NUTRITION Enteral nutrition products are covered under the "prosthetic device" benefit of Medicare Part B.18 This provision requires permanent dysfunction of a body organ. For items to be covered by Medicare, they must "fit into a defined Medicare benefit category and be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body mernber.t" Coverage and payment rules for enteral nutrition specify that there must be a permanent nonfunction or disease of the structures that normally permit food to reach the small bowel or a disease of the small bowel that impairs digestion and absorption of an oral diet. Sufficient nutrients must be provided to maintain weight and strength commensurate with the patient's overall health status and the condition must be a permanent impairment, i.e., of long and indefinite duration (at least 3 months). Adequate nutrition must not be possible by dietary adjustment and/or oral supplementation. The implication of the Medicare perspective is that the GI tract is the malformed body part and the feeding tube is the prosthesis that replaces the swallowing mechanism or absorptive capacity of the gut. This interpretation illustrates the dilemma that nutrition support practitioners face in qualifying patients for home enteral nutrition. It also explains why coverage for oral nutrition is rarely obtained. The requirement of "permanent dysfunction" is often misinterpreted. Medicare defines permanent as life-long or lasting 90 days or longer. Permanent means indefinite, not forever." Home health care providers struggle with explaining this definition to physicians as they complete the required certificate of medical necessity. If the patient will receive enteral nutrition for at least 90 days or for indefinite duration, the code 99 should be selected on the CMN (Fig. 25-1). If an exact time frame is specified, e.g., 4 months, and the patient then requires home enteral nutrition for 6 months, a revised CMN must be submitted with an explanation for the change. If the patient dies before the 9().day requirement, the intent of life-long therapy is met, and coverage will typically be
SECTION IV • Principles of Enteral Nutrition
III!!IIBII
309
Selected ICD·9 Codes for Diagnoses Pertinent to the Need for Enteral Nutrition·
Code
Anatomic Conditions
Code
Motility Disordel"ll--
145.9 141.9 151.9 195.0 230.0 230.1 230.2 230.7 530.3 530.84 537.3 537.4 569.81 802.2
Carcinoma of the mouth Carcinoma of the tongue Carcinoma of the stomach Carcinoma of the head, face, neck Carcinoma of the oral cavity Carcinoma of the esophagus Carcinoma of the larynx Carcinoma of the intestine Esophageal stricturejstenosis Tracheo-esophageal fistula Duodenal obstruction Gastro-jejunocolic fistula Intestinal fistula Mandible fracture
530.81 536.3 536.9 560.9 564.2 643 787.2
Esophageal reflux Gastroparesis Unspecified functional disorder of the intestine Pyloric obstruction Post gastrectomy dumping syndrome Hyperemesis gravldarurn Dysphagia
Code
Intestinal DlaeasejMalabsorptive Disorders
Code
Cognitive, Neurologic, and Neuromuscular Conditions
191.0 290.0 331.0 332.0 335.2 336.9 340.0 343.2 343.9 358 434.9 436.0 780.0 780.03
Brain tumor Senile dementia Alzheimers disease Parkinsons disease Amyotrophic lateral sclerosis Spinal cord compression Multiple sclerosis Quadriplegia Cerebral palsy Myasthenia gravis Cerebral infarct Cerebral vascular accident Coma Persistent vegetative state
157 277.0 555.0 577.0 577.1 579.30 579.4 579.9
Cancer of the pancreas Cystic fibrosis Regional enterltlsjCrohn's disease Acute pancreatitis Chronic pancreatitis Short bowel syndrome Pancreatic steatorrhea Intestinal malabsorption
Code
Malnutrition
261.0 262.0 263.0 263.1 783.4 783.41 783.7
Severe malnutrition Proteln-calorie malnutrition Moderate malnutrition Mild malnutrition Lack of normal physiologic development Failure to thrive-child Failure to thrive-adult
Code
Motility Disorders
478.3 507
Vocal cord paralysis Aspiration pneumonia
Code
Inborn Errors of Metabolism
270.1 270.2 270.3 270.4 270.5
Phenylketonuria Tyrosinemia Maple syrup urine disease Homocystinuria Hlstidlnemia
*International Classification of Diseases, ICD-9-CM, 9th rev. Chicago, American Medical Association, 2001, vols 1 and 2.
received. Except for occasional approvals from commercial insurers, home enteral nutrition will not be covered if a patient only needs short-term (i.e., a few weeks) therapy. One specific exception is coverage for short-term enteral nutrition in children or adolescents with Crohn's disease if there is growth failure and inadequate intake during exacerbation of the disease. A bill passed into law in 1996in New Hampshire requires insurers "to cover the provision of non-prescription enteral formulas for the treatment of impaired absorption of nutrients caused by disorders affecting the absorptive surface, functional length, or motility of the Gl tract."20 Physicians must issue a written order stating that the enteral nutrition is "needed to sustain life, is medically necessary, and is the least restrictive and most cost effective means for meeting the needs of the patient. "20 Other states appear to be following New Hampshire with passage of similar laws. Medicare guidelines further delineate eligible conditions as anatomic or resulting from a motility disorder. Anatomic indications may include obstructing carcinoma of the mouth, tongue, larynx, esophagus, stomach, or intestine if feeding distal to the site is feasible. Other anatomic conditions in which home enteral nutrition
may be appropriate are bronchoesophageal, tracheal, gastric, or intestinal fistulae or fractured jaws. Documentation must include the pathology report, radiographic verification of the obstruction, or an operative report detailing the anatomic obstruction. Procedural or endoscopic notes for placement of feeding gastrostomy or jejunostomy tubes should specify that the indication for the tube is malnutrition, when present, and the inability to chew, swallow, or eat due to the underlying condition. Swallowing studies are not usually needed if the indication for enteral nutrition includes anatomical obstruction. 19 A patient receiving home enteral nutrition because of obstructing carcinoma of the tongue was told by a home care agency that he did not meet Medicare's eligibility criteria because a swallowing study had not been done. For this patient, documentation of the tumor at the base of the tongue and his inability to eat was provided along with a physician letter of medical necessity stating that swallowing studies were contraindicated and not required in this situation. The patient's Medicare claim was paid on the first submission. Patients receiving home enteral nutrition for motility disorders typically have symptoms precluding adequate
310
25 • Home Enteral Nutrition Reimbursement Certificate of Medical Necessity Enteral Nutrition INITIAL --.1_'_
Certification Type/Date:
Section A
Patient Name, Address, Telephone and HIC Number
(
-
)
REVISED
RECERTIFICATION
--.1_'_
Supplier Name, Address, Telephone and NSC Number
(
HICN
Place of service Name and Address of Facility if applicable (See reverse)
-'-'-
HCPCS Code
)
-
NSC#
PTOOB .-1_1_; Sex_(M/F); HT._(in.); WT._(lbs.) Physician Name, Address (printed or typed) Physician's UPIN: Physician's telephone # (_)_-__
Information In this section may not be completed by the supplier of the items/supplies.
Section B
EST. Length of need (# of months):
1-99 (99=lifetime) Diagnosis codes (ICD-9)
Answer questions 7, 8 and 10-15 for enteral nutrition
Answers
(Circle V for yes, N for no, or D for does not apply, unless otherwise noted) Questions 1-6, and 9, reserved for other or future use.
y
N
7. Does the patient have permanent non-function or disease of the structures that normally permit food to reach or be absorbed from the small bowel?
y
N
8. Does the patient require tube feedings to provide sufficient nutrients to maintain weight and strength commensurate with the patient's overall health status?
A) B)
10. EriD1 product name(s). A) B)
11. Calories per day for each product? 12. Days per week administered? (Enter 1-7)
1
2
y
3 N
4
0
13. Circle the number for method of administration? 2-Gravity 3-Pump 4-Does not apply 1-Syringe 14. Does the patient have a documented allergy or intolerance to semi-synthetic nutrients? 15. Additional information when required policy:
Name of person answering section B questions, if other than physician (please print): Title: Employer: Name: Section C
Narrative Description of Equipment and Cost
(1) Narrative description of all items, accessories and options ordered; (2) Supplier's charge; and (3) Medicare Fee Schedule Allowance for each item, accessory, and option. (See instructions on back)
Section D
Physician Attestation and Signature/Date
I certifythat I am the physician identifiedin SectionA of this form. I have receivedSections A, Band C of the Certificateof Medical Necessity(including chargesfor itemsordered). Any statementon my letterheadattachedhereto,has been reviewedand signed by me. I certify that the medical necessity information In SectionB is true, accurateand complete, to the best of my knowledge, and I understand that any falsification, omission,or concealmentof material fact in that section may subject me to civil or criminalliability.
Physician's signature
Date ---1---1
(Signature and date stamps are not acceptable)
FIGURE 25-1. Certificate of Medical Necessity (CMN).
SECTION IV • Principles of Enteral Nutrition
oral intake including reflux, dysphagia, dumping syndrome, or gastroparesis. In this situation evidence of an impaired swallowing mechanism or radiographic verification of gastric dysmotility is imperative. Progress notes from a speech and language therapist often provide extensive evaluation of the swallowing disorder and documentation of aspiration when present. For patients with gastric dysmotiIity, it is necessary to provide evidence that trials of pharmacologic treatment failed. Coverage may be possible under Medicare or commercial insurers for patients with partial impairments who can only swallow small amounts of food or who have malabsorption. An example of how to document this situation follows. An 80-year-old male was discharged home from a skilled nursing and rehabilitation center and is to receive gastrostomy feedings. His primary diagnosis is stroke and dysphagia. He is receiving a 1.5 callmL formula infused for 14 hours at 75 mUhr by a feeding pump. A recent swallow evaluation revealed severe oropharyngeal dysphagia and aspiration. He is currently apraxic, unable to speak, unable to chew, has loss of taste sensation, and is having difficulty with bolus propulsion and formation with honey-thick consistency. He is taking only small spoonfuls of baby food and custard for pleasure. His tube feeding provides 30 callkg and 1.1 g of protein/kg and meets 100% of his caloric requirements.
Patients with documented malabsorptive syndromes may also qualify for Medicare reimbursement under the partial impairment criteria. There must be substantial evidence that the patient is unable to maintain weight, strength, and nutrition status commensurate with overall health without the supplemental tube feeding. Nutrition support practitioners typically document minimal oral intake as "for patient's comfort only" to designate dependency on enteral nutrition even when oral diet is allowed. Home enteral nutrition is not covered for patients who have a functional GI tract and whose need for enteral nutrition is due to refusal or forgetting to eat, lack of appetite, or anorexia or nausea associated with mood disorders or end-stage disease. Although these conditions may be clinically appropriate indications for tube feeding, they do not qualify under the Medicare prosthetic device clause because there is no dysfunction of the GI tract. A flag may be raised when claims for home enteral nutrition are submitted with a bill for formula that is not accompanied by a bill for tubing, bags, equipment, or supplies. Some patients, particularly those receiving bolus feedings, may not need equipment or supplies. This should be clearly noted. Most insurers will not pay for baby food or regular food ground in a blender that is infused or delivered as tube feeding, overthe-counter products, vitamin/mineral supplements, food thickening products, or oral electrolyte solutions. Standard infant formulas will typically be covered if they are administered via tube feeding and the criteria for coverage of enteral nutrition are met. Infant formulas and specialized infant formulations are not covered when taken by mouth unless specifically mandated by state law. Some state laws do mandate insurance coverage for "special medical foods" including products prescribed orally or enterally for treatment of inborn errors
311
of metabolism such as phenylketonuria, maple syrup urine disease, homocystinuria, histidinemia, and tyrosinemia. Coverage for oral enteral nutrition for an adult who required a high branched-ehain amino acid/low aromatic amino acid-eontaining oral diet for control of hepatic encephalopathy for an autoimmune liver disease and for a patient with Crohn's disease who was successfully weaned from parenteral nutrition was obtained locally. The insurance company covered oral nutrition for treatment of these conditions, but persistence on the part of the patient to champion payment, patient advocacy on the part of the physician and dietitian, and extensive clinical documentation were necessary.
MEDICARE PRODUCT CLASSIFICATION The Statistical Analysis DME Regional Carrier (SADMERC) has classified enteral nutrition formulas into six categories (Table 25-2). The most recent product classification list was posted on August 15, 2003, on the Web site http://www.palmettogba.com. The list can be accessed by clicking on SADMERC, then on product classification lists, and then on enteral nutrition. This review contains 260 products. Nutrition support and home care practitioners should familiarize themselves with the product coverage categories. Not all products within a specific category are clinically equivalent or interchangeable despite the fact that they may be reimbursed at the same rate. Clinically similar products may also be categorized differently. For example, formulas within category III have hydrolyzed protein and amino acids; however, some of these products are very low in fat and others contain approximately 30% of their calories as fat. This has implications for product substitution if the DME or infusion provider maintains an enteral formulary. Practitioners should evaluate whether the planned product substitution is clinically acceptable. Standard polymeric, meal-replacement diets are considered to be appropriate for the majority of patients requiring enteral nutrition. Medical necessity must be
• . Medicare Enteral Nutrition Product . . Classification Category Code Description B4150/B4151
II III
B4152 B4153
IV
B4154
V VI
B4155 B4156
Semisynthetic intact protein/protein isolates or natural intact protein products Calorically dense products Hydrolyzed protein/amino acids Defined formula for special metabolic needs Modular components Standardized nutrients
From DMERC Region A Supplier Manual. Chapter 18.1 Enteral Nutrition, rev. 13, March 2000; http://www.tricenturion.com/content/dmerc/ch 18_enteral.cfm.
312
25 • Home Enteral Nutrition Reimbursement
stated for calorically dense products with additional documentation specifying high calorie requirements, fluid restriction, volume sensitivity, and cyclic or nocturnal infusions. For patients with compromised or limited GI function or pancreatic insufficiency a detailed narrative is required, explaining the need for hydrolyzed proteins and amino acids and including a description of intolerance and/or evidence of diarrhea or steatorrhea with a standard polymeric diet. Similarly, the need for disease-specific products or those modified for organ system dysfunction must be well documented with laboratory data and treatment plans. Modular nutrients are not typically used in home care; however, a detailed rationale with supporting clinical documentation should be submitted if these products are prescribed. The following scenario illustrates an example of documentation of medical necessity for a patient who required a specialty product. A 5D-year-old male was referred forhome nutritionalsupport because of intractable vomitingand a 3D-pound weight loss. The patient has chronic renal failure requiring hemodialysis and congestive heart failure. He underwent a hernia repair and placement of a feeding jejunostomy. He weighs 59 kg. His serum albumin level is 2.0 g/dL. Multiple trials of oral feeding were made during his hospitalization, but in each attempt he vomited large amounts of bile and undigested food. An upper GI series suggested partial small bowel obstruction. Tube feedings were initiated with a calorically dense renal formulation [insert product name] because of elevated blood urea nitrogen and high creatinine levelsand hyperphosphatemia [insertlaboratoryvalues and dates] and were administered over a 12-hour period to accommodate his dialysis schedule and lifestyle. He requires an enteral infusion pump because of jejunostomy feedings at a rate of 60 mUhr and a history of congestive heart failure. His tube feeding provides 1440 cal (29 cal/kg) and 50 g of protein (0.8 g/kg). He has an inabilityto tolerate oral feedings because of intractable vomiting and requires home enteral nutrition for an indefinite duration to provide sufficient nutrients to maintain weight and strength commensurate with his overall health status. Enteral nutrition products are billed for in lOlkal units. Orders for home enteral nutrition should therefore include the number of calories prescribed. A caloric prescription of 20 to 35 callkg is considered appropriate in the Medicare guidelines. If a prescription falls outside this range, appropriate documentation should be provided. Examples of situations in which less than 20 callkg may be necessary in home care include patients with conditions for which weight reduction is desired and bedridden patients who have very low activity or documentation of weight gain with the current therapy. Patients may require greater than 35 callkg in home care for reasons such as continued weight loss with lower calorie prescriptions, uncontrolled movement, increased requirements due to recovery from metabolic stress, major burns or trauma, aggressive rehabilitation programs, pressure ulcers or nonhealing wounds, or malabsorption. Prescriptions for cyclic or nocturnal feedings may raise the suspicion that a patient is only receiving supplemental enteral nutrition. Selection of an appropriate length of infusion to assure that calorie needs are
• . Resources for DMERC Manuals and . . Information Centers for Medicare & Medicaid Services (CMS): http://cms.hhs.gov Region A-Health Now (Connecticut, Delaware, Maine, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont): http://www.umd.nycpic.com/dmerc.html Region B-Admlnlstar Federal (Illinois, Indiana, Maryland, Michigan, Minnesota, Ohio, Virginia, Washington DC, West Virginia, Wisconsin): http://www.astar-federaI.com/anthem/ allillates/adminastar/dmerc/index.html Region C-Palmetto Government Benefits Administrators (Alabama, Arkansas, Colorado, florida, Georgia, Kentucky, Louisiana, Mississippi, New Mexico, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Virgin Islands): http://www.palmettogba.com/index.html Region D-CIGNA (Alaska, Arizona, California, Hawaii, Idaho, Kansas, Missouri, Montana, Nebraska, Nevada, North Dakota, Oregon, South Dakota, Utah, Washington, Wyoming): http://www.c1gnamedicare.com/ dmerc/lndex.html
being met is important for reimbursement purposes. An example of documentation for a patient requiring a change in calorie prescription due to weight gain from inactivity is shown below. A female in her 60s has received gastrostomy feedings at home for the past 6 months due to a progressive neuromuscular disorder [insert diagnosis] and dysphagia. She has no significant oral intake because of a severe swallowing dysfunction. She is wheelchair bound, requires assistance with all activities of daily living, and has minimalphysicalactivity. She has had a 20% weight gain, probably due to inactivity, since tube feedingshave been initiated. Her prescription has been changed to decrease the caloric intake from 1600 kcal (35 cal/kg) to 1400 cal (25 cal/kg) with future plans to decrease intake to less than 1200 calories (20 kcal/kg) ifshe continues to gain weight. Resources for DMERC manuals and information are listed in Table 25-3.
COVERAGE REQUIREMENTS FOR EQUIPMENT, SUPPLIES, AND PUMPS If coverage requirements are met, administration supplies and equipment are covered. Medicare limits payment to no more than three nasogastric tubes or one gastr,pstomy tube or jejunostomy tube every 3 months; catheter/tube anchoring devices are considered to be included in the supply kits. Although the method of administration of tube feeding at home should be based on feeding site, clinical status of the patient, type of formula, mobility and quality of life of the patient, and caregiver needs, gravity or bolus feedings are typically prescribed because these are less expensive. Most insurance plans, including Medicare, will only pay for an enteral feeding pump when gravity or bolus feeding fails. Enteral feeding pumps are therefore considered exceptions rather than the rule. A pump is covered under the DME benefit if there is documentation that gravity feeding is not tolerated due to
SECTION IV • Principles of Enteral Nutrition
_
• .
.
Sample Documentation for Medical Necessity for Enteral Feeding Pump
Patient experienced aspiration with gravity feeding that resulted in pneumonia. Continuous feedings are required because of nausea, vomiting, or diarrhea when bolus infusions were attempted. Patient requires controlled delivery of nutrients because of fluid imbalance or overload or because of congestive heart failure or pulmonary edema. Patient has insulin-dependent diabetes and requires a pump for feeding to achieve adequate blood glucose control.
reflux, aspiration, severe diarrhea, dumping syndrome, uncontrolled blood glucose, circulatory overload, infusion via jejunostomy tube, or infusion rate less than 100 mUhr. Table 25-4 illustrates sample documentation that can be included with claims for feeding pumps. The clinician should not use the word prevent when documenting the need for an enteral feeding pump because Medicare does not pay for preventative therapies." The need for a feeding pump should be stated as aspiration rather than prevention of aspiration in a high-riskpatient. An example of documentation is shown below. A woman in her 80s with dementia and Parkinson's disease has had a progressive decline in function including the ability to swallow. She was recently treated for aspiration pneumonia and required hospitalization. A combined gastrostomy/jejunostomy feeding tube was placed on [insert date] for total nutritional support, fluids, and medication administration. A standard fiber-containing formula [insert product name] will be infused at 40 mUhr, delivering 24 callkg and 1.1 g of protein/kg. She requires a feeding pump because of documented aspiration. She is not expected to resume any oral nutrition. She will require enteral nutrition for indefinite duration, probably for the rest of her life.
REIMBURSEMENT FOR PROFESSIONAL SERVICES Medicare Part B does not pay for nursing care for administration of tube feedings; however, limited coverage for teaching the patient and family how to administer feedings is available under Medicare Part A. Supplemental insurance may provide coverage for additional home nursing visits or care for nonenteral nutrition-related needs. Reimbursement policies of commercial insurers for teaching about enteral feeding vary considerably. Most policies recognize that training and education of the patient and family are important, and some specify that it is required at the initial therapy session; however, most indicate that training and education are not separately billable but are included in the reimbursement for the service or therapy. Some plans will authorize per diem nursing visits beyond the initial assessment and teaching visits in accordance with their specific home infusion agreement. Physicians' current procedural terminology (CPT) codes exist for oversightservices or supervision of patients under the care of home health
313
agencies." Separate payment under Medicare Part B may be made for physician care plan oversight (CPO) services for patients with complex medical conditions or those who require multidisciplinary care modalities or 30 or more minutes of physician time per month. This generally includes regular physician development or revision of care plans, review of laboratory and other studies, communication with other health care professionals involved in the patient's care, and adjustment of medical therapy.P
COMPLETING THE CERTIFICATE OF MEDICAL NECESSITY The CMN must be signed and be on file before the home care company can submit a claim for enteral therapy (see DMERC Form 10.028 in Fig. 25-1). Each issue identified in the coverage guidelines should be addressed, and supporting documentation must be submitted. The ICD-9 code listed firstshould be the diagnosis that relates to the need for enteral therapy. Section B of the form cannot be filled out by the provider but may be filled out by a member of the hospital nutrition support team (nurse, dietitian, or pharmacist not employed by the provider). The physician must sign section D. The form should be completely and accurately filled out, leaving nothing blank. Supporting documentation should always accompany any claim for enteral nutrition with use of a specialty formula or pump. The physician is expected to have seen the patient within 30 days of the initial CMN submission. Figure 25-2 illustrates a checklist that can be used to help organize required documentation and to make a home care referral for enteral nutrition. A cover page outlining the documents being submitted and clearly identifying how the patient meets the eligibility criteria should accompany the submission. The claims analyst should not have to guess what the indication for therapy is or the rationale for the supporting documentation. A revised CMN is required in the following situations: • Change in the number of calories per day • Change in the number of days per week therapy is administered • Change in the method of infusion (syringe, gravity, or pump) • Change in the route of feeding (tube to oral) • Change in product to a category IV or V formula • Stated length of therapy originally less than 90 days • Therapy prescribed for longer than originally stated
APPEALS PROCESS FOR DENIALS If a claim for home enteral nutrition therapy is denied, there is a Medicare appeals process. 23,24 A review or hearing may be requested by the supplier or the patient or beneficiary receiving the therapy. Before the review is requested, it is worthwhile to contact the regional insurance carrier to determine the basis for denial. Claims may be denied because of errors in completing the CMN
314
25 • Home Enteral Nutrition Reimbursement
Section A:
(May be completed by the supplier)
Certification Type/Date:
If this is and initialcertification for this patient.indicate this by placing date (MM/DD/YY) neededinitiallyin the space marked"INITIAL." If this is a revised certification (to be completed when the physician changesthe order, basedon the patient'schanging clinical needs), indicatethe initial date needed in the space marked "INITIAL," and also indicate the recertification date in the space marked"REVISED." If this is a recertification, indicatethe initial date neededin the space marked"INITIAL," and also indicatethe recertification date in the space marked "RECERTIFICATION." Whethersubmitting a REVISED or a RECERTIFIED CMN, be sureto alwaysfurnishthe INITIALdate as well as the REVISED or RECERTIFICATION date.
Patient Information:
Indicate the patient'sname, permanent legal address, telephonenumberand his/herhealth insurance claim number(HICN) as it appearson his/herMedicare card and on the claim form.
Supplier Information:
Indicatethe name of your company (supplier name), addressand telephone numberalong with the Medicare SupplierNumberassigned to you by the National SupplierClearinghouse (NSC).
Place of Service:
Indicate the place in whichthe item is being used, i.e., patient's home is 12, skilled nursingfacility (SNF)is 31, End Stage RenalDisease (ESRD) facilityis 65, etc. Referto the DMERCsuppliermanualfor a completelist.
Facility Name:
If the placeof service is a facility, indicatethe nameand complete addressof the facility.
HCPCS Codes:
List all HCPCS procedure codesfor items orderedthat requirea CMN. Procedure codesthat do not require certification shouldnot be listed on the CMN.
Patient 008, Height, Weight and Sex:
Indicate patient'sdate of birth (MM/DDIYY) and sex (male or female); height in inchesand weight in pounds, if requested.
Physician Name, Address: UPIN:
Indicate the physician's name and complete mailingaddress. Accurately indicate the ordering physician's Unique Physician Identification Number(UPIN).
Physician's Telephone NO:
Indicate the telephone numberwherethe physician can be contacted (preferably where records would be accessible pertaining to this patient)if more information is needed.
Section B:
(May not be completed by the supplier. While this section may be completed by a non-physician clinician. or a physician employee, It must be reviewed, and the CMNsigned (In Section D) by the ordering physician.)
Est. Length of Need:
Indicate the estimated lengthof need (the length of time the physician expectsthe patientto requireuse of the ordereditem) by filling in the appropriate numberof months. If the physician expectsthat the patient will require the item for the duration of his/herlife, then enter 99.
Diagnosis Codes:
In the first space, list the ICD9code that represents the primaryreason for orderingthis item. List any additional ICD9codesthat wouldfurther describethe medical need for the item (up to 3 codes).
Question Section:
This section is usedto gather clinical information to determinemedicalnecessity. Answer each questionwhich appliesto the itemsordered, circling"Y" for yes, "N" for no, "0" for does not apply, a numberif this is offered as an answeroption, or fill in the blank if other information is requested.
Name of Person Answering Section 8 Questions:
If a clinical professional other than the ordering physician (e.g.,home health nurse, physical therapist, dietitian) or a physician employee answersthe questions of SectionB, he/she must print his/hername, give his/herprofessional title and the nameof his/heremployerwhere indicated. If the physician is answering the questions, this spacemay be left blank.
Section C:
(To be completed by the supplier)
Narrative Description of Equipment and Cost:
Suppliergives (1) a narrativedescription of the item(s) ordered, as well as all options, accessories, supplies and drugs; (2) the supplier'schargefor each item, option, accessory, supply and drug; and (3) the Medicare fee schedule allowance for each iternloption/accessory/supply/drug, if applicable.
Section 0:
(To be completed by the physician)
Physician Attestation:
The physician's signature certifies(1) the CMN whichhe/she is reviewing includesSectionsA, B, C and 0; (2) the answers in Section B are correct; and (3) the self-identifying information in Section A is correct.
Physician Signature and Date:
After completion and/orreviewby the physician of SectionsA, Band C, the physician must sign and date the CMN in Section0, verifying the Attestation appearing in this Section. The physician's signature also certifies the itemsorderedare medically necessary for this patient. Signature and date stampsare not acceptable.
FIGURE 25-2. Sample checklist to determine Medicare eligibility and to assist in home care referral. Courtesy of M. Winkler.
SECTION IV • Principles of Enteral Nutrition
or incorrect or questionable dates on the CMN, which can be easily clarified. Denial may also occur because of failure to meet coverage criteria. The first level of appeal is an informal review. The patient or supplier should provide additional supporting documentation to demonstrate how the patient meets eligibility for home enteral nutrition. A detailed letter from the patient's physician attesting to the medical necessity of the therapy should be submitted during an informal review, along with laboratory reports and clinical evidence of the need for enteral nutrition. The second level of appeal consists of a fair hearing. This is typically conducted by telephone but may occur in person. The person conducting the hearing may be a hearing officer, registered nurse, or lawyer. Participants in the hearing may include representatives from the reimbursement department of the home care company and a nurse or a dietitian who knows the patient. The hearing usually begins with the hearing officer asking the supplier to state the case. The patient's medical conditions and need for home enteral nutrition should be summarized. The information presented should relate directly to the eligibility criteria. The goal is to clarify how the patient meets Medicare coverage. The hearing officer will often ask questions and may request that additional documentation be submitted. [f a third appeal is necessary, this occurs in front of an administrative law judge (ALl). An AU reviews all the materials from the earlier reviews, written submissions, and oral testimony if a hearing has been conducted. Often the AU will request a review by an independent court-appointed physician who will testify at the same time as the beneficiary or supplier. It may be beneficial to have the attending physician provide testimony and to have legal counsel guide this process. A fourth level of appeal may be made to a department appeals board and a final appeal may be requested for judicial review. For this final appeal, a complaint must be filed in a federal or district court of appeals.
ROLE OF NUTRITION SUPPORT PRACTITIONERS AND HOME CARE PERSONNEL Having a thorough understanding of the reimbursement eligibility criteria and required documentation for government and private payers can facilitate the efficiency of a home care referral for enteral nutrition. Physicians, nutrition support practitioners, case managers, and discharge planners referring a patient should anticipate being asked questions related to the need and indications for home enteral nutrition, nutrition assessment data (e.g., height, weight, and relevant laboratory values), and documentation of formula tolerance. For purposes of reimbursement, the home care company or DME provider will request that the physician or referring institution provide copies of radiographic, operative, or other procedural notes supporting the indication for this therapy. The home care company or DME provider should make every effort to obtain the original source documentation of an anatomic obstruction, dysmotility
315
disorder, swallowing evaluation, and malabsorption studies during the referral process. Submission of a complete package with an accurate CMN and accompanying supporting documentation will typically result in an approved claim. An enteral formulary chart to allow clinically equivalent substitutions should be established and periodically reviewed by a registered dietitian and pharmacist. Inservice education about indications and reimbursement for home nutrition support therapy should be the responsibility of both the hospital-based nutrition support team and home health care provider.f Hospital-based nutrition support practitioners may also provide assistance to the ordering physician about the appropriate documentation for home enteral nutrition, medical necessity, ordering of swallowing tests, and/or malabsorption when indicated and guidance on completion of the CMN. REFERENCES 1. DeLeggeMH: Home enteral nutrition. JPEN J Parenter Enteral Nutr 2002;26(5suppl):S4-S7. 2. Giglione L: Building your base of business with enteral nutrition. Infusion 2002;8:12-16. 3. Sceery NL: Managing nutrition support in the home: Integrating hospital and home care services. Support Line 2002;24:9-16. 4. Howard L, Heaphey LL, Fleming CR:Four years of North American Registry Home Parenteral Nutrition outcome data and their implications for patient management. JPEN J Parenter Enteral Nutr 1991;15:384-393. 5. British Association of Parenteral and Enteral Nutrition: Report of the British Artificial Nutrition Survey (BANS), August 1999. Maidenhead, British Association of Parenteral and Enteral Nutrition, 1999. 6. The Economic and Budget Outlook: Fiscal Years 1999--2008, Section 12, Appendix F-Medicare Projections, January 1998. Available at http://www.cbo.gov, accessed March 13,2003. 7. Reddy P, Malone M: Cost and outcomes analysis of home parenteral and enteral nutrition. JPEN J Parenter Enteral Nutr 1998;22: 302-310. 8. Ireton-Jones C: Home enteral nutrition from the provider's perspective. JPEN J Parenter Enteral Nutr 2002;26(5 suppl):S8-S9. 9. Sanchez R: The payer's perspective. JPEN J Parenter Enteral Nutr 2002;26(5suppI):SIO. 10. DMERC Region A Supplier Manual: Chapter 2, Supplier Enrollment and Standards, rev 6, pp 2-19, December 2000. Wilkes-Barre, PA: HealthNow NY, Inc. 11. National Association for Home Care: 2002 Legislative Blueprint for Action. Available at http://www.nahc.org/nahc/legreg/02bp/ Ibp09.htmI#9-7,accessed December 24,2002. 12. Senate Committee on Appropriations, Subcommittee on Labor, HHS, and Education: Testimony of Janet Rehnquist, Inspector General, Hearing, June 12,2002. 13. National Academy of Sciences Institute of Medicine: The Role of Nutrition in Maintaining Health in the Nation's Elderly: Evaluating Coverage of Nutrition Services for the Medicare Population. Washington, DC, National Academy Press, 2000. 14. Goff K: Enteral and parenteral nutrition: Transitioning from hospital to home. Nurs CaseManag 1998;3:67-74. 15. Dickerson RN, Brown RO: Parenteral and enteral nutrition in the home and care settings. Am J Manag Care 1998;4:445-455. 16. Tyco Healthcare Group LP and Mead Johnson Nutritionals: Enteral Product Reimbursement Guide for Skilled Nursing Facilities and Homecare Providers, May 2002. Evansville, IN: Mead Johnson Nutritionals. 17. A.S.P.E.N. Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002;26(1 suppl):205A. 18. DMERC Region A Supplier Manual: Chapter 18.1,Enteral Nutrition, rev. 13, March 2000. Available at http://www.tricenturion.com/ content/dmerc/ch 18_enteral.cfm.
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25 • Home Enteral Nutrition Reimbursement
19. Health Now NY, Inc. DMERC A. Spring 2002 Workshop: Enteral Nutrition, Concord, NH, June ~, 2002. 20. Silberman S: New Hampshire Legislation Requires Coverage of Outpatient Enteral Nutrition. Crohn's & Colitis Foundation of America. New York, NY. 21. Carriers Manual: Part 3, Chapter XV, Fee Schedule for Physicians' Service. 15513. Care Plan Oversight (CPO) Services (CPT Codes G0064·G0066). Available at http://www.cms.hhs.gov/manuals/ 14_car/3bI5052.asptt_l_61a, accessedMarch 26, 2003. 22. Boling PA: Improving economics of home care practice: An update on business aspects of home care work by medical providers. Home Health Care Consultant 2001;8(2):36-43. 23. DMERC Region A Service Office: United Healthcare. Helpful hints for filing reviews. DMERC Medicare News 2000;50(March):14. 24. DMERC Region A Service Office: United Healthcare. Requesting a fair hearing of AU hearing. DMERC Medicare News 1999;45(Sept): 16-20. 25. Winkler MF, Watkins CK, Albina JE: Transitioning the nutrition support patient from hospital to home. Infusion 1998;39-44.
BIBLIOGRAPHY Delegge MH: Changes in Medicare reimbursement policy may restrict nutrition therapy options [editorial]. Nutrition 1997;13:926-927.
Evans-Stoner N: Guidelines for the care of the patient on home nutrition support. An appendix. Nurs Clin North Am 1997;32: 769-775. Howard L, Ament M, Fleming R, et al: Current use and clinical outcome of home parenteral and enteral therapies in the United States. Gastroenterology 1995;109:355-365. Ireton-Jones C, Orr M, Hennessey K: Clinical pathways in home nutrition support. J Am Diet Assoc 1997;97:1003-1007. Park RH, Galloway A, Russell RI, et al: Home sweet HEN-A guide to home enteral nutrition. Br J Clin Pract 1992;46:105-110. Puntis JWL: Nutritional support at home and in the community. Arch Dis Child 2001;84:295-298. Roberge C, Tran M, Massoud C, et al: Quality of life and home enteral tube feeding: A French prospective study in patients with head and neck or oesophageal cancer. Br J Cancer 2000;82: 263-269. Schneider SM, Pouget I, Staccini P, et al: Quality of life in long-term home enteral nutrition patients. Clin Nutr 2000;19: 23-28. Thomas-Payne L: Medicare coverage of enteral nutritional therapy. Reimbursement Review, Mead Johnson Nutritionals, Fall 1999. Thomas-Payne L: Medicare coverage of enteral nutritional therapy. Reimbursement Review, Evansville, IN: Mead Johnson Nutritionals, Winter 1999.
Enteral Nutrition Support in the Critically III Pediatric Patient Kathy Prelack, PhD, RD
CHAPTER OUTLINE Introduction Inflammatory Response to Acute Illness in Children Effect of Acute Illness on Body Composition in Children Enteral Feeding Plan in the Critically III Child Nutritional Screening and Assessment during Acute Illness
Determining Macronutrient Requirements Energy Requirements Protein Requirements Micronutrient Requirements Minerals
Enteral Feeding Types in Critically III Children Infants Children 1 to 3 Years of Age Children 4 to 9 Years of Age Children 10 Years of Age and Older
Mode and Timing of Administration Route of Administration Early Enteral Nutrition
Monitoring Response to Enteral Feedings Transition to Oral Diet Conclusion
INTRODUCTION Critically ill children represent a diverse populace with unique nutritional requirements. Common to most critically ill pediatric patients is the onset of an acute-phase response. The pattern of hormonal, metabolic, and immunologic reactions in this inflammatory state, whether triggered by infection, trauma, or acute illness, is universal. However, its magnitude and duration can
vary according to the severity of injury. In addition, agespecific differences in body composition, organ development, and maturity of immune system can modulate the stress response that is elicited in children. A significant number of critically ill children have underlying chronic conditions, each with distinguishing metabolic aberrations and associated nutritional risk factors. The challenge for the clinician is to integrate this information into the development of an effective enteral feeding plan appropriate for the individual child. Recovery from critical illness is often depicted in phases marked by both clinical and physiologic end points. The most clinically effective forms of nutritional therapy are in accord with the metabolic conditions and outcome goals of each recovery phase. During the acute phase of illness, treatment plans should provide metabolic support to accommodate increased energy expenditure and protein turnover; minimize loss of body cell mass; and enhance processes for recovery such as wound healing, immune function, and survival. Rapid depletion of energy and protein reserves underscores the importance of prompt initiation of enteral nutrition in patients during this phase of illness. Unfortunately, altered nutrient utilization, gastrointestinal impairment, dietary intolerance, and certain clinical procedures pose barriers to enteral nutritional support. Clinicians approach these challenges with alternative enteral feeding modalities, specialized diets, and accurate assessment of nutrient requirements to provide cost-effective and safe nutritional care during critical illness. In children who require prolonged intensive care, protracted bed rest, exaggerated by a persistent catabolic response, leads to severe muscle atrophy and debilitation. Enteral nutritional care during this next phase of rehabilitation from acute illness must be restorative and sufficient to sustain the high-energy demands that accompany aggressive physical therapy, yet it must also be consistent with the overall objective of promoting independence, which includes a return to normal oral nutrition ifpossible. Many patients will continue to require nutritional therapy beyond hospitalization. Those who 317
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26 • Enteral Nutrition Support in the Critically III Pediatric Patient
require repeated hospitalizations throughout their childhood are at riskfor chronic malnutrition. For them, growth faltering is often a consequence of unrelenting environmental stresses. Anabolic therapy is sometimes used as an adjunct to aggressive nutritional therapy to support catch-up growth and improve nutritional status during convalescence.
INFLAMMATORY RESPONSE TO ACUTE ILLNESS IN CHILDREN The stress response to acute trauma or illness includes a universal pattern of changes generated by the immune and neuroendocrine systems.I A cascade of events, mediated by cytokines and the activation of the hypothalamicpituitary-adrenal axis, disturbs normal physiology and triggers a catabolic state characterized by alterations in glucose, amino acid, and fatty acid metabolism." The hormonal response to stress is similar among children and adults. In both, the sick euthyroid syndrome is produced, which is characterized by a reduction in triiodothyronine, low or normal levels of thyroxine, and an elevated level of reverse triiodothyronine.P Increased adrenergic activity is typical of the acute stress response and appears to be necessary forsurvival.l-'Consequently, increased cortisol levels enhance lipolysis to stimulate circulating levels of nonesterified free fattyacids, a potentially useful fuel source during stress."" Fat oxidation, however, is impaired, and there is substantial recycling of free fatty acids into triglycerides.v? Growth hormone secretion is increased in adults and may be increased, decreased, or normal during the acute-phase response in children. 2,5,7,B Typically a disruption is seen in the growth hormone/insulin-like growth factor axis, where secretion of growth hormone is not accompanied by increments in insulin-like growth Iactor-I and insulin-like growth factor binding protein-S levels.P This growth hormoneresistant state is believed to be at least partly responsible for the protein catabolism observed during post-traumatic illness. It may also contribute to alterations in glucose metabolism in both children and adults. Increased peripheral insulin resistance, increased glucose production, and diminished glucose uptake contribute to stress hyperglycemia in children and adults/" This futile recycling of energy precursors paired with increased whole body protein turnover contributes to increased rates of energy expenditure and nitrogen loss from the body.v'?
EFFECT OF ACUTE ILLNESS ON BODY COMPOSITION IN CHILDREN The acute-phase response, if of long duration, causes changes in nutritional status and body composition (Fig. 26-1). Under such circumstances, weight loss is common, despite aggressive nutritional therapy.I I Adipose tissue losses account for approximately one half of the weight loss experienced during severe catabolic injury in adults.'! The other one half occurs within the body cell mass (BCM) component in the lean body mass,
FIGURE 26-1. Effect of acute illness on body composition. BCM, body cell mass; ECS, extracellular space; ECM, extracellular mass; ECW, extracellular water; ICW. intracellular water; LBM, lean body mass.
where net protein breakdown results in erosion of muscle." Losses in intracellular water, the major component of BCM, accompany losses in total body protein and total body potassium.r'-" Changes within the extracellular mass also occur owing to increases in extracellular water. 15,16 This gain in extracellular water often masks the losses in intracellular water that occur as the BCM deteriorates.P:" Because the expansion in extracellular mass accompanies the diminution of the BCM, changes in lean body mass are often unremarkable. I In general, children have a greater risk than adults for wasting during times of critical illness because they have smaller energy reserves to mobilize relative to their metabolic rate. During growth, changes in organ size, body composition, and substrate utilization occur, so that the effect of a catabolic state on both fat and fat-free tissue is age-dependent. Neonates and young infants have relatively larger brains, viscera, and skin, explaining their increased metabolic rate for size. Because their body surface area per unit of body weight is greater than that during adulthood, they also have proportionately larger insensible water and electrolyte losses." Throughout infancy, fat is the predominate contributor to weight gain, reaching 30% of total body weight by 3 months of age. This is beneficial under conditions of semistarvation. However, their enhanced reliance on glucose oxidation to meet basal energy requirements combined with a diminished skeletal muscle mass (representing 27% of total body weight, compared with 40% in the reference adult male) places infants at greatest risk for rapid depletion of the labile protein pool. The resultant muscle wasting is sometimes undetected owing to masking by the increased presence of adipose tissue. IB,19 After the age of 2, glucose contributes less to basal energy metabolism. The accelerated rate of fat deposition wanes, whereas fat-free mass increases as a percentage of body weight. By 7 or 8 years of age, fat and fat-free mass occupy approximately 13% to 20% and 80% to 87% of body weight, respectively." During this time, changes in the chemical composition of the fat-free mass also
SECTION IV. Principles of Enteral Nutrition
occur. The amount of total body water decreases, primarily due to decreases in the extracellular water fraction. Correspondingly, the amount of intracellular water (the primary component of body cell mass) increases, along with protein and bone mineral content." In essence, the fat-free mass becomes more dense and of better quality. The clinical implication of these changes is that the rate at which lean body mass becomes depleted during conditions of increased metabolic demand decreases with age in prepubertal children. However, owing to diminishing fat mass over time, these patients become less capable of accommodating shortfalls in caloric intake as they get older. With little fat reserves to draw upon, deficits in energy balance will be met at the expense of the lean body mass." During the adolescent years, gains in both fat and fat-free mass are made. Sexual dimorphism becomes much more pronounced, particularly for fat-free mass. The intensity (rate of gain) and duration of the adolescent spurt in fat-free mass are much greater in males than Iernales.P Conversely, incremental fat gain is greater in females than in males, so that by age 16, fat claims a larger portion of female body weight." Contemporary data used to construct body composition models for adolescents by age and gender indicate that both males and females have increased weight and fat mass compared with those of earlier reference models." During adolescence, body size and phenotype begin to mimic those achieved with adulthood. Older adolescents have greater energy reserves and lean body mass in relation to metabolic rate and appear to be less at risk for wasting during chronic illness than their younger counterparts. However, age-related changes in body composition continue despite physical maturity, as defined by achievement of Tanner stage 5 of puberty, final height, and epiphyseal fusion in older adolescents. In both sexes, increases in lean body mass continue, albeit more markedly in males. This occurs despite the appearance of maturity indices. Lean body mass accretion does not plateau until age 20in males and age 17 to 18 in females. Taken together these data indicate that adolescents, despite their physical appearance and even similar body size, are still at greater risk than adults until peak levels of lean body mass components are attalned"
ENTERAL FEEDING PLAN IN THE CRITICALLY ILL CHILD
Nutritional Screening and Assessment during Acute Illness All children who are critically ill should receive a nutritional screening using well-defined criteria upon admission. For the majority, a formal assessment of their current nutritional status using anthropometric and biochemical data, medical and diet history, and physical examination should precede initiation of any feeding regimen. Evaluation of growth and developmental history are an integral part of this initial assessment. Children
319
with the greatest nutritional risk are those who were previously malnourished or those who have a history of inadequate dietary intake." These patients require judicious monitoring of fluid and electrolyte levels, and guidelines should be established for gradual, incremental provision of nutritional therapy to avoid refeeding syndrorne.P
Nutritional assessment is an ongoing process because of the changing circumstances in clinical status and management of the critically ill patient. The most commonly used tools for nutritional monitoring are measures of weight, energy and protein balance studies, and biochemical indicators such as albumin, prealbumin and C-reactive protein levels. These markers of nutritional status help the clinician in monitoring day-to-day efficacy of diet therapy. However, because they rely on many assumptions that do not hold true during metabolic stress, they do not provide a completely accurate assessment of nutritional status. 24•25 Measures of total body weight or weight change, which are usually good measures of the adequacy of nutritional intake are altered by derangements in fluid homeostasis during critical illness. An expansion of extracellular fluid volume occurs early in the course of critical illness and slowly diminishes throughout the course of recovery, limiting the value of weight monitoring to assess the status of lean tissue." Because of its shorter half-life, prealbumin is favored over albumin as an indicator of nutritional adequacy. Because its synthesis, like that of albumin.F is downregulated during the acute-phase response, simultaneous measurement of C-reactive protein, an acute-phase reactant and marker of physiologic stress, is recommended. Taken together, concentrations of C-reactive protein and prealbumin are useful both as prognostic indicators and in assessing dietary adequacy.28.29 Nitrogen balance studies can be used to estimate changes in lean tissues; however, they are often flawed as a result of many obstacles in accurate data collection and in their reliance on assumptions that are not valid during physiologic stress. The level of urinary urea nitrogen may be a poor predictor of protein turnover rate; however, serial measures can help identify trends in protein metabolism, thereby allowing nutritional therapy that is responsive to episodes of accelerated nitrogen loss or conversely to signs of diminished catabolism.P A comparison of actual caloric intake to the estimated requirement is probably the most convenient and commonly used indicator of nutritional adequacy.
DETERMINING MACRONUTRIENT REQUIREMENTS
Energy Requirements Accurate provision of calories and protein is crucial in an intensive care environment. Overfeeding of calories results in hyperglycemia, net lipid synthesis, and hepatic fat deposition." At the same time, due to their limited
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26 • Enteral Nutrition Support in the Critically III Pediatric Patient
energy reserves, critically ill children are quickly at risk for acute protein-energy malnutrition and its associated consequences if not properly fed. In children receiving mechanical ventilation, poor nutritional status impairs ventilatory drive, pulmonary defense mechanisms, and respiratory muscle function." Because nutritionally related hypercapnia and excessive fluid administration may inhibit successful weaning, precision in the delivery of calorie requirements is particularly important in this subgroup of patients. 32•33 A common practice for estimating energy requirement is to use predictive equations that begin with a determination of metabolic rate and then add a stress factor to account for the effects of disease or trauma on metabolic rate. The intermittent effects of clinical interventions, physical manipulation, sleep deprivation, pain, and stress are also evaluated for their potential contribution to total energy expenditure. This factorial approach for determining energy requirements may be too imprecise in children and can lead to overfeeding. Indirect calorimetry studies now indicate that measured energy expenditures in critically ill children are significantly [ower than those determined by predictive equations specifically developed for hospitalized children. The average measured energy expenditure in mechanically ventilated, critically ill pediatric patients is 1.5 times the predicted basal metabolic rate." Total energy expenditure measured by doubly labeled water in severely burned children averaged 1.33times the predicated basal energy expenditure.P This result is consistent with caloric provisions associated with wound healing and minimal weight loss in the same population.'! Such findings are probably a result of many improvements in the clinical care of critically ill children, which include better pain management, infection control, provision of a properly heated environment, and appropriate sedation. These clinical interventions may be the reason why metabolic rates in critically ill children are often [ower even than their predicted basal metabolic rates for any given age and size.36•37 Measures of resting energy expenditure in children with sepsis or systemic inflammatory response syndrome are lower than the recommended daily allowance and are not different from those for control children matched for age and weight." This finding refutes the conventional belief that energy requirements in critically ill children are augmented by the need to sustain growth. It is more likely that energy processes necessary for growth are diverted to recovery. Therefore, the goal of feeding during acute illness in children should be to provide energy substrates necessary for recovery and minimization of weight loss rather than to promote growth. In this context, routine measures of energy expenditure are ideal in a dynamic intensive care setting in which energy requirements are not static. Because performance of repeated measures of energy expenditure by indirect calorimetry is impractical in most hospital inpatient environments, estimation of energy requirements with periodic reassessment and adjustment of metabolic stress factors in accordance with clinical status is a reasonable alternative, keeping in mind the fact that many aspects of clinical care (i.e., better
pain control, minimization of heat loss, and sedation) are likely to lower energy requirements (fable 26-1). The relative contributions of fat and carbohydrate to meet energy requirements during critical illness are commonly debated. Occasionally a higher fat intake is advocated in patients receiving mechanical ventilation to minimize endogenous carbon dioxide production. However, most studies indicate that glucose exerts a greater protein-sparing effect than fat, which is often inefficiently utilized and recycled." Glucose is considered a preferred fuel source for tissues involved in wound healing and repair. In enterally fed children with bums, muscle protein degradation was markedly decreased during high-carbohydrate feedings compared with high-fat feedings. This result was attributed to decreased rates of protein breakdown, which may be the result of increased endogenous insulin concentrations. Such evidence combined with a greater reliance on glucose in especially young children supports the use of feedings with a higher carbohydrate content.
Protein Requirements An important part of the physiologic response to injury is amino acid efflux from skeletal muscle.P These amino acids are used in tissue repair, acute-phase protein production, cellular immunity, and gluconeogenesis. Inadequate intake results in depletion of tissue levels, which in tum alters biologic and physiologic function. Eventually, deterioration of cell function manifests clinically as impaired wound healing, infection, and diminution of muscle function." In extreme cases, when protein malnutrition progresses to the point where body cell mass losses exceed 40%, death occurs." At the very least, the degree of muscle protein breakdown after injury has significant implications for outcome with respect to nutritional status and rehabilitation. Defining protein requirements in quantitative terms for children in a given state of critical illness incorporates results obtained from metabolic balance studies and measures of whole body protein turnover." Normal protein requirements vary by age, decreasing from 3 to 4 g/kg/day in low-birth-weight infants to 0.8 g/kg/day in adolescents. These estimates are based on a factorial approach that assigns a protein requirement for tissue maintenance, growth, and factors that accommodate variation in growth and efficiency of utilization. In critically ill children a common practice is to provide 1.5 g of protein/kg/day." This amount may be sufficient for tissue maintenance in children with mild to moderate levels of stress, particularly if one assumes that growth processes abate during the acute-phase response. However, in contrast to the diminishing effects of clinical intervention on energy metabolism, many aspects of critical care intensify nitrogen losses (fable 26-2). Furthermore, major trauma elicits extreme rates of protein breakdown that often exceed rates of protein synthesis. For example, in pediatric trauma patients, whole body protein synthesis rates peaked at 4 g of protein/kg." In children with severe bum injuries, rates of protein
SECTION IV • Principles of Enteral Nutrition
321
_ _ Factors That Influence Energy Expenditure in Critically III Children
Clinical Variable
Effects on Measured Resting Energy Expenditure (REE) or Total Energy Expenditure (fEE)
Comments
Disease-Specific Condition Burn injury
Increased TEE by 30W.
Head injury Multiple trauma Malnutrition
Increased REE by 50~. Increased REE by 0%-15% Decreased REEby 5'Yo-15%
Age
No effect
Systemic inflammatory response syndrome
No effect
Fever
Increased REEby 12% in basal metabolic rate occurs for each degree increase in body temperature No effect
Sepsis
REEincreases in proportion to burn size; a plateau of 50% increase above normal metabolic rate reached at burn size of ~50% body surface area Little increase in REEwith increase in severity of illness In children wIth mild chronic protein energy malnutrition, REEIs decreased by 5%-15%; in chronic protein energy malnutrition with acute insult, REE correlates with severity of illness No difference in measured REEin critically ill children compared with age-matched healthy control subjects No increase in REEin patients with sepsis or systemic inflammatory response syndrome in comparison to healthy control subjects Describes change in metabolic rate in sleeping infants with fever No difference in critically ill children with or without sepsis; REEmay be lower during multiple system organ failure
Medication Effects Sedation/neuromuscular blockade
Decreased REEby IO'K.
Anabolic therapy
No effect
Vasoactive agents Corticosteroids
Increased REE Increased REE
Marginal lowering effect of lO:Y., or 15 cat/kg/day of neuromuscular blockade among patients who are already sedated Because of their effect on protein metabolism, anabolic agents may actually reduce caloric requirement associated with increased protein intake
Clinical Intervention Mechanical ventilation
Increased REE
Physical therapy
Increased TEE
Timing of commencement of nutritional support Surgical procedures
No effect No effect
Mode of ventilation, level of sedation can modulate effects on energy expenditure Increased physical exertion, pain, and anxiety associated with rehabilitation can substantially increase total daily expenditure, particularly if long in duration, and repeated throughout the day No reduction in REE among early versus delayed enteral nutritional support REEconsistent with predicted basal metabolic rate following cardiac surgery in children
Environmental Factors Pain Temperature control
Increased metabolic rate for duration of pain-related activity Increased REE to maintain body core temperature
breakdown approached 6 g of protein/kg/day. Although the contribution of skeletal muscle is similar to normal at 19%, this elevated rate of muscle catabolism means that young children have a particularly severe risk of lean body mass wasting." Common intakes for children with burn injuries are reported to be 3 to 4 g of protein/kg/day or 23% of total calorie intake. 42,43 Large gaps remain in our knowledge about the qualitative aspects of enteral protein requirements, in part because of the role of the splanchnic region in
May not be reflected in measures of REE unless experienced during measurement Heated environment and/or occlusive wound dressing substantially minimize REE associated with evaporative water losses
altering the metabolic fate of certain amino acids. After absorption, many amino acids enter pathways of protein synthesis or energy metabolism within the intestinal tract, thus limiting their availability to the peripheral tissue." Clearly, amino acids are considered conditionally indispensable in various pathophysiologic states (Table 26-3). Glutamine, comprising approximately 6% of mixed whole body protein, is unique among amino acids in that it is a favored fuel of rapidly dividing cells, such as enterocytes and immune cells. An important
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26 • Enteral Nutrition Support in the Critically III Pediatric Patient
BED Factors That Influence Protein Requirements During Critical Illness Altered Requirements
Mechanism
Populations At Rlsk
Disease-Specinc Conditions Open wounds Increased nitrogen losses in wound exudate Acute renal failure
Medication Effects Neuromuscular blockade Propranolol Insulin Anabolic therapy Corticosteroids
Procedure-Related Bed rest Surgical procedures
lncreased filtration of amino acids and peptides across hemofilters
Burn patients, major trauma, estimated needs 3-4 g/kg/day Standard therapy of 1.5 g/kg/day may be Insufficient in children receiving continuous venovenous hemofiltration with or without dialysis
Increased skeletal muscle breakdown Diminished protein catabolIc rate Increased protein synthesis and decreased protein breakdown Decreased protein breakdown and increased protein synthesis with growth hormone and oxandrolone Increased protein catabolIc rate
Critically ill, mechanically ventilated patients Burn patients, major trauma Critically ill patients
Increased protein breakdown from muscle atrophy Increased urinary nitrogen excretion
Prolonged bed rest, paralysis
gluconeogenic precursor, glutamine, is released by skeletal muscle during stress states. Glutamine also may enhance intracellular repletion of glutathione, an important scavenger of reactive oxygen species.45.46 It follows that intracellular glutamine levels are rapidly depleted during times of stress." However, there is a disparity in the literature about the benefit of glutamine supplementation in lowering infection and improving overall outcome.48,49 In one of the few studies conducted among children, short-term enteral glutamine supplementation did not improve protein turnover after burn injury." Itwas effective in improving tolerance to enteral feeding and lowering rates of sepsis in low-birth-weight
Burn patients Transplant patients
Burn patients, patients requiring multiple surgical procedures
infants." The specific role of glutamine use in critically ill children remains to be defined.
Micronutrient Requirements Enteral support of critically ill children includes daily provision of vitamins, macrominerals, and trace elements. Micronutrients are essential as intermediaries in metabolism and for their potential roles in wound healing, cellular immunity and antioxidant activity. Although their importance is widely recognized, guidelines for their provision during critical illness are empirical.
_ _ Indispensable Amino Acids In Critically III Children Amino Acid
Altered Physiology
Practical Considerations In Children
Glutamine
Increased utilIzation for gluconeogenesis Increased utilization by rapidly replicating cells such as enterocytes, lymphocytes, macrophages
Arginine
Increased utilization in burned and pediatric patients with sepsis Important In wound healIng, immunity and nitrogen metabolism Critical role in production of nitric oxide pathway that may help relieve pulmonary hypertension In acutely ill children Increased cysteine flux In critically ill parenterally fed children with sepsis
Indicated for children with bowel disease May be beneficial during critical illness, immune deficiency Recommended dose: 0.3-0.6 g/kg/day in children (in addition to desired total protein intake to avoid substitution of glutamine for essential amino acids) Distribute In 3 bolus doses/day (mix with 20-60 mL of water, then flush with water, to avoid interaction of glutamine with feedings and adherence to tubing) Pharmacologic effects at high doses through increased nitrous oxide production may result in cardiac dysfunction Requirement In critically ill children unknown
Cysteine
Low cysteine Intake In parenteral feedings lImits glutathione synthesis, a direct scavenger of free radicals
SECTION IV • Principles of Enteral Nutrition
323
_ _ Altered Minerai Physiology during Critical Illness Changes In Requirement during Critical Illness
Associated RIsk Factors
Phosphorus
Increased intracellular uptake mediated by insulin with administration of glucose in diet
Mechanical ventilation Initiation of feeding Anabolism
Calcium
Altered protein-binding properties Altered absorption/availability Bone demineralization
Acid-base imbalance Hypoalbuminemia High phosphorus intake Prolonged bed rest Vitamin D deficiency
Magnesium
Increased intracellular uptake Increased renal excretion
Initiation of feeding Anabolism Aminoglycoside antibiotics, amphotericin B
Zinc
Increased urinary excretion Increased wound losses Increased uptake with wound healing Increased needs during inlection
Postsurgical patients Burn injury, fistulas Burn injury
Copper
Increased urinary excretion Increased wound losses Increased need for wound healing Decreased plasma levels
Patients receiving zinc supplementation
Micronutrient
Practical Considerations for Monitoring and Supplementation During Acute Phase Response
Macrominerals Monitoring and supplementation requirement greatest during early acute phase and with initiation of feedings Total calcium not indicative of ionized levels-monitoring of ionized levels recommended Check for and correct if necessary hypomagnesemia or hypophosphatemia before supplementation Refractory hypomagnesemia occurs during hypokalemia
Trace Elements
Selenium
Iron
Increased need during erythropoiesis
Burn patients
Increased sequestration in wound and liver during acute-phase response Serum levels poor indicator of status 1-2 mg/day in addition to standard enteral feeding sufficient to cover urinary losses 20 rug/day above standard enteral diet suggested to cover wound losses in burned children Toxicity seen with levels >2 x RDA Copper antagonist Plasma levels increased owing to increased ceruloplasmin during burn injury in children Enteral requirement during critical illness unknown, supplementation should focus on normalizing urinary excretion (low when deficient) and maximizing glutathione peroxidase activity Liver sequestration via ferritin Supplementation advised only after ferritin level normalizes 3 mg/kg/day recommended
Burn patients
RDA, Recommended Daily Allowance.
• .
Tables 26-4 and 26-5 highlight nutrients for which requirements may be increased during critical illness.
•
• Micronutrient
Dally Enteral Supplementation
Zinc" Copper" Selenium Iron! Vitamin C Vitamin At Vitamin Et B complex!
1-2 mg; 20 mg in patients with severe burns 2.5mg 50-170 J.lg Not supplemented 200 mg Not supplemented Not supplemented Not supplemented
Minerals Trace Elements Altered distribution of minerals during the acute-phase response makes it difficult to define specific micronutrient requirements. Regulation of transport proteins is a natural component of the injury response and is a means of redistributing minerals such as zinc, iron, copper, and selenium within the body. This is believed to provide some advantage to the host. For zinc and iron, hepatic sequestration and peripheral uptake of these elements
Example of a Single Nutrient SUpplementation Protocol In Critically III Children
"Addition of a multivitamin supplement with trace elements may be sufficient for meeting requirements. tSupplemented as part of a enteral multivitamin regimen 2 times daily or via adult enteral formula.
324
26 • Enteral Nutrition Support in the Critically III Pediatric Patient
by other organs or wounded tissue may ensure its availability for essential processes such as wound healing and synthesis of acute-phase proteins. 51,52 A reduction in free circulating zinc and iron mediated by endogenous humoral factors may be a means of protecting against infection. In these instances, low concentrations are not indicative of a deficiency and may reflect an adaptation, which is beneficial to the host.-' However, high mineral losses, decreased bioavailability, diminished gastrointestinal absorption, and increased urinary losses are typical during acute illnesses, supporting the need for increased requirements.P-"
Macrominerals--calcium, Phosphorus, and Magnesium Aside from their structural role in bone, the macrorninerals play regulatory functions within the body. As electrolytes, they are involved in numerous physiologic and biochemical processes including neuromuscular excitation, enzymatic activation, blood coagulation, and membrane permeability. Many aspects of critical care, of which drug-nutrient interactions predominate, are associated with their deficiencies. These include the use of ulcer prophylactic agents, sodium lactate, diuretics, and antibiotics. Imbalances also occur with large gastrointestinallosses, acid-base imbalances, malnutrition, fever, or accelerated metabolism. Because of their part in maintaining cellular homeostasis, the need for monitoring and supplementing these micronutrients is explicit. Their proper management can have a substantial and measurable impact on nutritional adequacy, hospital costs, and patient outcome/"
Vitamins Critically ill patients are also prone to vitamin depletion. Vitamins serve as coenzymes in energy and protein metabolism and are involved in a variety of cellular functions including cellular differentiation and proliferation, skeletal formation, immune function, antioxidant activity, and blood coagulation." For vitamins involved in energy processes, such as the B complex vitamins, amounts provided in standard enteral products are probably sufficient because their intakes are increased in proportion to available energy substrate in the formula. Additional supplementation may be needed for other vitamins. A commonly supplemented vitamin for which needs are thought to increase during critical illness is vitamin A. Its role in vision, cellular differentiation, and cell immunity is well known. Low circulating vitamin A levels are associated with increased risk of epithelial damage with direct consequences for gut mucosal Integrity." Itsenrichment in the diet of enterally fed burned children is associated with a decrease in diarrheal complications. For them, a dose of 5000 IV of vitamin A is recommended." At this time the full benefits or risks associated with these intakes in critically ill children are yet to be firmly established. Given that retinol transport is compromised during stress and that vitamin A stores exist, supplementation of this nutrient in high doses as a general rule is not
advised. Vitamins E and C have antioxidant capability and appear to be rapidly utilized." Their increased utilization leads to low plasma levels despite adequate enteral nutritional support. This suggests the need for dietary fortification to maintain adequate levels. Because vitamin C assists in the regeneration of vitamin E, and its properties deem it to be relatively safe, supplementation of vitamin C is common. Pharmacologic supplementation of vitamins as a means of antioxidant therapy is attractive. However, appropriate dosing, administration schedules, and identifiable risks and toxicities must first be clarified. Full inhibition of oxidative reactions after stress may be harmful in patients. Until more research-based evidence is available, supplementation to standard nutritional therapy to prevent deficiency is advised. Because of their interdependent nature, maintenance of all micronutrients within an antioxidant defense system should lower requirements for anyone specific nutrient. In this context, vitamin supplementation as part of a multisupplement appears prudent at this time.
ENTERAL FEEDING TYPES IN CRITICALLY ILL CHILDREN Once nutritional requirements are defined, the composition and type of feeding product that best meets a child's individual needs are determined. Here condition-specific and age-related aspects of nutritional management are integrated into a single feeding plan. Most manufactured enteral tube feeding products are nutritionally complete, and their calorie-to-nitrogen ratio, amino acid composition, fiber content, and micronutrient availability are inflexible. However, a vast array of formula types and modular products exist, making it possible to support the nutritional needs of critically ill children who might benefit from enteral feedings.
Infants Immaturity of renal and gastrointestinal organ systems is largely the basis for feeding infant formula in critically ill children under the age of 1. A diet history should be obtained to determine the chronology of food introduction and whether any food allergies exist. Because most children are unable to consume adequate formula to meet the increased needs of stress, formula is provided by a feeding tube. Formula can be modified by concentrating the solution from 20 to 30 calor more per ounce or by adding modular energy substrate in the form of fat or glucose polymers. The method of concentrating caloric intake depends on the desired calorie-to-nitrogen ratio, the relative contribution of fat and carbohydrate to energy content desired, fluid needs or limits, and renal solute load (Table 26-6). For many patients, particularly those with severe trauma or burn injuries, the estimated nonprotein calorie-to-nitrogen ratio of standard infant formula (240:1) is too high, making it difficult for protein requirements to be met without excessive intakes of
SECTION IV • Principles of Enteral Nutrition
BEll
325
Methods for Nutrient Enhancement of Infant Formula According to Clinical Status of Patient
Clinical Objective
Modulation
Decrease fluid intake Compensate for weight loss Decrease calorie/nitrogen ratio Transition to intermittent feedings Decrease protein intake
Concentrate feedings to 24 or 30 cal/oz may also add modular fat or carbohydrate Add modular glucose or fat to feedings/assess protein adequacy Add modular protein to feedings Concentrate feedings to run over fewer hours Lower rate of base formula Add modular fat or carbohydrate Additional electrolytes, micronutrient supplementation may be required Reassess caloric need to prevent against overfeeding; if fat added to increase caloric intake, do not exceed 55% of calories as fat
Decrease carbon dioxide production
formula. These patients can have a modular protein supplement added to their feedings to optimize the proportional contribution of energy and protein substrates. Similarly, fat in the form of oil or glucose polymers can be added, as indicated by clinical need, to increase caloric density. Standard infant formula contains a higher fat content than other enteral tube feeding products. Using glucose to increase caloric value is consistent with data suggesting a greater reliance on glucose during stress.6,57 This is useful if fluid is restricted, and the child cannot tolerate high-volume feedings or if it is undesirable to increase electrolyte concentrations and/ or micronutrient intake with a concentrated formula. Conversely, concentrating feedings is a convenient way to increase calories and nitrogen and support accompanying micronutrient needs as part of maintenance intake.
Children 1 to 3 Years of Age Pediatric infant formulas are available and can be useful in younger children who are critically ill. Like infant formula, pediatric feedings are designed to accommodate nutritional requirements for growth. The casein-to-whey ratio of 82:18 in pediatric formula is comparable to that in infant formula. Pediatric formulas commonly have enhanced amounts of nutrients that are conditionally essential in children such as taurine and tyrosine. Electrolyte content closely approximates recommendations from the National Academy of Sciences-National Research Council for maintaining good acid-base balance." In addition, vitamins and minerals are provided in amounts and proportions that are important for growth, with additional provisions to accommodate increased needs during metabolic stress or lack of bioavailability associated with commonly used medications. This supplementation seems to be adequate for meeting increased requirements for vitamins A and E and magnesium but may still be inadequate in its provision of vitamin C, selenium, and zinc. Pediatric formulas resemble adult formulas in their caloric density, which is about 1 callmL. Protein represents approximately 12% of total calories. This translates into a nonprotein calorie-to-nitrogen ratio of 185: 1. Although this ratio is higher than that in infant formula, it may still not be adequate for among patients with high nitrogen demands. A modular protein
supplement is therefore often used. The fat content of infant formula, nearly 50% of total calories, is another reason why its use may be viewed less favorably in critically ill patients. In addition to the small role it plays in protein sparing, fat has immunomodulatory effects that may be undesirable in certain patlents.f Many children in this age category who have increased metabolic needs can be given adult formula. The advantages in those who can tolerate this feeding are many and will be described in the next section.
Children 4 to 9 Years of Age Although the amino acid and micronutrient compositions of many adult formula do not parallel requirements for growth, they are well suited for meeting the metabolic demands of a hypermetabolic state in most children. First, the nonprotein calorie-to-nitrogen ratio in standard adult formulas is approximately 150:1, which begins to approach the levels that are indicated during conditions of stress. Secondly, their increased concentrations of sodium, potassium, and macrominerals help correct electrolyte imbalances associated with critical illness and therapeutic intervention. The need for additional micronutrient supplementation can be avoided in many younger children because of the increased provision of vitamins and minerals in such formulas designed to meet adult requirements. Feedings may sometimes be provided without the need for adjusting macronutrient composition through modular supplementation as well (Table 26-7). Although standard enteral adult formula is well tolerated in children, the fiber content of some feedings may be excessive for some children. This may contribute to constipation, which is a common problem in patients in intensive care units who are receiving opiate narcotics. For patients who can benefit from fiber, a mixture of fiber-free and fiber-enriched formula can be used to provide optimal amounts.
Children 10 Years of Age and Older Enteral nutritional support for children in this age category is unique because specialty formulas that are condition-specific are appropriate for use. As children become older, their metabolic rate per unit of body
326
26 • Enteral Nutrition Support in the Critically III Pediatric Patient
.-
Formulas Available for Use In Critically III Children Older than 1 V..r of Age
Fonnula
Calories (kcal/L)
Ages 1-3 Years Pediasure
Protein (gIL)
Nonprotein Calorie/N Rallo
Ca/p/Mg
Na/K (milL)
(milL)
Nutrillonal Adequacy
30
185:1
38/130
97/80/200
May be Insufficient In protein, electrolytes, vitamin C, selenium, zinc Increases maintenance electrolyte intake including Ca/P/Mg Increased micronutrient provlslonsufficient to meet increased needs for most nutrients including zinc, vitamin A, for children <10 years Higher nonprotein calorie/nitrogen ratio may eliminate need for modular protein Same as above with Osmolite HN Fiber content 13.6 gIL may be excessive for age at high infusion rates
Ages 4-9 Years Osmolite HN
1.06
44.4
125:1
930/1570
760/760/286
Jevity
1.06
44.4
125:1
877/1480
858/716/286
Ages 10 and Older Promote 1.0 +/- fiber
62.5
75:1
930/1980
930/1980/400
Oxepa
1.5
62.5
125:1
1310/1960
1060/1060/425
AlitraQ
1.0
52.5
94:1
1000/1200
733/733/267
weight dramatically decreases, so that energy needs are easily met with feedings that contain a lower calorie-tonitrogen ratio. This is a key characteristic of adult formula designed to meet nutrient needs specific to critical illness. In addition, unlike standard enteral feeding solutions that generally provide between 30% and 45% of calories as fat and between 40% and 55% of calories as carbohydrate, formulas designed for metabolically stressed patients offer more calories in the form of carbohydrate, consistent with findings in much of the literature on substrate utilization described earlier in this chapter. Many formulas are also enhanced with specific nutrients known to be involved in key processes such as wound healing, immunity, and free radical scavenging such as zinc, selenium, and vitamins C and E. Formulas with conditionally indispensable amino acids can also be used in this age group. The actual benefit in outcomes still needs to be established in children. However, these formulas are often a useful option in older children with complications such as poor wound healing, preexisting malnutrition, severe lung injury, or suspected mucosal atrophy, who may benefit from such therapy.
High protein formula for patients with Increased needs for wound healing Increased supplementation of zinc: 24 mg/L, selenium: 70 ~g/L, vitamin C: 345 mg/L Low carbohydrate feeding (28% of calories) for critically ill, mechanically ventilated patients Fortified with elcosapentaenolc acid and ,..linolenic acid; vitamin C: 844 mg, Ikarotene: 181 mg, vitamin E: 310 mg, selenium: 77 J.l.g High vitamin A content: 11,9851U High osmolality: 493 mOsm/kg H2O Glutamine added: 14 gIL
MODE AND TIMING OF ADMINISTRATION
Route of Administration The use of enteral nutrition has been advocated because it maintains the functional integrity of the gut, a probable mechanism in the prevention of bacterial translocation, although no direct evidence that enteral nutrition protects against human bacterial translocation exists.59,GO The risk of infectious complications is lower with enteral nutrition, and its use may modulate immunologic and metabolic mediators after injury, making it the preferred mode of nutritional therapy.61,62 However, the most effective route of delivery in critically ill patients remains controversial. Enteral feedings in critically ill patients are most commonly provided through nasogastric or nasoenteric feeding tubes. Nasogastric feedings have the advantages of being simple to administer and easy to monitor for tolerance by tube aspiration of gastric residuals. In patients receiving gastric feedings, goal rate is achieved sooner and with fewer placement attempts than for patients receiving small bowel feedings.P Proponents of gastric
SECTION IV • Principles of Enteral Nutrition
feedings suggest they are well tolerated in children when begun early, are beneficial for ulcer prophylaxis, and can be delivered without a high risk of pulmonary aspiration.63-65 Despite their advantages, gastric feedings are associated with complications. Primary among these are high gastric residual volumes and gastric regurgitation.66•67 In addition, continuous gastric feedings may increase gastric colonization because of their high pH, which in turn may increase the risk of nosocomial pneumonia. However, this risk pertains also to patients receiving postpyloric feedings who are treated with antacids and histamine H2 blockers/" A number of clinical circumstances and patient conditions are associated with failure to progress with gastric feedings. Sedation, chemical paralysis, mechanical ventilation, and hormonal conditions related to the hypermetabolic state are more likely to result in gastroparesis in children.P:" For them, postpyloric feedings are preferable. However, difficulty in establishing and maintaining transpyloric feedings, combined with increased costs and exposures to radiation as a result of repeated fluoroscopic procedures, create barriers for some clinicians. A number of techniques for nonradiographic assessment of feeding tube placement, including gastric insufflationand pH-assisted insertion of feeding tubes, have been successfully used in children.72•73 They provide a useful, cost-effective means of postpyloric feeding that can be adopted for populations that require this mode of feeding. The critically ill children who are most likely to benefit from jejunal feedings are surgical patients. Because gastric feedings must be stopped perioperatively to avoid aspiration, this approach can lead to extensive periods of inadequate nutritional support in patients requiring frequent surgical procedures. One approach to overcome the necessary cessation of continuous enteral nutritional support in children who often undergo surgical procedures is the use of jejunal feeding. Jenkins and associares" have proven that jejunal feedings are safe and effective in maintaining nutritional adequacy during the perioperative phase in children. Nasojejunal feedings have been associated with a significant reduction in gastric residual volume and a lower requirement for parenteral feedings."
Early Enteral Nutrition Early administration of enteral feeding among critically ill children has recently emerged as a common practice. This trend is based in part on animal studies demonstrating decreased gut permeability and a reduction in the hypermetabolic response with immediate postburn enteral feedings." In human studies, early enteral feedings reduced septic morbidity but did not attenuate the hypermetabolic response.T" In children with bums, there was no improvement in indicators of the hypermetabolic state (such as measured energy expenditure and levels of counter-regulatory hormones), nutritional status, rates of sepsis or wound infection, days needing mechanical ventilation, or length of stay among those
327
fed within 24 hours postbum compared with those fed later. In fact, a higher incidence of adverse effects, including bowel necrosis, was reported with early versus delayed enteral feedings." In a follow-up analysis, increased incidence of bowel necrosis appeared to be related to the extent of the bum injury, the need for greater resuscitation volumes, and the need for inotropic agents among these children/" In a number of similar case reports and observational studies, small bowel necrosis has been reported in patients receiving early enteral support during critical illness. Common factors linking these patients are clinical findings resembling sepsis, early postoperative enteral nutrition, use of inotropic agents, and diminished mesenteric blood f1ow. 81,82 The incidence of small bowel necrosis to date is rare; however, given the high mortality rate associated with it, cessation of enteral feedings during episodes of sepsis or hypoperfusion or before completion of fluid resuscitation is advised.
MONITORING RESPONSE TO ENTERAL FEEDINGS Monitoring of the response to enteral nutrition requires collection and interpretation of data on gastrointestinal tolerance, metabolic balance including fluid and electrolyte equilibrium, and nutritional adequacy. Evaluation of gastrointestinal tolerance in critically ill children is similar to that in children of normal health and depends on the type of diet, mode of feeding, and the physiologic aspects of the child's condition that may impact his or her ability to tolerate an enteral diet. Typical indicators of intolerance include delayed gastric emptying, vomiting, abdominal distention, and constipation. As indicated in the preceding sections, there are numerous situations within a critical care environment that may predispose patients to one or more gastrointestinal complications. For example, although delayed gastric emptying is common in patients fed intragastrically, diarrhea is often reported in patients fed into the jejunum or in those receiving prolonged antibiotic therapy. Constipation is common among patients receiving high doses of narcotics. Because of the dynamic nature of a critical care environment, more frequent monitoring may be needed because medications and other intervention strategies that influence nutrient absorption and gut function are likely to change. Table 26-8 highlights the key indictors of gastrointestinal intolerance, contributing factors, and recommended interventions. Evaluating the metabolic effects of enteral feedings in a critical care environment includes routine assessment of fluid and electrolyte balance and serum indices of ionized calcium, magnesium, and phosphorus (Table 26-9). The frequency of monitoring should be greatest with the initiation of feedings to avoid electrolyte disturbances, namely, hypophosphatemia, hypomagnesemia, and hypokalemia, with the administration of glucose. These disturbances resemble a wellknown phenomenon that is commonly described in malnourished patients with refeeding syndrome. The underlying mechanism appears to be related to the
328
26 • Enteral Nutrition Support in the Critically III Pediatric Patient
_ _ Monitoring and Management of Gastrointestinal Complications Gastrointestinal Complications High gastric residual volumes
Monitoring
Potential Cause
Management
Every 2-4 hours
Gastroparesis Surgery Chemical paralysis Neuromuscular blockade Sepsis High amylin levels
Stop for residual volumes >2 times the hourly rate or 80 mL (whichever Is greater) Elevate head of bed >30 Dilute formulas with high osmolality to hall strength and gradually increase concentration over 1-2 days Avoid soluble fiber-containing tube feedings Provide motility agents Place feeding tube postpyloric ally Hold feedings Rule out ileus or obstruction Provide formula at room temperature Evaluate fiber Intake based on child's age and diet history Evaluate formula; enteral intake if eating Dilute feedings/lower volume of feedings/avoid flavored feedings Evaluate infectious etiology Evaluate medications, including vitamin/mineral supplements (i.e., zinc, iron) Evaluate medications, particularly antibiotics; consider probiotic therapy Dilute feedings Check stool cultures Provide elemental feedings until tolerance improves Reduce rate Initiate bowel regimen immediately with all patients receiving narcotics Fiber may worsen constipation Increase fluid intake if possible
Abdominal distention
Before initiation of feedings; daily or more frequently with increased distention
Ileus Obstruction Formula too cold Excessive fiber intake Lactose intolerance
Nausea/vomiting
Every shift
Intolerant to feedings Infectious origin Medications
Diarrhea
Every shilt
Constipation
Every shilt
Medication related Hyperosmolar feedings Infectious origin Intestinal atrophy due to malnutrition Post pyloric feedings High dose narcotics Prolonged bed rest
rapid intracellular entry of these electrolytes induced by insulin.P Nutritional adequacy is most conveniently monitored by comparing actual to desired intake for calories and protein. The anthropometric and biochemical indices of nutritional adequacy have been described in an earlier section. The manifestations of the inflammatory state are similar to and often obscure clinical signs of malnutrition; repeated measures of indices such as weight and prealbumin and C-reactive protein levels are useful for identifying trends. Although each individual measure
0
alone may not be a reliable indicator, taken together these indices provide useful information about dietary adequacy.
TRANSITION TO ORAL DIET During the transition from intensive care to rehabilitative care, a shift in the goal of enteral nutritional support from supporting catabolism to promoting anabolism occurs. Because weight gain and recovery of muscle
_ _ Bi9Chemical Monitoring for Children Receiving Enteral Nutritional Support Monitoring Schedule Measurement
High Risk, Mechanically Ventilated
Moderate Risk
Serum sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, glucose Urinary glucose
Every 8 hours with initiation of feedings; then dally
Daily with Initiation of feedings; then biweekly, unless clinical condition warrants more frequent monitoring None
Serum ionized calcium Phosphorus, magnesium SGOT, SGPT, alkaline phosphatase, bilirubin (total, direct) Serum albumin, total protein Serum prealbumin, C-reactive protein Urinary nitrogen, urinary creatinine
Daily for first 3 days, or with elevated serum glucose levels Biweekly Every 8 hours with initiation of feeding; then dally; biweekly if hemodynamically and clinically stable Weekly unless clinical condition warrants more frequent monitoring Every 2 weeks Biweekly Weekly
SOOT, serum glutarnlc-oxaloacetic transaminase; SOPT, serum glutamic-pyruvic transaminase.
Weekly Biweekly Every 2 weeks unless clinical condition warrants more frequent monitoring Every 2 weeks Weekly Weekly
SECTION IV • Principles of Enteral Nutrition
_ Caloric Goal
329
Sliding Scale Intermittent Tube Feedings
= 1440 cal
Check oral Intake at 3 pm Iforal intake <500; otherwise continue to hold TF
Tube Feeding (fF) Goal Rate
= 60 mL/hr (1 cal/ml.)
Tube Feeding Schedule 3 pm-7 am
Check oral Intake at 7 pm If oral intake <700
<800 <900 <1000
strength are desirable clinical outcomes, enteral nutritional support remains important in that process. However, the focus of enteral nutrition changes from aggressive diet therapy by means of a feeding tube to the promotion of normal nutrition via an oral diet. This process requires a creative environment that can stimulate appetite and facilitate learning and the regaining of feeding skills while providing nutritional rehabilitation. Unfortunately, the need for various medications that diminish appetite remains during this phase. Children may also experience pain and anxiety during rehabilitation sessions, and depression is common. These factors serve as obstacles to eating. Also, because appetite control is highly regulated in children, they are unlikely to eat if their caloric needs are met. Enteralfeedingsshould become intermittent, with provisions based on daily intake. Table 26-10 illustrates a sliding scale tube feeding schedule designed to promote the eventual transition to an oral diet without compromising caloric intake.
CONCLUSION The provision of enteral nutrition is very age specific with respect to the amount and proportion of nutrients required for preservationof body composition. However, because growth is not possible during the inflammatory state, nutrient requirements are altered compared with those of normal children. Critically ill children are not homogeneous. Their needs are complex and are often condition specific. Many factors related to the clinical management of these patients, such as surgical needs, mechanical ventilation, and medication use influence nutritional status and the ability to feed a patient. With each change in clinical status, reassessment of nutrient requirement and type and mode of feeding is necessary. REFERENCES 1. PlankDL, Hill GL: Sequentialmetabolic changes following induction of system inflammatory response in patients with severe sepsis or major blunt trauma. WorldJ Surg 2000;24:630-638. 2. Weissman C: The metabolic response to stress: An overview and update. Anesthesiology 1990;73:308-327. 3. Joosten KJM, de Kleijn ED, Westerterp M, et al: Endocrine and metabolic responses in children with meningococcal sepsis: Striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab 2000;85:3746-3753.
7 pm-7 am 7 pm-5 am 7 pm-4 am 7 pm-3 am 7 pm-2 am 7 pm-12 am Hold TF; offer oral supplement
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26 • Enteral Nutrition Support in the Critically III Pediatric Patient
23. Solomon SM, Kirby OF: The refeeding syndrome: A review. JPEN J Parenter Enteral Nutr 1990;14:90-97. 24. Rettmer RL, Williamson JC, Labbe RF, et al: Laboratory monitoring of nutritional status in bum patients. Clin Chem 1992;38:334-337. 25. Spiekerman AM: Proteins used in nutritional assessment. Clin Lab Med 1993;13:353-368. 26. Prelack K, Sheridan R, Yu YM, et al: Sodium bromide by instrumental neutron activation analysis quantifies change in extracellular water space with wound closure in severely burned children. Surgery 2003;133:396-403. 27. Spiess A, Mikalunas V, Carlson S, et al: Albumin kinetics in hypoalbuminemic patients receiving total parenteral nutrition. J Parenter Enteral Nutr 1996;20:424-428. 28. Gottschlich MM, Baumer MJ, Khoury J, et al: The prognostic value of nutritional and inflammatory indices on patients with bums. J Bum Care Rehabil 1992;13:105-113. 29. Prelack K, Washek M, Sheridan R: Pre-albumin and C-reactive protein are predictive of nutritional adequacy in burned children. J Burn Care Rehabil2002;23:S171. 30. Prelack K, Dwyer J, Yu YM, et al: Urinary urea nitrogen is imprecise as a predictor of protein balance in burned children. J Am Dietet Assoc 1997;97:489-495. 31. Pingleton SK: Nutritional support in the mechanically ventilated patient. Clin Chest Med 1988;9:101-109. 32. White M, Shepard J, McEniery J: Energy expenditure in 100 ventilated, critically ill children: Improving the accuracy of predictive equations. Crit Care Med 2000;28:2307-2312. 33. Chwals WJ, Lally KP,Woolley MM: Measured energy expenditure in critically ill infants and young children. J Surg Res 1988;44:467-472. 34. Tilden SJ, Watkins S, Tong TK: Measured energy expenditure in pediatric intensive care patients. Am J Dis Child 1989;143:490-492. 35. Goran MI, Peters EJ, Herndon ON: Total energy expenditure using the doubly labeled water technique. Am J Physiol 1990;259 (Endocrinol Metab 22):E576-E585. 36. Vernon 0, Madolin W: Effect of neuromuscular blockade on oxygen consumption and energy expenditure in sedated, mechanically ventilated children. Crit Care Med 2000;28:1569-1571. 37. Briassoulis G, Venkataramn S, Thompson AE: Energy expenditure in critically ill children. Crit Care Med 2000;28:1166-1172. 38. Turi R, Petros A, Eaton S, et al: Energy metabolism of infants and children with systemic inflammatory response syndrome and sepsis. Ann Surg 2001;233:581-587. 39. Long CL, Birkhahan RH, Geiger JW, et al: Contribution of skeletal muscle protein in elevated rates of whole body protein catabolism in trauma patients. Am J Clin Nutr 1981;34:1087-1093. 40. Young VR: 1987 McCollum Award Lecture. Kinetics of human amino acid metabolism: Nutritional implications and some lessons. Am J Clin Nutr 1987;46;709-725. 41. Winthrop AL,Wesson DE, Pencharz PB, et al: Injury severity, whole body protein turnover, and energy expenditure in pediatric trauma. J Ped Surg 1987;22:534-537. 42. Cunningham JJ, Lydon MK, Russell WE: Calorie and protein provisions for recovery from severe burn infants and young children. Am J Clin Nutr 1990;51:553-557. 43. Mayes T, Gottschlich M, Warden G: Clinical nutrition protocols for continuous quality improvements in the outcomes of patients with burns. J Burn Care RehabilI997;18:365-368. 44. Young VR: Proteins, peptides and amino acids in enteral nutrition: Overview and some research challenged. In Furst P, Young (eds): Nestle Nutrition Workshop Series Clinical and Performance Program. Basel, Nestec LTD; Vevey/S. Karger AG, 2000, vol 3, pp 1-23. 45. Knight C, Fleming SE: Oxidation of glucose carbon entering the TCAcycle is reduced by glutamine in the small intestine epithelial cells. Am J Physiol 1995;268(Gastrointest Liver Physiol 31): G879-G888. 46. Nurjhan N, Bucci A, Perriello G, et al: Glutamine: A major gluconeogenic precursor and vehicle for interorgan carbon transport in man. J Clin Invest 1995;95;272-277. 47. Parry-Billings M, Evans J, Calder PC, et al: Does glutamine contribute to immunosuppression after major burns? Lancet 1990;336:523-525. 48. Wischmeyer PE, Lynch J, Liedel J, et al: Glutamine administration reduces gram-negative bacteremia in severely burned
patients: A prospective randomized double blind trial versus isonitrogenous control. Crit Care Med 2001;29:2075-2080. 49. Coghlin TM, Wong RM, Negrin RS, et al: Effect of oral glutamine supplementation during bone marrow transplantation. JPEN J Parenter Enteral Nutr 2000;24:61-66. 50. Sheridan RL, Prelack K, Yu, YM et al: Short term enteral glutamine does not enhance protein accretion in burn patients: A stable isotope study. Presented at the Annual Meeting of the American Burn Association, April 2001, Boston, MA. 51. Neu J, Roig J, Meetze W, Veerman M, et al: Enteral glutamine supplementation of very low birth weight infants decreases morbidity. J Pediatr 1997;131:691-699. 52. Singh A, Smoak BL, Patterson KY, et al: Biochemical indices of selected trace minerals in men: Effect of stress. Am J Clin Nutr. 1991;53:126-131. 53. Shippee RL, Koppenheffer T, Watiwat SR, et al: The effect of burn injury and zinc nutriture on fecal endogenous zinc, tissue zinc distribution, and t-lymphocyte subset distribution using a murine model. Proc Soc Exp BioI Med 1988;189:31-38. 54. Shewmake KB, Talber GE, Bowser-Wallace BH, et al: Alterations in plasma copper, zinc, and ceruloplasmin levels in patients with thermal trauma. J Bum Care Rehabil 1988;7:69-76. 55. Khilnani P: Electrolyte abnormalities in critically ill children. Crit Care Med. 1992;20:241-249. 56. Greene HL, Burns RA: Vitamins. In Fischer JE (ed): Nutrition and Metabolism in the Surgical Patients, 2nd ed. Boston, Little, Brown, 1996, pp 267-292. 57. National Research Council: Recommended Dietary Allowances, ed 10, Washington, DC, National Academy Press, 1989. 58. Blok WL, Katan MB,van der Meer JW: Modulation of inflammation and cytokine production by dietary fatty acids. J Nutr 1996;126: 1515-1533. 59. Lipman TO: Grains or veins: Is enteral nutrition really better than parenteral nutrition? A look at the evidence. JPEN J Parenter Enteral Nutr 1998;22:167-182. 60. Lipman TO: Bacterial translocation and enteral nutrition in humans: An outsider looks in. JPEN J Parenter Enteral Nutr 1995;19;156-165. 61. Kudsk KA, Croce MA, Fabian TC, et al: Enteral versus parenteral feeding. Effects of septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:505-511. 62. LowryS: The route of feeding influences injury responses. J Trauma 1990;30:S1o-s 15. 63. Neumann DA, Delegge MH: Gastric versus small-bowel tube feeding in the intensive care unit: A prospective comparison of efficacy. Crit Care Med 2001;30:1436-1438. 64. Trocki 0, Michelini A, Robbins ST, et al: Evaluation of enteral feeding in children less than 3 years old with smaller burns (8-25 per cent TBSA). Burns 1995;21:17-23. 65. Valentine RJ, Turner WW, Borman KR, et al: Does nasoenteral feeding afford adequate gastroduodenal stress prophylaxis? Crit Care Med 1986;14:599-601 66. Klodell C, Carroll M, Carrillo E, et al: Routine intragastric feeding following traumatic brain injury is safe and well tolerated. Am J Surg 2000;179:168-171. 67. Heyland OK, Drover JW, MacDonald S, et al: Effect of postpyloric feeding on gastroesophageal regurgitation and pulmonary microaspiration: Results of a randomized controlled trial. Crit Care Med 2001;29:1495-1501. 68. Tejada Artigas A, Beloo Dronda S, Chacon Valles E, et al: Risk factors for nosocomial pneumonia in critically ill trauma patients. Crit Care Med 2001;29:304-309. 69. Mentec H, Dupont H, Bocchetti M, et al: Upper digestive intolerance during enteral nutrition in critically ill patients: Frequency, risk factors, and complications. Crit Care Med 2001;29: 1955-1961. 70. Sheridan R, Prelack K, Kadilak P, et al: Supplemental parenteral nutrition does not increase mortality in children. J Burn Care Rehabil 2000;21 :234(S). 71. Mayer AP, Durward A, Turner C, et al: Amylin is associated with delayed gastric emptying in critically ill children. Intensive 'Care Med 2002;28:336-340. 72. Krafte-Jacobs B, Persinger M, Carver J, et al: Rapid placement of transpyloric feeding tubes: A comparison of pH-assisted and
SECTION IV • Principles of Enteral Nutrition
73. 74. 75. 76. 77.
standard insertion techniques in children. Pediatrics 1996;98: 242-248. Harrison MA, Clay B, Grant MJ, et al: Nonradiographic assessment of enteral feeding tube position. Crit Care Med. 1997;25: 2055-2059. Jenkins ME, Gottschlich MM, Warden GO: Enteral feeding during operative procedures in thermal injuries. J Burn Care Rehabil 1994;15:199-205. Davies AR, FroomesPR, French CJ, et al: Randomized comparison of nasojejunal and nasogastric feeding in critically ill patients. Crit Care Med 2002;30:586-590. Mochizuki H, Trocki 0, Dominioni L, et al: Mechanism of prevention of postburn hypermetabolism and catabolism by early enteral feeding. AnnSurg 1984;200:297-308. Eyer SO, Micon LT, Konstantidnides F, et al: Early enteral feeding does not attenuate metabolic response after blunt trauma. J Trauma34:639-643.
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78. Kompan L, Kremzar B, Gadzijev E, et al: Effects of early enteral nutrition on intestinal permeability and the developmentof multiple organ failure. Intensive Care Med 1999;25:157-161. 79. Gottschlich MM, Jenkins ME, Mayes T, et al: An evaluation of the safety of early vs delayed enteral support and effects on clinical, nutritional, and endocrine outcomes after severe burns. J Burn Care Rehabil2oo2;23:401-415. 80. Riegel T,Allgeier C,Gottsclich M, et al: Fluidresuscitation, inotropic agents and early feeding: Is there a relation to bowel necrosis? J BurnCare Rehabil 2OO3;24:S61. 81. Munshi I, SteingrubJ, Wolpert L: Small bowel necrosis associated with early postoperative jejunal tube feeding in a trauma patient. J Trauma 2000;49:163-165. 82. Marvin R, McKinley B, Mcquiggan M, et al: Non-occlusive bowel necrosisoccurring in critically ill trauma patients receivingenteral nutrition manifests no reliable clinical signs for early detection. Am J Surg2000;179:7-12.
ED Enteral Nutrition in the Home Debra S. Kovacevich RN, MPH Heather A. Rowe RD, CNSD
CHAPTER OUTLINE Introduction Patient Selection Home Infusion Provider Patient Assessment General Assessment Nutritional Assessment
Education Feeding Tubes Care of Enteral Tubes Flushing Checking Gastric Residual Volumes
Formula Selection Feeding Administration Syringe Bolus Gravity Feedings Pump Administration Feeding Pump Selection Formula Hang Times Administering Medications
patients in the United States receiving home enteral nutrition.' The exact number is unknown because of the lack of a national registry, but it is generally believed that the number of patients is increasing on a yearly basis with an estimated annual growth rate of 25% per year. The reasons for this explosion are multifactorial with the most important being that patients do better in their own home environment. Other reasons include the following: a greater emphasis being placed on home care due to the significant cost savings associated with providing care in the home versus a hospital; strides to ensure that patients being sent home receive the appropriate route of nutritional support, thereby further decreasing costs because it has been estimated that home enteral nutrition (HEN) is close to 9 times less expensive than that of home parenteral nutrition-; the development of feeding tubes that do not require insertion under general anesthesia; and further refinement of commercial tube feeding products and administration techniques.
PATIENT SELECTION
Complications Feeding Tube Clogging Feeding Intolerance Enteral Tube Site Complications
Care Planning Monitoring Transitioning to Oral Intake Enteral Feeding Tube Removal
Caregiver Aspects Outcomes Quality of Life Conclusion
INTRODUCTION Data obtained in 1992 from Medicare and the North American Home Parenteral and Enteral Nutrition Patient Registry indicated that there were an estimated 152,000
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Indications for HEN are based on a functional gastrointestinal tract. Major categories are digestive diseases that limit the absorption of nutrients (inflammatory bowel disease and short bowel syndrome), diseases that limit the ability to feed orally (swallowing difficulties and esophageal atresia or stenosis), catabolic diseases (chronic liver and renal failure, cholestatic liver, cystic fibrosis, and cancer), metabolic inherited diseases (glycogen storage disease and enzyme deficiencies in the urea cycle), and miscellaneous indications (chronic neuromuscular diseases, cerebral palsy, and anorexia). An appropriate diagnosis is crucial when a clinician considers discharging a patient with a feeding tube, but, the foremost consideration is that the patient must be willing to tolerate HEN, and appropriate support systems must be in place before discharge. Establishing tolerance to enteral nutrition while the patient is still in the hospital will provide a more favorable outcome for HEN. If the patient's medical condition has not stabilized, use of HEN should be delayed to avoid rehospitalization.
SECTION IV • Principles of Enteral Nutrition
As part of the initial assessment, the clinician should determine whether the patient's home environment is safe and appropriate for discharge with a feeding tube. A clean, comfortable place to administer the enteral feedings as well as an appropriate place to store supplies must be available. A refrigerator would need to be available in the home to store opened containers of formula and used feeding bags. The patient must have access to both hot and cold running water. It is important that the patient be involved as much as possible in the administration of HEN to help maintain their independence. Although some patients are able to manage their tube feedings completely on their own at home, it is beneficial to have a caregiver available for support. The caregiver should be present for HEN training and available during times of feeding at home. Informing the patient and caregiver up front about what is involved in HEN, including financial responsibility and the need for medical follow-up, is a priority. Many patients feel more comfortable having a visiting nurse present in the home during the initiation of HEN. Contact information for a physician, a home nursing agency, and a home infusion provider to use as resources for questions or other concerns should be given to the patient before discharge.
HOME INFUSION PROVIDER The home infusion provider will probably be determined by the patient's insurance policy. The provider should follow the American Society of Parenteral and Enteral Nutrition's Standards for Home Nutrition Support that were developed by a multidisciplinary group of nurses, dietitians, pharmacists, and physicians who are committed to promoting quality patient care, education, and research in nutrition.' These standards serve as a guide to assist home care organizations and health care professionals in providing safe and appropriate nutrition care. Some infusion providers that are hospital based may have staff available to train patients on HEN before discharge. If this service is not available, tube feeding education needs to be provided by the inpatient staff or visiting nurse agency. In selecting a home infusion provider, consideration should be given to whether monitoring and follow-up of patients for the duration of their therapy is part of the service. Monitoring of patients receiving HEN is not a reimbursable service for physicians and can be labor intensive." Some home infusion providers offer a team approach, providing complete monitoring of home therapies to assist physicians with this task. The role of the dietitian has broadened in the home care field, and a dietitian is a beneficial addition to the nutrition team.
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therapy assessment should include a thorough health history with information on primary diagnosis, past medical and surgical history, medication allergies, and vital signs including height and weight. A psychosocial assessment documenting mental status, living arrangements, social support, and health risk behaviors should be performed including a screening tool for abuse. A functional assessment including ability of the patient to perform daily activities should be obtained and appropriate medical referrals should be made if needed. Physical findings, with current status of wounds, if present, should be documented for future reference. The patient should be assessed for pain and referred to a physician for pain management if necessary. In the initial assessment, the patient's feeding tube will need to be inspected for catheter type, brand, and size to facilitate appropriate supply ordering. In addition, the distal end of the feeding tube should be located to determine the appropriate method of formula administration. Pediatric patients should be screened for developmental milestones, psychosocial issues, and immunizations. Pertinent laboratory test results should be noted including swallowing function tests. Finally,an assessment of the home will need to be performed to identify possible limitations when the patient returns there. The information obtained in the assessment should be used to determine what items need to be monitored by the home care clinician while the patient is receiving HEN.
Nutritional Assessment Assessing a patient's nutritional status has been covered in detail in Chapter 16. Once a patient's medical condition is stable and he or she is returning home, slight modifications in the nutritional needs may be indicated. For example, as the patient returns to normal life, he or she may be more active and ambulatory, requiring additional calories. If the patient was febrile in the hospital and is now afebrile, caloric needs may decrease slightly. A physical assessment should be made to determine if any nutrient deficiencies or toxicities exist and to assess hydration status. Wounds and/or healing pressure ulcers may still require additional protein. Pediatric patients need periodic nutritional reassessment while receiving HEN to ensure proper growth and development. Regular growth chart plotting is necessary to monitor their growth, typically every 2 to 3 months up to age 2, every 6 months up to age 5, and annually thereafter. Careful and proper plotting techniques are required to accurately assess and monitor the child's growth.
EDUCATION PATIENT ASSESSMENT
General Assessment Providing home care to patients receiving enteral nutrition requires a complete patient assessment in addition to the nutritional assessment. The initial home infusion
Lack of formal training leaves patients and their caregivers unprepared for the technical, physical, and emotional aspects of HEN therapy. This leads to undue stress, complications, and rehospitalizations. Patients and their caregivers desire formalized training but only 59%to 88% of family caregivers report that this process occurs."
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27 • Enteral Nutrition in the Home
Designing an instruction program requires a process that promotes learning which is tailored to the patient's abilities, knowledge structures, and expectations. A needs assessment must be performed to determine the patient's needs and readiness to learn. Once this has been accomplished, goals and objectives can be mutually set. Instruction should be matched to the individual's readiness to perform complex tasks, divided into smaller, achievable sequential learning units. It may be helpful to organize these complex tasks, such as learning about the feeding pump, in easy-to-remembergraphics or schematic drawings. Materials in the form of handouts, computerassisted instruction, or videotapes should be given to help deliver the message. Feedback should be provided immediately. The instruction should be concluded by having the individual review what he or she has learned. It has been estimated that dietitians spend an average of 2 hours and 35 minutes educating and preparing patients
receiving HEN for discharge, which is clearly worth the associated costs of preventing complications and promoting nutrition." Time spent educating patients and their caregivers increases when the time of physicians, home infusion provider clinicians, and hospital and visiting nurses is taken into account. Table 27-1 provides an example of a training checklist for HEN education.
Feeding Tubes The most common problem for patients receiving HEN is the accidental removal of the tube. Many patients/caregivers are supplied with additional low-profile gastrostomy devices and are taught how to safely change these at home, decreasing the number of times the patient has to be taken to the hospital or clinic. It is important that all gastrostomy and jejunostomy feeding tubes be replaced
_ _ Home Enteral Nutrition (HEN) Educational Checklist Education Need
Learning Objective
Capability and motivation to learn HEN regimen
Understands the reasons for HEN Agrees to follow HEN regimen while in hospital and at home States the definition and understands nutritional components States goals and outcome of HEN therapy Demonstrates: Clean technique for cleaning around the catheter Flushing technique before and after medication/tube feeding administration Medication administration States when to use and how to use declogging kit Verbalizes when to use a dressing around tube site Demonstrates: Handwashing technique Equipment set-up Ability to set rates of administration States: How to troubleshoot administration device Formula preparation, amount, and feeding schedule Amount of free water needed to maintain hydration Frequency of feeding set and syringe changes Understands action to be taken for a missed dose or for feeding pump failure States: Type of tube feeding formula Hang time for tube feeding How to properly store product Demonstrates where to find expiration date on product Inspects product for contamination, separation States: Importance of monitoring Parameters to monitor, i.e., weight, hydration, blood tests Frequency of monitoring Understands: Possible causes and corrective actions for mechanical and infectious complications Possible causes and corrective actions for metabolic complications Importance of monitoring Knows when and how to order supplies Uses supplies appropriately States home infusion provider name and how to contact them Understands: Importance of notifying home Infusion provider for emergency situation in home or community Mechanism that home infusion provider will use if emergency occurs States: How to clean and disinfect Infusion pump if required How to inspect infusion pump for electrical hazards Home safety requirements for fire, mobility, cleanliness
Feeding tube care
Tube feeding administration
Tube feeding product
Monitoring
Complications
Ordering supplies Home safety and emergency preparedness Home and equipment safety
SECTION IV • Principles of Enteral Nutrition
as soon as possible if they are inadvertently removed,'? because the stoma can begin to heal within a few hours. With all the different types of feeding tubes that can be used by patients receiving long-term enteral nutrition, determining the right tube is difficult. In a study of 82 patients with malignant dysphasia, percutaneous endoscopic gastrostomy, low-profile endoscopic gastrostomy (PEG button), percutaneous endoscopic jejunostomy (PEJ), low-profile endoscopic jejunostomy (PE.I button), and surgical jejunostomy tubes were examined for durability." Findings indicated that low-profile tubes were most durable, lasting a mean of 1701 days, followed by surgical jejunostomy tubes lasting 1114 days; the least durable were PE.I tubes at 591 days. Further studies are needed in this area because the majority of patients in this study had either PEG or PEG buttons, and it is difficult to determine the influence of the length of therapy in each group.
Care of Enteral Tubes Proper care is required to preserve the integrity of the feeding tube and surrounding tissue. Patients with nasoenteric feeding tubes are instructed to change the tape that secures the tube to the nose. The tape should be removed carefully so the feeding tube is not dislodged. The area around the tube should be cleansed and inspected for redness or sores. It is beneficial to mark the feeding tube at the point where it enters the nose to ensure that the tube has not moved further in or out of the nose. After inspection, the tube should be retaped to the nose. Feeding tubes that are placed directly into the stomach or small intestines will require site care. When the feeding tube is initially inserted, the site will be dressed with gauze. This gauze generally stays in place for 24 hours. It is then removed, and the site is cleansed with a 1:1 mixture of hydrogen peroxide and water followed by antibacterial soap using a cotton tip applicator in a spiral pattem moving outward. The site is rinsed with water and patted dry. This is done two to three times per day for the first 2 weeks and then once daily thereafter. For the first several days it is not unusual for the feeding tube site to leak some gastric fluid; the patient should be instructed not to be alarmed. The fluid may dry around the tube and form a crust. In this case, plain water, normal saline, or the hydrogen peroxide/water mixture can be applied in the same spiral pattern as described above. After any dried fluid is removed, the tube site should be cleansed with antibacterial soap and rinsed with water. The gauze can be replaced if leaking persists, but it should be changed as soon as it becomes soiled to prevent infection. Afterthe tube site has healed, gauze dressings should not be used. Letting air reach the tube site will help promote healthy skin. If the site becomes red or inflamed, if purulent drainage is present, or if the patient is febrile, the physician should be contacted because of possible tube site infection. The tube should be inspected daily for changes in length, indicating possible tube migration. The patient may shower 24 hours after gastrostomy tube
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(GT) or jejunostomy tube (IT) placement but should not immerse the tube under water for at least 1 week.
Flushing One of the most important tasks that the patient must be taught is how to flush the feeding tube. This is done by drawing water into a needleless syringe and injecting it into the feeding port. The two main reasons why flushing is so important at home are to maintain tube patency and to provide the patient with adequate hydration. A water flush is recommended before and after administration of every medication, before and after each intermittent feeding is given, and every 4 to 8 hours during continuous feeding. For adults, a flush volume of between 20 and 60 mL is appropriate and for pediatric patients 5 to 30 mL is sufficient. The feeding tube is flushed before use to clear the tube of any residual medication, formula, or gastric juices. The feeding tube is flushed after each use to push the medication or formula out of the tube to deter build up. Flushing is also very important to provide adequate hydration. Formula alone does not usually provide enough fluid to prevent dehydration. When syringes are ordered for home use, compatibility of the feeding tubes and any adaptors should be checked. If the syringe is used solely for water flushes and medication, it can be reused for 3 to 4 days and then should be discarded.
Checking Gastric Residual Volumes Generally, gastric residual volumes are not checked at home because a tolerated regimen is likely to be established before discharge. In addition, most patients are able to tell if they are too full to continue feeding. It would be appropriate to check residual volumes at home in patients with compromised mental status or in pediatric patients.
FORMULA SELECTION With the abundance of formulas available on the market, it is necessary to be familiar with different brands. Many infusion providers will only carry a specific brand of formula. Therefore, an equivalent formula may need to be substituted for the one used in the hospital. Making the patient aware of this change before discharge will reduce confusion when supplies are delivered to the home. Home tube feeding regimens should be made as simple as possible for the patient to administer. Individual cans of formula (240 to 250 mL) are more commonly used in the home than ready-to-hang prefilled containers (1000 to 1500 mL) to reduce the amount of wasted formula. An attempt should be made to develop an enteral feeding regimen for which feedings can be administered as whole or half cans, rather than an odd amount. If necessary, extra formula can be stored in the refrigerator for up to 48 hours. Details on the types of formulas available are covered in other chapters.
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FEEDING ADMINISTRATION
Syringe Bolus A HEN feeding regimen can be administered in several different ways. The easiest, fastest, and most economic method is by syringe bolus. This method would only be used if the distal end of the feeding tube is in the stomach. A large syringe (60 mL) is used to draw up the formula, which is pushed into the feeding tube over several minutes. The likelihood of intolerance to bolus feedings is fairly high if the feeding regimen has not been well established.
Gravity Feedings Gravityfeedings are a favorable alternative to bolus feedings when intermittent feedings are desired. Gravityfeedings would again only be administered into a gastric feeding tube because of the fast rate at which they are delivered. The gravity feeding set is composed of a 1000or 1200-mL bag, tubing, roller clamp, and drip chamber. Depending on the size of the feeding tube lumen, the volume of formula being administered, and the patient's tolerance, the feeding can take from 20 up to 90 minutes. The rate at which the formula is delivered can be modestly controlled by setting the roller clamp partially open. A pole or some sort of secure device to hold the feeding set over the patient's head by 11}2 to 2 feet is necessary. To prevent regurgitation and aspiration, the patient's head should be elevated at a minimum 30degree or greater angle during feeding, and the patient should remain in that position for at least 30 minutes after the feeding. Gravity feeding sets should be rinsed with water after each use, kept in an airtight container, and stored in the refrigerator between feedings. Each set should be discarded after 24 hours but, if handled properly, can be used for up to 2 days if cost is an issue. A cost-saving alternative to gravity feeding is the use of a 60-mL syringe from which the plunger has been removed; the syringe is connected to the feeding port and held upright while the formula is poured slowly into the cylinder of the syringe. This is different from a syringe bolus in that the formula is not forced into the stomach but rather allowed to flow in as tolerated.
Pump Administration When gravity feedings are not tolerated, if nocturnal feedings are desired, or if a patient is being fed into the small intestine, a feeding pump is necessary. Patients have reported a decrease in flatulence, epigastric fullness, regurgitation,vomiting, and diarrhea when a change is made from gravity to pump feedings." By changing to nocturnal feedings via an infusion pump, some of these discomforts can be avoided, which may lead to better compliance. Additionally, blood glucose control is improved by the use of a feeding pump because it will
deliver the formula at a continuous, controlled rate. The best results are usually obtained when the feedings are initiated over 24 hours, then gradually cycled to 10- to 14-hour feedings. In general, adult patients can tolerate a 10 to 20 mUhr increase every 1 to 4 days to achieve a cycle. Pediatric patients can usually tolerate a 5 to 10 mUhr increase every 1 to 4 days. Cycling can be completed in the home and does not need to be established before discharge. The time of day at which the feedings are delivered is arbitrary, although most patients prefer nocturnal feedings. In pediatric patients, it is common to administer a bolus feeding during the day using a pump. The rate is set between 100 and 300 mUhr to deliver up to one can of food one to three times per day. Most children are then fed the remaining portion of their formula using the pump overnight. Feeding pumps are generally rented from an infusion provider and they can be very costly if adequate reimbursement is not available. Additional documentation may be required to secure payment.
Feeding Pump Selection There are numerous types of feeding pumps available, although most infusion providers will only offer one or two styles. A thorough assessment of the patient population is crucial for selection of feeding pumps. For example, if the population is mainly ambulatory with feedings administered during the day, ambulatory pumps should be strongly considered. A decision to lease or purchase a pump must also be made. The following aspects should be taken into account in making such a decision: Does the manufacturer offer maintenance? If not, who will service the pump? Is there a warranty for the pump? The size of the pump as well as its weight is a concern if it will be used by an active child. If portability is not an issue, then a larger, but less expensive, pump may be the better choice. An evaluation of the size of the feeding set should also be done. The portable carrying case may only accommodate a 500-mL bag, which mayor may not be appropriate. If the portable carrying case holds a 1000-mL bag or larger, it may be too bulky and heavy to carry, especially for pediatric patients. The features of pumps vary. For instance, some pumps might have a built-in priming feature whereas others do not and require manual priming. Setting a dose is not required with some pumps but is necessary with others. The rate at which the pump delivers the formula may increase in increments of one to five milliliters with the maximum rate varying among brands. There may be a volume feature that resets itself each time a feeding is complete, or it may be a cumulative volume. The pump may have a feed interval setting that allows formula administration to be interrupted and restarted automatically. When this feature is used, care should be taken to avoid having the formula hanging beyond its recommended hang time. Some pumps possess the ability to
SECTION IV • Principles of Enteral Nutrition
automatically deliver a water flush intermittently to keep the feeding tube patent. Choosing the appropriate feeding pump involves research. Battery life should be a consideration, especially if the pump will be used portably. How long does the battery take to recharge, and what is the total charge capacity? Can the pump run on electricity simultaneously? A pump manufacturer may agree to allow a small sample of a patient population to try a pump before the purchase of a large quantity. It is worthwhile to investigate which pump(s) other infusion providers are using and how well they meet the needs of their population.
Formula Hang Times The length of time a formula can be hung at room temperature when being delivered by feeding tube varies, depending on how the formula is packaged (Table 27-2). Most commercially prepared formulas available in a can may be hung at room temperature for 8 hours. This includes pediatric and elemental formulas. Any formula that has to be reconstituted (powder or liquid concentrate) is safe at room temperature for 4 hours. A canned product that has a modular supplement added (i.e., protein or carbohydrate enhancer) has a hang time of 4 hours as well. Freshly collected breast milk is safe at room temperature for 4 hours when administered through a feeding tube. It should be noted that the fat in breast milk will immediately begin to bind to the tubing of the feeding set, thus reducing the caloric content; therefore, it should be hung for the shortest amount of time possible." If a milk fortifier is added to breast milk, the hang time is decreased to a maximum of 2 hours. Many formulas are available in ready-to-hang 1000- to 1500-mL prefilled containers that are used primarily in the inpatient setting. Once opened, the prefilled container can be hung for up to 36 hours.
Administering Medications Patients commonly have several different medications to take and having enteral access may facilitate compliance
• . Recommended Hang Times of . . Enteral Formulas Maximum
Type of Formula
Hang Time-
Commercially prepared ready-to-feed cans Commercially prepared can with modular added Reconstituted formula (powder/liquid concentrate) Breast milk
8 hours 4 hours
Breast milk with fortifier added Ready-to-hang pre filled container 'Hang times may vary among manufacturers.
4 hours 4 hours (less than 2 hours optimal) 2 hours 36 hours
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with their complicated drug regimens. Thus, it is important to know that administering medications through a feeding tube significantly increases the risk of clogging. A few simple steps will help prevent clogging of the feeding tube. (1) Always flush the feeding tube with water before administration of medication to clear the tube of any residual formula. (2) Always administer medications separately with a water flush between each drug to minimize incompatibilities. (3) Never mix medications with formula; some medications can cause the formula to coagulate. (4) Before crushing a pill, check with a health care professional to be certain that it is suitable for crushing. Many pills should not be crushed, including all sustained released medications. If crushing the pill is permitted, be sure to crush it completely to a powder and dissolve it in water to prevent particles from clogging the feeding tube. Use of a liquid form of the medication is always preferable. (5) Dilute syrups with water to prevent them from adhering to the feeding tube lumen and to prevent osmotic diarrhea due to their high osmolality. (6) After the medication has been administered, always flush the feeding tube with additional water." A medication profile should be completed and verified with a pharmacist to avoid drug-nutrient interactions.
COMPLICATIONS Feeding Tube Clogging As discussed earlier in this chapter, flushing the feeding tube with water is a very important aspect of patient education. Occluded feeding tubes occur in 3.8% to 20% of patients receiving HEN.15,16 Frequent flushing is the best way to prevent clogs. A clog should be suspected if (1) the feeding tube cannot be flushed, (2) formula is leaking from the insertion site, or (3) the occlusion alarm of the feeding pump sounds repeatedly." Feeding tubes may clog despite good care techniques; thus, patients should be trained on how to attempt to clear clogs on their own. Well-educated patients will require fewer visits to the hospital emergency department or clinic. The first step in an attempt to clear a clogged feeding tube is to use a gentle plunging motion with a syringe filled with warm water attached to the feeding port. The syringe should be held tightly to the feeding port to prevent the water from spraying out of the tube. If this process is unsuccessful, a commercially prepared feeding tube declogging kit usually works well. A declogging kit should be provided with the initial delivery so it is available for the patient's use. Digestive enzymes in a powder form that are reconstituted with water and administered with a syringe are included in commercially prepared declogging kits. An applicator provided in the kit may be needed for nasoenteric feeding tubes to administer the solution as close to the clog as possible. No object should ever be inserted into a feeding tube in an attempt to mechanically remove a clog in the tube because this can result in perforation of the feeding
338
27 • Enteral Nutrition in the Home
tube and/or damage to the gastrointestinal tract. If a commercially prepared declogging kit is not available, a prescription can be given for the following solution: one pancrelipase tablet containing lipase. protease, and amylase (Viokase) crushed and mixed with one tablet of sodium bicarbonate (324 mg) in 5 mLof water. 18The solution is injected into the feeding tube, which is clamped and leftto sit for at least 5 minutes. Then, the feeding tube is flushed with 30 to 60 mL of water. If the patient is still unable to unclog the feeding tube, it is possible that the tube has become internally kinked or malpositioned; the patient will then need to be seen by the physician.
is very seldom the enteral nutrition formula. For instance, a new medication may be causing diarrhea, or the patient may have contracted a viral infection. If the patient is receiving antibiotics, he or she might experience loose stools for several days after the antibiotic course is finished. Formula is too easily blamed and is often changed unnecessarily. If new signs of intolerance to tube feedings arise, the patient needs to be fully assessed before the tube feeding regimen is changed. If no other cause for intolerance is determined, the tube feeding regimen may then need to be adjusted. Refer to Table 27-3 for signs of and solutions for issues associated with HEN.
Feeding Intolerance
Enteral Tube Site Complications
If a tube feeding regimen is established before the patient's
As discussed earlier in this chapter, care for the site in which the feeding tube is placed is important. The tube site should be assessed daily for redness, swelling, drainage. and skin breakdown. The incidence of
discharge from the hospital, the likelihood of intolerance at home is greatly decreased. If feedings have been well tolerated and diarrhea suddenly appears, the cause
_ _ Possible causes and Solutions to Problems Associated with Home Enteral Nutrition
From Home Enteral Nutrition Manual, HomeMed. Ann Arbor, University of Michigan Hospitals and Health Centers, 2003.
SECTION IV • Principles of Enteral Nutrition
infection around tube sites has been reported to range from 2.2% to a high of 16.3%.8,16 Particular attention should be paid to tube sites in patients who are receiving chemotherapy because the incidence of inflammation and cellulitis increases to 56% during periods of severe neutropenia.l? Leakage of gastric juices onto the skin may also cause inflammation and cellulitis, occurring in 1.1 % to 2.5% of patients. To minimize complications at the tube site, gauze should only be placed over the site if there is leakage. When the tube site no longer leaks, the gauze should be removed to allow air to reach the skin. If gastric leakage persists, an ointment such as zinc oxide can be applied to protect the skin. It may be helpful to apply an adhesive wafer around the tube to protect the skin and stabilize the tube." It can take up to 4 weeks for the skin around the tube to heal completely. If an infection is suspected, the patient's physician should be contacted, because it may be necessary to prescribe a topical cream or oral antibiotic. Granulation tissue forms at the tube site in 2.5% of patients when the feeding tube is kept in long term." The tissue becomes red or purple in color and is raised around the tube site. It becomes painful for the patient if too much granulation tissue builds up around the tube site. Silvernitrate is often applied and reapplied on several occasions to decrease the amount of granulation tissue. Other complications associated with enteral feeding tubes and administration that have been reported in the literature include aspiration pneumonia, laryngeal ulceration, esophageal stricture, gastric perforation, and metabolic complications."
CARE PLANNING Development of the plan of care for HEN should begin before the patient goes home. The involvement of all clinicians and organizations who will be caring for the patient is crucial. Discussing the patient's expectations with him or her will help to facilitate appropriate and obtainable goals. The initial nutritional goal for most adult patients is to maintain weight and/or stop weight loss. A long-term goal may be to gain weight. Pediatric patients who require a feeding tube are often well below the 5th percentile on growth charts. It may be more appropriate to strive for these patients to follow their own growth curves over time rather than a seemingly unachievable 50th percentile. Other goals that should be included in a care plan for patients receiving HEN are maintaining a patent enteral access port including a healthy tube site, disposing of used enteral supplies appropriately, monitoring pain so that it does not interfere with administration of the enteral nutrition, and monitoring the patients' functional status to ensure their ability to care for themselves. Refer to Table 27-4 for an example of an HEN care plan.
MONITORING To monitor patients receiving HEN, the clinical pathways established by the American Society for Parenteral and Enteral Nutrition should be followed.P Laboratory data
339
including a complete blood count and measurements of serum electrolyte, serum glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, serum magnesium, serum phosphorus, serum calcium, and serum albumin concentrations should be checked before initiation of enteral nutrition. Arrangements should be made to have abnormal laboratory values rechecked after discharge at appropriate intervals. Current weight is one of the most important pieces of data that should be monitored at home. Typically, it is appropriate to have patients weigh themselves weekly after discharge and then monthly when a goal weight or growth curve is established. Obtaining accurate weight is often difficult, depending on the patient's clinical condition. Weighing an immobile patient at home is almost impossible and relying on weight obtained at a clinic visit may be the only option. Assessment of fluid status at home is critical, and it should be monitored at every follow-up visit. It is usually relatively easy to assess fluid intake, but output is not easily obtainable. All sources of fluid intake should be assessed, including water used for flushing the feeding tube. The patient and caregiver should be aware of the signs of dehydration so they can take an active role in monitoring hydration status. Tolerance to the feeding regimen should be monitored including nausea, vomiting, diarrhea, constipation, abdominal cramping, or distention. Adjustments to the enteral formula may need to be made if no other sources of gastrointestinal distress can be determined. In addition to tube feeding tolerance, monitoring of readiness to take food by mouth should be included in the care plan. The nutrition care plan should be reassessed regularly and revised for changes in the patient's clinical condition, environment, psychosocial status, or drugs/therapy or for failure to achieve nutritional goals. Change in care should be documented in the clinical medical record.
TRANSITIONING TO ORAL INTAKE HEN may be a permanent form of nutrient intake for some patients. However, if oral intake becomes possible, the transition from tube feedings to complete oral intake should be monitored by a clinician. If a complete transition to oral intake is not possible, the use of supplemental tube feedings is an option. After oral intake is approved by the physician and the diet is resumed, the patient should begin to keep a food intake diary. The patient should be educated about the importance of keeping an accurate account of food intake to provide adequate information for transitioning. A food intake diary should include time of day an item is consumed, an accurate measurement of the amount consumed (measuring or weighing food is helpful), and the brand name of the food or items included in the recipe; the amount of fluid intake including water should be recorded to assess hydration. If the patient is consuming less than 25% of estimated nutrition needs by mouth, the full volume of tube feeding should be continued. If the patient is meeting 50% to 75% of estimated nutrition needs by mouth,
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_ _ University of Michigan Home Enteral Nutrition care Plan Problem or Need Balled on Patient~Dlent
Patient is referred to pharmacy services for treatment/ prevention of: o Malnutrition (adult) o Moderate • 5%-10% weight loss • reduced calorie intake • mild tissue loss o Severe • > 10% weight loss • loss of subcutaneous tissue • muscle wasting • edema
o Malnutrition (pediatric) _ _ _ % height-age _ _ _ % weight-age
BMI-age
Desired Therapeutic Outcome/Goals
Goal Outcome ~Dlent Measurements
The patient will exhibit an improvement in status as evidenced by:
o weight maintenance of _ - _ Ib/kg o weight maintenance of _ - _ Ib/kg o wdgltl 11Id1l1lelldJILI::: of __- __ Ill/kg
o weight
Measurement Score
,j:>.
o Intervention/Monitoring Parameters
Evaluate and review status of patient's symptoms and progress via feedback from: • Patient/caregiver • Visiting nurse • Physician
Modification of Monitoring Patient Balled on Reassessment(s) (Initial and Date)
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per month and follow own growth curve
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o Absence of fatigue related to weight loss demonstrated by __ activity
o Transition to oral intake o Transition to
TEN intake
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3 months for pediatric patients Intake is equivalent to nutritional requirements Protein: Kcal: Fluids:
grn/day per day mL/day
Monitor weight response to therapy SGA: 0 q 3 months o q 6 months
o Transition to palliative care
(Initial and date)
o Intake is equivalent to nutritional requirements Protein: Kcal: Fluids:
g/day per day mL/day
(Initial and date)
o Intake is equivalent to nutritional requirements Protein: g/day Kcal: __per day Fluids: _ _ _ml.zday (Initial and date)
DATE INITIALS
Continued
_ _ University of Michigan Home Enteral Nutrition
Problem or Need Based on Patient Assesnnent
care Plan-cont'd Goal Outcome Assessment Measurements
Desired Therapeutic Outcome/Goals
Measurement Score Formula-related side effects have not occurred Patient/caregiver understands how to relieve and/or prevent certain side effects Patient/caregiver possesses written information about the purpose and side effects of formula Patient/caregiver understands the • Abdominal fullness and dosage, route, and duration of discomfort formula Patient/caregiver understands the proper storage and administration (] Fluid imbalance, as evidenced by: .I weight loss or gain of ~3 lb for of the formula 2 consecutive days or more .I lower extremity edema .I dry mucous membranes (dry mouth, decreased secretions) DATE .I change in urine output INITIALS (frequency, quantity, and color) Formula provided has the potential to illicit adverse effects in patient inclusive of: • Nausea and vomiting as evidenced by: .I frequency of emesis .I diminished intake
• Constipation • Diarrhea .I no. of stools; baseline of _ _ per day
Minimize infusion device-related problems, and provide accurate efficient delivery of prescribed therapy Method of formula delivery: (] gravity (] syringe (] infusion pump
Measurement Score (] Infusion device will deliver prescribed formula(s) without missed feedings (not >1 mo) in therapy due to device malfunction (] Infusion device will deliver prescribed formula(s) without missed feedings _ per month in therapy due to device malfunction
InterventionfMonitoring Parameters
Modification of Monitoring Patient Based on Reassessment(s) (Initial and Date)
Provide written patient drug/food interaction sheet with initial delivery Evaluate and review patient status for side effect history via feedback from: • patient/caregiver • visiting nurse • physician (] Evaluate nutrient requirements: intake vs. needs, nutrient deficiencies, readiness for oral/enteral feedings at least q 6 months (] Evaluate input/output; thirst, urine output, weight (] Evaluate characteristics and frequency of stool output; no. of stools/day ,., Evaluate gastric residual volumes ~lOO mL for gravity feedings or >2 x the rate for pump feedings Frequency of monitoring will be a minimum of q _ Record goal measurement score a minimum of every: (] patient/caregiver contact (]month o 3 to 4 months o 6 months (] annually Assess proper functioning of infusion device via communication with nurse and/or patient/caregiver throughout therapy Document the number of interruptions in therapy due to device malfunctions
(Initial and date) (] Frequency of monitoring will be a minimum of: q"..-----,---,----,-----,-----
(Initial and date)
q ----------(Initial and date) q -----------(Initial and date)
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_ _ University of Michigan Home Enteral Nutrition care Plan-cont"d Problem or Need Based on Patient Assessment
Desired Therapeutic Outcome/Goals
o Patient possesses an enteral access device for therapy administration Brand o Gastrostomy o PEG o Gastric button o Jejunostomy o Gastrojejunostomy _ ONGorNDjNJ o Other
Goal Outcome Assessment Measurements
Measurement Score Maintain patency and function of access device
N
InterventionjMonitoring Parameters
Modification of Monitoring Patient Based on RelUllleSSlllent(s) (Initial and Date)
o Follow guidelines outlined in
o Increase/decrease frequency of
UMH5-HC HomeMed Enteral Nutrition Manual
Absence of displaced enteral tube Absence of obstructed enteral tube Maintain optimal skin integrity
o Facilitate enteral tube replacement (initial and date)
Evaluate tube for: • Resistance to flush • Displacement • Loss of integrity
o Add use of enteral tube declogger
o Parents/caregivers instructed by
o Increase no. 01 dressing changes,
pediatric surgery/service to replace gastric button device
(initial and date)
flushing (initial and date)
solution (initial and date) (initial and date)
Evaluate for aspiration precautions (initial and date)
DATE INITIALS
o Patient has uncompensated functional limitations that may affect or be affected by services provided
Measurement Score Patient will not miss any doses/therapy due to uncompensated functional limitations
Evaluate for changes in functional status with each patient/caregiver or visiting nurse follow-up
o Functional status has changed, see progress notes (initial and date)
o Visiting nurse/caregiver or other Specify limitations
DATE INITIALS
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Evaluate access site for infection • Erythema or inflammation • Swelling • Tenderness/pain • Temperature >lOO.5°F, orally
o Access device changed
N
will administer TEN therapy
Continued
_ _ University of Michigan Home Enteral Nutrition care Plan-
Patient Assessment
o Potential for noncompliance with therapy as evidenced by suboptimal TEN intake
Desired Therapeutic Outcome/Goals
Goal Outcome Assessment Measurements
Intervention!Monitoring Parameters
Modification of Monitoring Patient Balled on Reassessment(s) (Initial and Date)
Measurement Score Reports following the prescribed health regimen
Monitor TEN usage with each delivery
o Reports modifying the
Consult with nurse/caregiver or patient regarding compliance
regimen as prescribed by health professional
o TEN therapy has changed; see progress notes (Initial and date)
Monitor TEN intake and compare to nutrient requirements (see enteral progress note) DATE INITIALS Potential for infusion-related complications
Monitor weight response
Measurement Score Patient/caregiver will use and dispose of enteral supplies as instructed
Patient/caregiver to be instructed on formula hang time
DATE INITIALS
o Patient is at risk for delayed growth and development (age <16 years) o See disease-specific care plan section
o Will follow own growth curve o Will achieve appropriate developmental milestones DATE INITIALS
o Pain therapy followed by APS o Patient identifies pain or is at risk for development of pain Scale used: 00-10 numeric (> 10 years) o Wong/Baker Faces (3-10 years) o FLACC (3 years) o See disease-specific care plan section
o Pain will not affect o
activities of daily living Pain score will be between and or $ _ DATE INITIALS
Patient/caregiver to be instructed on formula storage
Measurement Score
Patient/caregiver to be instructed on supply utilization o Other Monitor (plot) growth curve and refer as indicated for failure to maintain or achieve goals Monitor age-appropriate developmental milestones and refer as indicated Frequency: o q 3 months Oat 1-2, 4, 6, 9, 12, IS, 18, 24 months of age o every 6 months for <5 years of age o school age and adolescence annually Monitor patient's level of pain Refer patient for pharmacologic pain management as needed Recommend nonpharmacologic pain management options
BMI (age >36 months) Weight-Height (age <36 months) VI
Height for age (all pediatric patients) Weight for age (all pediatric patients)
m
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Measurement score scale: Y = goal met; N = goal not met. D (unchecked box) denotes nonapplicable. ./ (checked box) denotes applicability. APS,Acute Pain Service; BMI, body mass index; FLACC, Faces, Legs, Activity, Cry, Consolability; NO, nasoduodenal; NG, nasogastric; NJ, nasojejunal; NPO, nothing by mouth; PEG, percutaneous endoscopic gastrostromy; SGA, small for gestational age; TEN,total enteral nutrition. From HomeMed, University of Michigan Hospitals and Health Centers.
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344
27 • Enteral Nutrition in the Home
the amount of tube feeding should be reduced by 50%. When oral intake exceeds 75% of estimated needs, the tube feeding can be discontinued. If nutrient intake is sufficient, but fluid intake is not, the feeding tube may remain in place for the purpose of hydration. As caloric intake increases, protein intake should be assessed as well. If the patient is eating a significant amount of calories from nonprotein sources, it may be appropriate to change to a high-protein formula. This will allow the tube feeding to provide less overall calories but adequate protein. It may be beneficial to keep a GT or IT in place for several weeks after the transition to an oral intake in case of a setback. If the feeding tube is not being used, it should be flushed daily with water to maintain patency.
Enteral Feeding Tube Removal Nasoenteric feeding tubes are easily removed by gently pulling the feeding tube out of the nose. There are minimal complications associated with this removal. A GTcan be removed in several ways, depending on the brand of the tube. Some types of GTs are designed to be removed by traction, meaning it is pulled from the outside, allowing the inner bumper to collapse and pass through the stoma. This type of GT removal can be very painful for the patient and may require the use of a local anesthetic to minimize discomfort." Certain types of GTsneed to be removed by an endoscopic procedure, a less favorable approach owing to the cost of needing an endoscopy suite and patient sedation. If the GT has an inner balloon, the balloon is easily deflated with a syringe and the tube is then removed. A more recent approach to removing smaller-bore GTsis the "cut and push" method described by Pearce et aJ.24 The GT is cut close to the level of the skin, and the inner bumper is allowed to pass through the gastrointestinal tract naturally. A concern with this type of removal is obviously the possibility of a bowel obstruction. ITs are often sutured internally and externally. Removal of a IT should be done in the clinic by a qualified professional. Depending on the fixation device, a IT may need to be removed with a guidewire using fluoroscopy. A complication associated with removing a GT or JT is leaking at the stoma site where the feeding tube was removed due to a persistent fistula. A recent study reported that the incidence of pediatric patients requiring surgical closure of the fistula was much greater if a GT had been in place for longer then 11 rnonths.P
CAREGIVER ASPECTS During 1999, it was estimated that more than 50 million people in the United States had provided care for a chronically ill, disabled, or aged family member or friend. 26 In a survey completed by the National Family Caregivers Association, 31% of the respondents spent less than $250 per month and another 31% spent more than $1250 per month for health services that included health care workers, home care equipment, therapists,
day-care service, medication, physician appointments, and community services. One of the types of organizations that caregivers wished to see more of was support groups. Patients receiving HEN and their caregivers are fortunate to have access to the Oley Foundation, which is nearing its 20th anniversary of providing information and emotional support. The Oley Foundation is a national independent, nonprofit organization that provides conferences, publications, regional activities, and emotional support to consumers, their families and caregivers, and professionals. Membership is free to patients receiving HENand their caregivers. The Oley Foundation can be joined by completing the membership form on their Web site (http://www.oley.org) or by calling 1-80Q-776-0LEY. Most of the earlier studies on caregivers focused on the negative aspects of providing care. However, recent research findings have indicated that there are also positive aspects." Negative concepts include caregiver stress, caregiver strain, caregiver burden, and the hassles of caregiving. Positive concepts include the gain in caregiving experience, finding or making meaning through caregiving, caregiver satisfaction, and uplifts of caregiving and caregiver esteem. Positive caregiving was reported in parents of children receiving HEN, who found a new sense of freedom from not having to devote as much time trying to get their child to eat. 28 Families with children with complex heart and liver diseases felt that HEN prolonged their child's life, enabling them to spend more time together and less time in the hospital. In one study caregiver stress was seen in parents of children who were receiving nothing by mouth and required enteral nutrition." Concerns centered on parents being worried about their child getting enough to eat and feeling that their child's eating pattern was hurting his or her physical health. Health care providers often perceive that caregivers experience more anxiety about the medical and physical aspects of tube feeding care than about other issues of caregiving. However, in a study of 24 caregivers of children receiving HEN, 7 of 10 problem situations involved psychosocial and recreational issues.P The two highest ranked problem situations were difficulties finding a qualified babysitter who would give tube feedings to their child and the feeling that the general public is ignorant about tube feedings.
OUTCOMES Studies of outcome in patients receiving HEN are limited. The largest study to date, which included 3931 patients, is the North American Home Parenteral and Enteral Registry.' This Registry collected data on usage and patient outcome during a 7-year period. Only two major disease categories contained enough patients for meaningful analysis: patients with neoplasms and those with neurologic swallowing disorders. Data showed that complications of HEN therapy for these two disease states that resulted in rehospitalization were rare: 0.9 complications per year for those with neurologic disorders and 2.7 complications per year for those with
SECTION IV • Principles of Enteral Nutrition
cancer. For neurologically impaired patients without cancer, the median survival was 1.5years, with 45% mortality. Only 15% were able to resume full oral nutrition, and 75% experienced minimal rehabilitation. Of the patients with cancer, only 25% were able to resume full oral nutrition, and 20% experienced complete rehabilitation. The majority of the patients in this study (75%) were 65 years of age and older. In another study of 417 patients with a mean age of 64 years of age, survival probability at year 1 was 59.2% to 56.3% for patients who were unable to resume oral nutrition as a result of digestive disorders and anorexia but was much lower for patients with dementia (20.4%), acquired immunodeficiency syndrome (8.9%), neurologic disorders (41.4%), and head and neck cancers (36.8%).31 These results raise some very important issues about end-of-life care, the benefit of tube feedings in older adults with specific diagnoses, and the possibility of helping patients and caregivers make better health care decisions. In fact, studies have demonstrated that patients with dementia are not candidates for endoscopic gastrostomy feeding. In a retrospective cohort of 361 patients requiring PEG placement for tube feeding administration, patients were categorized into four groups: oropharyngeal malignancy (either perioperatively or inoperable), acute monohemispheric stroke with dysphasia, dementias, and miscellaneous (head injury, motor neuron disease, multiple sclerosis, Parkinson disease, cerebral palsy, and human immunodeficiency virus infectionj.F The mean age for the groups ranged from 54.8 to 77.1 years of age. Results from the entire cohort demonstrated a high initial mortality of 28% at 30 days, 52% at 6 months, and 65% at 1 year. The group with dementia had a significantly worse overall prognosis with 54% dying at 1 month and 90% at 1 year. Finucane and colleagues'" reviewed the literature to identify whether tube feedings prevented aspiration pneumonia, prolonged survival, reduced the risk of pressure sores or infection, improved function, or provided palliation in patients with advanced dementia. They found no direct data to support the fact that any of these conditions improved with the initiation of tube feeding and recommended changes in oral feedings such as food preparation, reminders to swallow, vibration, and increasing personal assistance. Before initiation of home enteral therapy in patients with these diagnoses, communication with the patient's caregiver should take place to establish a clear understanding of the risks, benefits, and patient wishes as set forth in an advance directives document. Studies done in children have shown positive benefits with HEN. In a study done in 14 patients with cystic fibrosis receiving supplemental feedings, body weight increased by 6 kg and weight for height increased by 9% 1 year after initiation of HEN.34 Perhaps more promising was the finding that lung function improved significantly as measured by vital capacity and forced expiratory volume in 1second (FEV1) values of 8.2%and 3.9%, respectively. Kang and associates" studied catch-up growth in 78 children with a median age of 20 months. Children had a variety of diagnosis and were further classified into
345
appropriate growth, wasted, and stunted growth groups according to anthropometric data (z scores) at the time of entry into their HEN tube feeding program. In the appropriate growth group, 50% experienced catch-up growth for weight and 33% for height. Of the patients in the wasted group, 92% improved their weight percentile and 75% their height percentile. Catch-up growth for height was experienced in 71% of those in the stunted growth group for weight and 74% for height. Throughout this study, adjustments in tube feeding regimens were made according to growth increases, and patients with more severe malnourishment and stunting were seen weekly to monthly by a pediatric dietitian. This intensive follow-up may have created a more positive impact on growth and complications of tube feeding. In a smaller study of 25 children with cancer, gastrostomy tubes were placed a mean of 3.5 months after diagnosis in patients with a mean weight loss of 10.1 % of desired weight." Weight gain averaged 12.9% of desired weight with all children either gaining or maintaining weight. In the severely malnourished group, 60% of the children returned to their desired body weight after an average of 4.9 months of therapy.
QUALITY OF LIFE Two studies have examined quality of life in patients with head and neck cancer who received only HEN. Roberge and colleagues" administered the European Organization of Research and Treatment of Cancer (EORTC) QLQ-C30 and H&N35 questionnaires that focus on function and symptom scales on days 7 and 30 of therapy in 39 patients. On day 7, physical scales of psychosocial and role functioning had the lowest scores. Symptoms with low impact included nausea/ vomiting, constipation, diarrhea, and financial difficulties. Intermediate impact symptoms were dyspnea, insomnia, appetite loss, and pain. The symptom with the highest reported impact was fatigue. At day 28, functional scores remained unchanged or slightly improved. Symptoms for which scores significantly improved were constipation, coughing, social function, speech, and body image/sexuality. However, no definite conclusions can be drawn from these results because only 5 patients were still receiving HEN at 28 days. In the second study, 33 patients who were receiving tube feedings via a PEG or nasogastric (NG) tube were given a quality of life questionnaire," Fifteen patients were in the NG group and 18 in the PEG group. Those in the PEG group reported greater mobility, cosmesis, and improved quality of life than those in the NG group. However, it is unclear at which point in their therapy the patients completed the questionnaire. In a study of patients with a variety of diagnoses, Reddy and Malone- administered a questionnaire on the impact of HEN therapy to patients older than 18 years of age. 2 Patients reported impacts on sleep, travel, exercise, leisure, and social life. Clearly, more studies on quality of life are needed with comparison groups, a wider range of diagnoses, and larger sample sizes.
346
27 • Enteral Nutrition in the Home
CONCLUSION Provision of enteral nutrition in the home can be a costeffective method of maintaining nutritional status in patients who are unable to eat orally. Although HEN may seem challenging to patients and caregivers initially, if adequate training and monitoring are provided, it can be a life-improving therapy. REFERENCES 1. Howard L, Ament M, Fleming CR, et al: Current use and clinical outcome of home parenteral and enteral nutrition therapies in the United States. Gastroenterology 1995;109:355-365. 2. Reddy P, Malone M: Cost and outcome analysis of home parenteral and enteral nutrition. JPENJ Parenter Enteral Nutr 1998;22:302-310. 3. Centers for Medicare & Medicaid Services: Available at http://cms.hhs.gov/medicare. Accessed March 3, 2003. 4. A.S.P.E.N. Board of Directors: Standards for home nutrition support. Nutr Clin Pract 1999;14:151-162. 5. Delegge MH: Home enteral nutrition. JPEN J Parenter Enteral Nutr 2002;25(5 suppl):S4-S7. 6. Silver HJ, Wellman NS: Family caregiver training is needed to improve outcomes for older adults using home care technologies. J Am Diet Assoc 2002;102:831-836. 7. McNamara EP, Flood P, Kennedy NP: Home tube feeding: An integrated multidisciplinary approach. J Hum Nutr Dietet 2001;14: 13-19. 8. Magne N, Marcy PY, Foa C, et al: Comparison between nasogastric tube feeding and percutaneous fluoroscopic gastrostomy in advanced head and neck cancer patients. Eur Arch Otorhinolaryngol 2001;258:89-92. 9. Methany NA,Tiller MG: Assessing placement of feeding tubes. Am J Nutr 2001;101:36-45. 10. Bowers S: All about tubes. Your guide to enteral feeding devices. Nursing 2000;30:41-47. 11. Schattner M, Barrera R, Nygard S, et al: Outcome of home enteral nutrition in patients with malignant dysphasia. Nutr Clin Pract 2001;26:292-295. 12. Shang E, Geiger N, Sturm JW, et al: Pump-assisted versus gravitycontrolled enteral nutrition in long-term percutaneous endoscopic gastrostomy patients: A prospective controlled trial. JPEN J Parenter Enteral Nutr 2003;27:216-219. 13. Brennan-Behm M, Carlson GE, Meier P, et al: Caloric loss from expressed mother's milk during continuous gavage infusion. Neonatal Network 1994;13:27-32. 14. Colagiovanni L: Preventing and clearing blocked feeding tubes. Nurs Times 2000;96:3-4. 15. Loser C, Wolters S, Folsch UR: Enteral long-term nutrition via percutaneous endoscopic gastrostomy (PEG) in 210 patients. Dig Dis Sci 1998;43:2549-2557. 16. Hull MA, Rawlings J, Murray FE, et al: Audit of outcome of longterm enteral nutrition by percutaneous endoscopic gastrostomy. Lancet 1993;341:869-871.
17. Kohn-Keeth C: How to keep feeding tubes flowing freely. Nursing 2000;30:58--59. 18. Marcuard SP, Stegall KS: Unclogging feeding tubes with pancreatic enzyme. JPEN J Parenter Enteral Nutr 1990;14:198--200. 19. Aquino VM, Smyrl CB, Hagg R, et al: Enteral nutritional support by gastrostomy tube in children with cancer. J Pediatr 1995;127: 58--62. 20. Kang A, Zamora A, Scott B, et al: Catch-up growth in children treated with home enteral nutrition. Pediatrics 1998;102:951-955. 21. Colomb V, Goulet 0, Ricour C: Home enteral and parenteral nutrition in children. Bailliere's Clin Gastroenterol 1998;12: 877-893. 22. A.S.P.E.N. Board of Directors: Clinical pathways and algorithms for delivery of parenteral and enteral nutrition support in adults. Rockville,MD, American Society for Parenteral and Enteral Nutrition, 1998, pp 2-17. 23. Duerkesen DR: Removal of traction-removable gastrostomy tubes with local anesthetic. Gastrointest Endosc 2001;54:420. 24. Pearce CB, Goggin PM, Collett J, et al: The "cut and push" method of percutaneous endoscopic gastrostomy tube removal. Clin Nutr 2000;19:133-135. 25. Kobak GE, McClenathan DT,Schurman SJ: Complication of removing percutaneous endoscopic gastrostomy tubes in children. J Pediatr Gastroenterol Nutr 2000;30:404-407. 26. National Caregivers Association: Family caregiving statistics. Available at http://www.nfcacares.org. Accessed May 12, 2003. 27. Hunt CK: Concepts in caregiver research. J Nurs Scholarsh 2003;35:27-32. 28. Holden CE, Puntis JWL, Charlton CPL, et al: Nasogastric feeding at home: Acceptability and safety. Arch Dis Child 1991;66: 148--151. 29. Burlow KA, McGrathe AM, Allred KE, et al: Parent perceptions of mealtime behaviors in children fed enterally. Nutr Clin Pract 2002;12:291-295. 30. Michaelis CA,Warzak WJ, Stanek K, et al: Parental and professional perceptions of problems associated with long-term pediatric home tube feeding. J Am Dietet Assoc 1992;92:1235-1238. 31. Schneider SM, Raina C, Pugliese P, et al: Outcome of patients treated with home enteral nutrition. JPEN J Parenter Enteral Nutr 2001;25:203-209. 32. Sanders DS, Carter MJ, D'Silva J, et al: Survival analysis in percutaneous endoscopic gastrostomy feeding: A worse outcome in patients with dementia. Am J Gastroenterol 2000;95: 1472-1475. 33. Finucane TE, Christmas C, Travis K: Tube feeding in patients with advanced dementia: A review of the evidence. JAMA 1999;282: 1365-1370. 34. Steinkamp G, von der Hardt H: Improvement of nutritional status and lung function after long-term nocturnal gastrostomy feedings in cystic fibrosis. J Pediatr 1994;124:244-249. 35. Roberge C, Tran M, Massoud C, et al: Quality of life and home enteral tube feeding: A French prospective study in patients with head and neck or oesophageal cancer. Br J Cancer 2000;82: 263-269. 36. Rowe HA, Carson S, Sullivan K, Stalo K: Home Enteral Nutrition Manual, University of Michigan, 2003, pp 1-37.
Enteral Nutrition after Severe Burn Kenneth 1. Woodside, MD Steven E. Wolf, MD
suffered from weight losses of more than 30% from hypermetabolism, probably leading to increased mortality in patients with larger burns. 1 Over the last three decades, a better appreciation of the type of nutritional support required and advances in blunting the hypermetabolic response, coupled with improvements in critical care and antibiotic use, have resulted in improved survival and outcomes (Table 28-1).
CHAPTER OUTLINE Introduction Pathophysiology Initial Nutritional Assessment Management Metabolic Modulation Complications Conclusion
PATHOPHYSIOLOGY
INTRODUCTION Severe burn (>40% total body surface area [TBSA]) results in a unique prolonged hypermetabolic response. Conceptually, this response served an evolutionary purpose. Aftersevere burn, the likelihood of survivalwas low; only with a massive and rapid mobilization of endogenous nutritional resources was survival possible. Before the availability of modern burn units, this profound catabolic state would result in survival or death decisively over a relatively short time. However, with the ability to provide medical support for burn victims, the hypermetabolic response persists beyond its acute practicality into the chronic phase. Before the introduction of continuous enteral nutritional support, burn patients often
BmIlD
After severe burn and resuscitation, numerous physiologic changes result in a profound catabolic state. Like most critically ill patients, those with severe burns exhibit a blunted or absent circadian rhythm for most hormonal axes. 2- 5 Muscle catabolism and glucose mobilization dramatically increase." Predictive variables for increased catabolism include subject weight, burn size, time from injury to excisional treatment, resting energy expenditure, fever, and sepsis.P In addition, age, male sex, height, and serum creatinine level (independent of renal failure) correlate with the degree of catabolism." This catabolic state persists for at least 9 months after injury, with eventual improvements in protein breakdown and lean body mass (Figs. 28-1 and 28-2).9-11 The prolonged nature of the hypermetabolic and catabolic response causes depletion of nutritional reserves and reduced lean body mass, probably resulting in increased infection rates and delays in wound healing. 12-14
Burn Monallty LDso for Age Groups (years)*
Bull and Fisher (1942-1952) Bull (1967-1970) Curreri and Abston (1975-1979) SBljUTMB (1980-1997)
N
0-14 yr
15-44 yr
45-64 yr
-es w
2807 1922 1508 2164
49 64
46 56 63 70
27 40 38 46
IO 17 23 19
77 98
'Numbers are the %TBSA bum at which 50% of patients would be expected to die.
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28 • Enteral Nutrition after Severe Burn
Time after injury FIGURE 28-1. Resting energy expenditure after burn by indirect calorimetry (mean ± 95%confidence intervals). At all time points, the energy expenditure was higher than the predicted basal metabolic rate for age-, sex-, weight-, and height-matched individuals by the Harris-Benedict equation. (From Hart OW, Wolf SE, Mlcak R, et al: Persistence of muscle catabolism after severe burn. Surgery 2000; 128:312-319.)
The catabolic effect on muscle protein results from simultaneous stimulation of protein synthesis and protein breakdown. However, protein breakdown occurs at a greater rate, as compensatory synthesis fails.15•16 This muscle breakdown results in a net amino acid efflux and a negative nitrogen balance. In addition, it is not caused by the prolonged bed rest associated with burn" and is not abrogated by additional nutritional support with protein and amino acid supplements several times higher than baseline requirements." The pain and fear associated with the injury activate the limbic system directly. The thermoregulatory set point
FIGURE 28-2. Serial lean body mass measurements by whole body dual energy X-ray absorptiometry (OEXA) scan (mean ± SEM, -» « 0.05 vs. baseline, tp< 0.01 vs. 9-month value). There is a loss of muscle from the time of full healing until 9 months after burn. (From Hart OW, Wolf SE, Mlcak R, et al: Persistence of muscle catabolism after severe burn. Surgery 2000; 128: 312-319.)
is raised by the hypothalamus, resulting in hyperthermia." As attempts are made to reach the higher set point, energy expenditure increases as shivering and futile substrate cycling are up-regulated for the production of heat. 8•9•2o Futile substrate cycling is initiated by simultaneous activation of opposing nonequilibrium reactions." Substrate is metabolized to produce high-energy phosphate bonds, which are then broken to resynthesize the substrate. Although there is no net increase or decrease in substrate, there is increased generation of heat. For example, the Cori cycle is up-regulated after a burn. 22 Lactate and pyruvate are produced from glucose in the periphery. These substrates are, in turn, converted back to glucose by hepatic gluconeogenesis. Gluconeogenic amino acids such as alanine and glutamine undergo similar cycling. As in many disease states, the inflammatory response results in systemic alterations in normal physiology. Systemic levels of interleukin (IL)-l~, IL-6, tumor necrosis factor-a. (TNF-a), and other cytokines and prostaglandins result in a proinflammatory envtronment.P:" further driving the metabolic response. These responses combine with neural stimulation and cause release of systemic catabolic hormones, with increased glucagon, 2-to l(}'fold increases in catecholamines and 1Ofold increases in cortisol.t-" The resulting hyperglycemia further actuates muscle protein catabolism (Fig. 28-3).31 When given to normal volunteers, these three hormones produce a similar hypermetabolic response, with similar nitrogen loss and hyperglycemia.F However, proteolysis and acutephase protein production are only elicited by concomitant inflammation.P Catecholamine levels remain high until completion of wound closure. Atthat time, metabolic control shifts from the thyroid axis to the sympathoadrenal axis. Glucagon remains elevated, whereas thyroid
FIGURE 28-3. Increased negative net phenylalanine (Phe) balance, reflecting net catabolism, with severe hyperglycemia (mean ± SO, *p < 0.05 vs, normal). (From Gore DC, Chinkes OL, Hart OW, et al: Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients. Crit Care Med 2002;30: 2438-2442.)
SECTION V • Disease Specific
hormone prevalence shifts from the active to inactive forms. Gluconeogenesis requires glycerol-based substrate, which is provided by degraded triglycerides and amino acids. Because most of the protein available to supply amino acids is in the active musculature, there is a resulting loss of lean body mass.7,12 Lactate and alanine, intermediates of these processes, are released in proportion to the extent of injury." Stores of muscle glutamine, the most prevalent amino acid in muscle, are rapidly depleted to one half of the baseline level." In addition, there is disproportionate muscle release of phenylalanine." Lipid metabolism is also altered. Lipolysis increases after burn, probably in response to circulating catecholarnines," resulting in elevated serum free fatty acid and glycerol levels. Ketogenesis is decreased." resulting in further increased requirements for gluconeogenesis. Free fatty acids are taken up in the liver for re-esterification and transport back to the periphery in chylomicrons. After severe burn, transport of triglycerides out of the liver is hampered by inefficient construction of chylomicrons, leading to fatty liver development regardless of the feedings given. 2-5 In addition to changes in lean body mass, these inflammatory and metabolic derangements result in alterations in gut integrity and immune competence. Severe bum results in rapidly decreased gut barrier function that is independent of gut hypoperfusion, with improvements seen by I day after injury.38-40 This decreased barrier function has been associated with increased bacterial translocation in animal models,41-43 probably resulting in increased bacterial infection. Because bacterial infection, either alone or in the presence of a bum, is associated with decreased T-cell function in intestinal Peyer's patches, an integral portion of the barrier defense." With bum, there is increased apoptosis of intraepithelial lymphocytes, Peyer's patch lymphocytes, B cells, and cytotoxic T cells (Fig. 28-4).45-48 Because intestinallymphocytes are probably involved in regulation of intestinal epithelium turnover.P"! there is further stress on the intestinal barrier, in addition to the probable decrease in
immune competence. With increased TNF-a production, fever, and risk of sepsis in response to increased bacterial translocation, there is a predicted increase in catabolism and hypermetabolism. 7•8,26-29,52 Furthermore, there is a shift toward an overall T-helper type 2 cell immune response,53-55 resulting in a less productive immune response and additional increased risk of sepsis.
INITIAL NUTRITIONAL ASSESSMENT Total energy expenditure (TEE) dramatically increases with the hypermetabolic response to burn." The total systemic energy expenditure has been correlated with the degree of muscle catabolism.P? TEEcan be measured using stable isotopic techniques. 58,59 Using doubly labeled water (2H 20 and H2180 ) , labeled hydrogen indicates the kinetics of water flux alone, whereas labeled oxygen indicates water flux and carbon dioxide flux during equilibration with free hydrogen ions through carbonic anhydrase. Differences in urine production and expired carbon dioxide over a prolonged period give an estimate of total carbon dioxide production. Because these measurements are made over time, they include more circadian variations. Although TEEis impractical to determine in a critically ill patient, resting energy expenditure (REE) provides an accurate indicator of TEE. REE is obtained at the bedside using indirect calorimetry; specifically, it is determined by measuring oxygen consumption and carbon dioxide production from inspired and expired gases. REE measurement occurs over a short period; thus, a steady state is assumed and it is best used in continuously fed patients. Because REE determination is noninvasive, reproducible, rapid, and quantifiable, it is used in the nutritional management of the critically ill bum patient when available. Although actual measurements are ideal, metabolic carts are expensive to maintain and may not always be available. By using the Harris-Benedict equation." REE can be estimated. Sex and total body surface area are used as independent variables to determine predicted
FIGURE 28-4. Increased apoptosis by transferase-mediated deoxyuridine triphosphate nick end labeling staining in murine Peyer's patches (x400) after 30% TBSA burn (A) compared with sham burn (8). (From Woodside KJ, Spies M, Wu XW, et al: Decreased lymphocyte apoptosls by anti-tumor necrosis factor antibody in Peyer's patches followinq severe burn. Shock 2003;
20:70-73.)
351
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28 • Enteral Nutrition after Severe Burn
basal energy expenditure (PBEE). With bum, there are the additional independent variables of TBSA burned and time after bum. 59 The TEEof 95% of burned children can be estimated with the resulting equation: Adult caloric requirements = (1.55 x PBEE) + (2.39 x PBEEo.75) For most bums of greater than 40% TBSA, TEE will approximate 2 x PBEE. Numerous other formulas have been developed to correct for inaccuracies in Harris-Benedict-derived equations. Although these formulas can be useful, the dynamic nature of the critically ill metabolic state requires actual measurement for optimal care. The classic and most widely utilized equation, the Curreri formula, is based on size and TBSA bumed.60,61 There is an additional correction for elderly patients: Adult caloric requirements = 25 kcal/kg + 40 kcal/%TBSA burned Elderly caloric requirements = 20 kcal/kg + 40 kcal/%TBSA burned The original Curreri formula was based on a retrospective analysis of nine patients observed over 20 days during the era of delayed excision and probably overestimates caloric requirements. Because children have greater body surface area (BSA) per kilogram, formulas based on BSA (square meters) are more appropriate for this age group. Many pediatric bum centers use the Galveston formulas.62-&l These formulas were devised retrospectively and are based on the daily amount of calories required to maintain total body weight during acute hospitalization. These formulas, which correct for the decreasing BSA per kilogram ratio with pediatric age, are as follows: Infant (0 to 1 year) caloric requirements = 2100 kcal/TBSA + 1000 kcal/TBSA burned Child (1 to 12 years) caloric requirements = 1800 kcal/TBSA + 1300 kcal/TBSA burned Adolescent (12 to 18 years) caloric requirements = 1500 kcal/TBSA + 1500 kcal/TBSA burned Again, although these formulas provide good guidelines, measured REE could be used to accommodate the dynamic nature of the critically ill state. Because recent evidence suggests that caloric delivery beyond 1.2x REE results in increased fat mass without changes in lean body mass (Fig. 28-5),65 theoretical caloric requirements based on these formulas may be modified for the clinical condition.
MANAGEMENT For patients with severe bums, oral intake is inadequate and is usually supplemented by enteral feeding or parenteral nutrition. Enteral feeding via transpyloric tubes should be initiated early during hospitalization, preferably during resuscitation. Early feeding is associated with a
FIGURE 28-5. Linear correlation between fat mass and lean body mass with caloric delivery indexed to measured REE. Increasing caloric delivery relative to REE increased fat accretion without effects on lean body mass. (From Hart DW, Wolf SE, Herndon DN, et al: Energy expenditure and caloric balance after burn: increased feeding leads to fat rather than lean mass accretion. Ann Surg 2002;235:152-161.)
decrease in the hypermetabolic response" and probably prevents bum-induced ileus.67 If placement of a transpyloric tube is difficult, gastric feedings can be performed, with careful attention paid to gastric residual volumes. With transpyloric placement of the feeding tube, gastric erosions can be prevented with a low basal level of gastric feedings. Feeding intolerance, especially in patients with transpyloric tubes, can be an ominous sign and has been associated with increased septic morbidity and mortality.68,69 As in many disease states, gastrointestinal feeding should be used in bum patients, with total parenteral nutrition being reserved for patients who absolutely cannot tolerate enteral feedings. Total parenteral nutrition, given via a central line, is associated with increased morbidity and mortality in bum patients (Fig. 28-6).7°,71 The ideal dietary composition of nutritional supplementation has been a topic of intensive investigation. One half of the caloric content of most commercially available enteral formulations is supplied as fat, and up to one third of the caloric content of total parenteral nutrition is often provided by lipid. There may be benefits for such formulations in certain patient populations, such as patients dependent on mechanical ventilation in whom excessive endogenous carbon dioxide production can be detrimental. Fats also have more than twice the caloric density of carbohydrates and protein. However, lipid administration is associated with increased infection rates, hyperlipidemia, hypoxemia, and postoperative mortality." In addition, high-fat diets are associated with whole body proteolysis with net fat gain." Because the goal of metabolic support of bum patients is to preserve or restore lean body mass, lipid-rich formulations are probably best avoided. In fact, recent evidence suggests that carbohydrate-rich diets are superior for the hypermetabolic response associated with bums, possibly because they drive endogenous insulin production."
SECTION V • Disease Specific
FIGURE 28-6. Increased mortality with total parenteral nutrition (TPN). Patients receiving enteral diets have lower mortality compared with those receiving parenteral diets. (From Herndon ON, Barrow RE, Stein M, et al: Increased mortality with intravenous supplemental feeding in severely burned patients. J Burn Care Rehabil 1989; 10:309.)
[n the 1970s, several studies demonstrated that urinary nitrogen excretion was inversely proportional to carbohydrate intake in patients receiving isonitrogenous dietary intake. Several studies originating at the U.S. Army Institute for Surgical Research explored the relationship between carbohydrate intake and nitrogen excretion.P'" They found that there was a progressive decrease in nitrogen excretion with increased enteral or parenteral carbohydrate intake (range 0 to 2300 kcal of
FIGURE 28-7. Model calculations of protein synthesis, protein breakdown, and net balancein patients receiving high-fat versus high-carbohydrate diets (mean ± SEM, *P < 0.05, tp < 0.01). Muscle protein degradation decreases and protein synthesis is unaltered in patients receiving a high-carbohydrate diet, resulting in improved net protein balance. (From Hart OW, Wolf SE, Zhang Xl, et al: Efficacy of a high-carbohydrate diet in catabolic illness. Crit Care Med 2001 ;29: 1318-1 324.)
353
carbohydrate/rrr' BSAlday). These effects were found in patients with high and mild hypermetabolism, as well as in patients with and without bacteremia. They did not find an association between fat intake and catabolism. However, they did note a correlation between increased carbohydrate intake and plasma insulin concentrations. Furthermore, they noted that the small number of subjects who were receiving carbohydrate feedings and who required exogenous insulin for clinical hyperglycemia demonstrated decreased protein catabolism." As for any critically ill patient, essential fatty acids must be adequately supplied. In a study of pediatric bum patients (>40% TBSA) receiving either Vivonex TEN (15% protein, 82% carbohydrate, and 3% fat) or a Vivonex-based high-fat formulation (14% protein, 42% carbohydrate, and 44% fat), we recently demonstrated an improvement in the net balance of skeletal muscle protein with the high carbohydrate formulation (approximately 1700 kcal of carbohydrate/m- BSAlday) compared with the high-fat formulation (approximately 1000kcal of carbohydrate/rtf BSAlday).74 Specifically, muscle protein degradation decreased and protein synthesis was unaltered in patients receiving the high-carbohydrate diet (Fig. 28-7). In addition, endogenous insulin concentrations increased with high-carbohydrate feeding (Fig. 28-8). Insulin is thought to be a protein-sparing anabolic hormone during severe illnessl5,78,79 and is a likely candidate for the improvements seen in these patients. Furthermore, hyperglycemia has been associated with increased muscle
FIGURE 28-8. Alterations in endogenous insulin levels with dietary manipulations (mean ± SEM, *P= 0.01). Subjects initially consuming high-carbohydrate diets had higher plasma concentrations of insulin than those consuming the high-fat diets. (From Hart OW, Wolf SE, Zhang XI, et al: Efficacy of a highcarbohydrate diet in catabolic illness. Crit Care Med 2001 ;29:
1318-1324.)
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28 • Enteral Nutrition after Severe Burn
protein catabolism in severely burned patients" and should be treated appropriately with exogenous insulin. Protein content in enteral feeding is important. The optimal dietary formula will provide 1 to 2 g/kg/day of protein,80,81 which corresponds to a calorie-to-nitrogen ratio of approximately 100:1. Higher levels of protein may be required in infants who have greater renal losses. Recent evidence in normal volunteers suggests that exogenous amino acids may enhance muscle protein synthesis.f suggesting a possible role for higher protein intakes in bum patients in the presence of adequate calories. As for any patient, essential amino acids must be appropriately supplied. Glutamine is of particular importance. Because glutamine is a preferred nutrient source for both lymphocytes and enterocytes,83,84 glutamine deficiencies may result in increased translocation and infection rates. Bum significantly depletes muscle stores of glutamine." In fact, exogenous glutamine has been shown in mice to decrease gut-derived bacterial translocation and improve survival after bum injury.86,87 Glutamine has been shown to reduce Gram-negative bacteremic episodes in bum patients" and to reduce septic episodes in multiple-trauma patients." Its effects on postbum hypermetabolism are not well described. Although not an essential amino acid, arginine may be important after bum injury. Arginine is associated with improved immune function 90,91 and wound healing. 92 Trials in bum patients are lacking; however, burned rats fed an arginine-enhanced diet have improved survival and decreased production of the proinflammatory cytokines interferon-y and TNF-a.93 Other amino acids have been evaluated for use in bum patients. Although the use of branched-chain amino acids (leucine, isoleucine, and valine) has shown some promise in selected subsets of critically ill patients, no significant improvements in outcome, protein synthesis, or immune function in burned animal experiments or bum patient trials have been demonstratedP'-" The exact nutritional formula used varies among bum centers. There are numerous commercial formulas available, some with purported immune-enhancing properties. An elemental formulation (e.g., Vivonex TEN) can be used for most patients receiving enteral nutrition by feeding tube. We also encourage milk and carbohydrate-supplemen ted fruit juices for those taking liquids or food orally. Vitamin supplementation is recommended by most bum centers." Vitamin C, a required vitamin for collagen cross-linking, has been demonstrated to decrease resuscitation requirements and inhibit wound conversion from partial thickness to full thickness," probably through antioxidant effects. Vitamin A, an important cofactor for collagen synthesis and maturation as well as for T-cell function, is often depleted after bum injury.98,99 Although vitamin C toxicity is rare, vitamin A toxicity can occur. In addition, the B vitamins increase skin strength and fibroblastic content in scar tissue. 98,99 Vitamin D deficiency can also be problematic and may cause abnormal bone metabollsm.'?' Supplementation of zinc and selenium is also important. Zinc is depleted after bum, probably by urinary
zinc loss and tissue redistribution. 101 Zinc deficiencies result in impairment of wound reepithelialization and decrease wound strength.l'" Selenium, a mineral that is important in all critically ill patients, is required for glutathione peroxidase activity. Unfortunately, selenium is diminished with the use of the topical silver preparations used after burn.l'" Monitoring the evolving nutritional status of bum patients can be somewhat problematic, because the dynamic and severe nature of the physiologic shifts that occur after injury make interpretation of the results difficult. Although the weight of the bum patient should be determined daily, it may be of little use in patients prone to fluid shifts and insensible losses. Nitrogen balance calculations are prone to error. Many centers use albumin for colloid replacement, making measurements useless. Even prealbumin is of uncertain value for nutritional assessment after bum. Determination of REE with a metabolic cart to assess nutritional requirements may not measure actual nutritional status, but probably remains the most clinically useful assessment of metabolic need.
METABOLIC MODULATION Although support of hypermetabolism may provide adequate caloric and protein intake, proteolysis and hypermetabolism persist. 18,73 This catabolic response may have had evolutionary advantages when humans had to recover quickly or die; however, long-term persistence of hypermetabolism in the presence of modem bum care is clearly detrimental. Because of the debilitating effects of this catabolic state, there has been intensive investigation on methods to modulate this response. Certain management techniques may reduce catabolism. Patients in rooms with lower ambient temperatures demonstrate increased energy expenditure (Fig. 28-9),9,20 as do patients with high fevers (=40°C),8 suggesting a significant metabolic benefit from temperature management.
FIGURE 28-9. Response to ambient temperature regulation. Increases in the environmental temperature decrease the metabolic needs for heat production as measured by oxygen consumption. (From Herndon ON. Mediators of metabolism. J Trauma 1981;21(8 suppl):701-70S.)
SECTION V • Disease Specific
355
FIGURE 28-10. Burn patients treated conservatively had higher serum levels of C-reactive protein (A) and C3 (8) compared with patients having early burn wound excision (mean ± SEM, *P < 0.05). (From BarretJP, Herndon DN: Modulation of inflammatory and catabolic responses in severely burned children by early burn wound excision in the first 24 hours. Arch Surg 2003; 138:127-132.)
FIGURE 28-11. Burn patients treated conservatively had higher serum levels of interleukin-6 (A) and tumor necrosis factor-a. (8) compared with patients haVing early burn wound excision (mean ± SEM, *P < 0.05). (From BarretJP, Herndon DN: Modulation of inflammatory and catabolic responses in severely burned children by early burn wound excision in the first 24 hours. Arch Surg 2003; 138: 127-132.)
Early excision and grafting of the burn scar does not further increase metabolism; in fact, early excision may partially abrogate the natural development of the hypermetabolic response and partially modulate the inflammatory response compared with patients with delayed or nonoperative management (Figs. 28-10 and 28-11).104 Patients who undergo delayed grafting have higher incidences of wound contamination, invasive wound infections, and sepsis (Figs. 28-12 and 28-13),105 which may be responsible for the higher metabolic needs of this patient subset. In addition, hyperglycemia has been associated with increased muscle protein catabolism31,106 and infection rates.l'" suggesting a role for aggressive glucose management. The hypermetabolic response to massive burn is characterized by accelerated protein breakdown without adequate compensatory synthesis.l'v" which results in a net efflux of protein in the form of amino acids from the muscle (Fig. 28-14). Pharmacologic alteration of the hypermetabolic response theoretically can alter the reduction in muscle protein content by decreasing the net efflux of amino acids from the muscle cells. Current agents under investigation can be divided
FIGURE 28-12. Percentage of patients with wound contamination or invasive wound infection. The incidence of significant wound contamination and invasive wound infection was significantly increased in patients with delayed burn wound excision (*P < 0.01 and *p < 0.05 between day 0 to 2 and day 3 to 6 groups; tp< 0.01 and §P< 0.05 between day 0 to 2 and day 7 to 14 groups). (From Xiao-Wu W, Herndon DN, Spies M, et al: Effects of delayed wound excision and grafting in severely burned children. Arch Surg 2002; 137: 1049-1 054.)
356
28 • Enteral Nutrition after Severe Burn
(
p~einJ Muscle Cell Amino Acids
Proposed Principle Defect
Blood FIGURE 28-13. Percentage of patients with sepsis as a function of time to burn wound excision. The incidence of sepsis was significantly increased in patients from both the day 3 to 6 group and day 7 to 14 group (P< 0.05). The difference was not significant between the day 3 to 6 group and day 7 to 14 group. (From Xiao-Wu W, Herndon ON, Spies M, et al: Effects of delayed wound excision and grafting in severely burned children. Arch Surg 2002;137:1049-1054.)
FIGURE 28-14. The effects of hypermetabolism on the muscle cell. Protein breakdown is increased relative to protein synthesis, resulting in a net efflux of amino acids from the muscle. Pharmacologic manipulation may block this efflux and allow reutilization of amino acids for protein synthesis.
FIGURE 28-1 5. Lean body mass changes measured by OEXA scan in patients receiving growth hormone versus control subjects (mean ± SEM, * P < 0.01). (From Hart OW, Herndon ON, Klein G, et al: Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Ann Surg 2001 ;233:827-834.)
FIGURE 28-16. Bone mineral content changes measured by OEXA scan in patients receiving growth hormone versus control subjects (mean ± SEM, * P < 0.0 I, t P 0.06). (From Hart OW, Herndon ON, Klein G, et al: Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Ann Surg 2001 ;233:827-834.) 0=
SECTION V • Disease Specific
357
into three classes of anabolic hormones'P: growth factors, anabolic steroids, and catabolic hormone antagonists. The most common growth factors used in burn care are growth hormone, insulin-like growth factor-I (IGF-I) , and insulin. Recombinant human growth hormone (rhGH) accelerates the rate of donor site healing and thereby reduces length of stay,109.11O reduces albumin and calcium supplementation requirements.'!' partially reverses nitrogen wasting!" and abates muscle catabolism and osteopenia (Figs. 28-15 and 28-16).113 In addition, it may have some beneficial effects on the cellular immune system. 114,115 However, there have been conflicting reports about the effects of rhGH on mortality in critically ill and burn patients. I I I,116,1I7 Many of the effects of rhGH are mediated by the IGF-I pathway. In fact, rhGH increases serum levels of IGF-I and its carrier protein, IGF binding protein-3 (IGFBP-3), in burn patients (Figs. 28-17 and 28-18),118 suggesting that IGF-I is a possible alternative to rhGH. IGF-I is a small polypeptide that is structurally similar to insulin.l" In circulation, it is bound by one of six binding proteins, with IGFBP-3 binding the majority of IGF_1. 12G-122 Although IGF-I improves protein oxidation,123 administration of IGF-1 alone is associated with hypoglycemia and peripheral neuropathies. However, it can be administered as the IGF-I-IGFBP-3 complex, which reduces the incidence of hypoglycemia and decreases its serum clearance.P' When given as a complex, IGF-I-IGFBP-3 stimulates net protein synthesis after burn,125,126 by increasing the efficiency of amino acid utilization within the muscle cell and thereby
improving net protein balance. Furthermore, IGFI-IGFBP-3 reduces the hepatic acute-phase response and 1L-6 production while increasing constitutive serum protein levels such as those of prealbumin, transferring protein, and retinol-binding protein."? It may also partially reverse the immunologic shift from cellular to humoral immunity that occurs after burn.P' Unfortunately, whereas IGF-I-IGFBP-3 therapy showed some promise, the drug has not been introduced to the marketplace. Insulin itself has several advantages. It is inexpensive, readily available, and easy to administer. Treatment with a basal rate of insulin despite adequate blood glucose levels has been termed euglycemic hyperinsulinemia and may require supplemental glucose to avoid hypoglycemia. High-dose insulin infusions (6 IlUlkg/min) have been shown to increase both protein synthesis and breakdown in muscle cells, with a greater effect on synthesis. There was also increased inward transport of amino acids. These changes resulted in significant anabolic improvements in net protein balance.!" Lower doses of insulin still improve net protein synthesis, as well as lean body mass and bone mass, but do not have the additional effect on inward amino acid transport (Fig. 28-19).78,129 Testosterone and oxandrolone are the two primary anabolic steroids in clinical use for burns. Both are inexpensive and may be given orally. Testosterone enanthate has been shown to increase protein synthetic efficiency twofold and decrease protein breakdown twofold in male adult burn patients, resulting in an improved net amino acid balance nearing equilibrium
FIGURE 28-17. Serum concentrations of IGF-I in burn patients receiving growth hormone (GH) versus placebo at baseline and when fully healed (mean ± SO, *P < 0.02 vs. placebo). (From Klein GL, Wolf SE, Langman CB, et al: Effects of therapy with recombinant human growth hormone on insulin-like growth factor system components and serum levels of biochemical markers of bone formation in children after severe burn injury. J Clin Endocrinol Metab 1998;83:21-24.)
FIGURE 28-18. Serum concentrations of IGFBP-3 in burn patients receiving growth hormone (GH) versus placebo at baseline and when fully healed (mean ± SO, *p< 0.025). (From Klein GL, Wolf SE, Langman CB, et al: Effects of therapy with recombinant human growth hormone on insulin-like growth factor system components and serum levels of biochemical markers of bone formation in children after severe burn injury. J Clin Endocrinol Metab 1998;83:21-24.)
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28 • Enteral Nutrition after Severe Burn
FIGURE 28-19. Body composition changes by OEXA scan during acute hospitalization in burn patients receiving insulin infusion versus placebo (mean percent change ± SEM, P < O.OS). LBM, lean body mass. (From Thomas SJ, Morimoto K, Herndon ON, et al: The effect of prolonged euglycemic hyperinsulinemia on lean body mass after severe burn. Surgery
2002;132:341-347.)
(Fig. 28-20) .130 Oxandrolone is an oral synthetic testosterone analog with fewer androgenic side effects than testosterone. Oxandrolone also improves protein synthetic efficiency but does not significantly alter muscle protein breakdown (Fig. 28-21). These changes result in improved net protein balance.I" These changes result in improved strength in rehabilitating burn patients, as well as improved wound healing and decreased length of hospitalization in acute burn patients. 132,133 Catabolic hormone antagonists usually target catecholamines or cortisol. When given at a dose to reduce heart rate by 20%, propranolol decreases myocardial work, while cardiac responsiveness is maintained in burned children.I34.135 It decreases peripheral lipolysis, reduces energy expenditure, and improves net protein balance by decreasing protein breakdown (Figs. 28-22 and 28-23).136-138 It may have the added benefit of decreasing hepatic fat storage.P? a common finding on autopsy of pediatric burn patients.!"
FIGURE 28-20. Increase in protein synthetic efficiency (PSE) and protein synthesis (PS)-to-protein breakdown (PO) ratio at baseline and after testosterone therapy (mean ± SEM, P < 0.01 vs. baseline). (From Ferrando AA, Sheffield-Moore M. Wolf SE, et al: Testosterone administration in severe burns ameliorates muscle catabolism. Crit Care Med 2001 ;29:1936-1942.)
SECTION V • Disease Specific
359
c::=J Protein synthesis rz.z;;j Protein breakdown _ Net balance FIGURE 28-21. Model calculations of protein synthesis, protein breakdown, and net protein balance for burn patients treated with oxandrolone versus placebo (tp < 0.05 vs. baseline, *p < 0.01 vs. baseline, P < 0.05 vs. time [treatment periodl control). PHE, phenylalanine. (From Hart OW, Wolf SE, Ramzy PI, et al: Anabolic effects of oxandrolone after severe burn. Ann Surg 2001 ;233:556-564.)
Burn-induced glucocorticoids have been associated with muscle protein proteolysis'" and lymphocyte apoptosis,45,46 possibly through IGF-I-IGFBP-3 mechanisms.lf Commonly investigated cortisol antagonists include ketoconazole, an inhibitor of adrenal cortisol synthesis, and mifepristone, a competitive glucocorticoid antagonist. Human trials are forthcoming.
COMPLICATIONS Although there are a number of complications from enteral feeding, most of them are also found in any critically ill patient. Feeding tube placement may be problematic, especially if the patient has burns to the nose or nasopharynx. Precautions to avoid aspiration
should be instituted in all patients, especially those with gastric tubes or borderline gastric residual volumes. The osmotic load of tube feedings may cause diarrhea, which can be treated with bulking agents, decreased feeding rates, or dilution of the formula if delivered postpylorus. Because most burn patients have received multiple antibiotics, the patient should be assessed for Clostridium difficile or other infectious etiologies before treatment for osmotic diarrhea. Overfeeding may cause increased carbon dioxide production with resulting respiratory difficulties, fatty infiltration of the liver, electrolyte imbalances, or azotemia. Electrolytes and liver function tests should be regularly monitored for abnormalities. Because critically ill patients are prone to development of complications, vigilance is required.
360
28 • Enteral Nutrition after Severe Burn
CONCLUSION The principles of nutrition for burn patients depend on recognition of the evolution of this profound catabolic state. Nutritional requirements must be rapidly assessed, with a carbohydrate-rich diet instituted as early as possible. Because the magnitude of this hypermetabolism is not productive over the length of time required for rehabilitation, catabolic modulation should be instituted in an effort to improve outcome. REFERENCES
FIGURE 28-22. Net protein balance changes from baseline in burn patients receiving propranolol versus placebo by 5-hour kinetic analysis of isotopically labeled phenylalanine (mean ± SEM, *p= 0.001 between the groups and P= 0.002 between the baseline value and the value at 2 weeks). (From Herndon ON, Hart OW, Wolf SE, et al: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001 ;345:1223-1229.)
..-.
C l/l
sE Q)
~
i.5
Q)
Cl
c:
III
..c:
o
Control group (n=10)
Propranolol group (n=12)
FIGURE 28-23. Significant changes in fat-free mass of burn patients after 4 weeks of treatment with propranolol or placebo by whole body potassium scanning (P = 0.003). (From Herndon ON, Hart OW, Wolf SE. et al: Reversal of catabolism by betablockade after severe burns. N Engl J Med 2001 ;345: 1223-1229.)
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between a conventional and branched-ehain amino acid-enriched nutritional therapy. Ann Surg 1988;207:421-429. 96. Mayes T, Gottschlich MM, Warden GD:Clinical nutrition protocols for continuous quality improvements in the outcomes of patients with burns. J Burn Care Rehabil 1997;18:365-368. 97. Tanaka H, Matsuda H, Shimazaki S, et al: Reduced resuscitation fluid volume for second-degree burns with delayed initiation of ascorbic acid therapy. Arch Surg 1997;132:158-161. 98. Barbul A, Regan MC: Biology of wound healing. In Fischer JE (eds): Surgical Basic Science, p 67. St Louis, Mosby, 1993. 99. Rock CL, Dechert RE, Khilnani R, et al: Carotenoids and antioxidant vitamins in patients after bum injury. J Bum Care Rehabil 1997;18:269-278. 100. Klein GL, Langman CB, Herndon DN: Vitamin D depletion following bum injury in children; A possible factor in post-bum osteopenia. J Trauma 2002;52:346-350. 101. Larson DL, Maxwell R, Abston S, et al: Zinc deficiency in burned children. Plast Reconstr Surg 1970;46:13-21. 102. Prasad AS;Clinical, endocrinological, and biochemical effects of zinc deficiency. Clin Endocrinol Metab 1985;14:567-589. 103. Boosalis MG, Solem ill, Ahrenholz DH, et al: Serum and urinary selenium levels in thermal injury. Burns Incl Therm Inj 1986;12: 236-240. 104. Barret JP, Herndon DN: Modulation of inflammatory and catabolic responses in severely burned children by early bum wound excision in the first 24 hours. Arch Surg 2003;138:127-132. 105. Xiao-WuW, Herndon DN, Spies M,et al: Effects of delayed wound excision and grafting in severely burned children. Arch Surg 2002;137:1049-1054. 106. McCampbell B, Wasil N, Rabbitts A, et al: Diabetes and bums: Retrospective cohort study. J Burn Care Rehabil 2002;23: 157-166. 107. Biolo G, Fleming RY, Maggi SP, et al: Inverse regulation of protein turnover and amino acid transport in skeletal muscle of hypercatabolic patients. J Clin Endocrinol Metab 2002;87: 3378-3384. 108. Ramzy PI, Wolf SE, Herndon ON: Current status of anabolic hormone administration in human bum injury. JPEN J Parenter Enteral Nutr 1999;23(6 suppl):SI9Q-S194. 109. Gilpin DA, Barrow RE, Rutan RL, et al: Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994;220:19-24. 110. Herndon ON, Barrow RE, Kunkel KR,et al: Effects of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990;212:424-429. 111. Ramirez RJ, Wolf SE, Barrow RE, Herndon ON: Growth hormone treatment in pediatric bums: A safe therapeutic approach. Ann Surg 1998;228:439-448. 112. Gore DC, Honeycutt D, Jahoor F, et al: Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. Arch Surg 1990;126:38-43. 113. Hart OW, Herndon DN, Klein G, et al: Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Ann Surg 2001;233:827-834. 114. Dobashi H, Sato M, Tanaka T, et al: Growth hormone restores glucocorticoid-induced T cell suppression. FASEB J 2001;15: 1861-1863. 115. Brocardo MG, Schillaci R, Galeano A, et al: Early effects of insulinlike growth factor-l in activated human T lymphocytes. J Leukoc Bioi 2001;70:297-305. 116. Public Communications from Pharmacia and Upjohn Pharmaceuticals and Rolf Gunnarsson, MD, to all industry and medical community involved with the use or potential use of recombinant human growth hormone, October 31, 1997. 117. Knox J, Demling R, Wilmore 0, et al: Increased survival after major thermal injury: The effect of growth hormone therapy in adults. J Trauma 1995;39:526-530. 118. Klein GL, Wolf SE, Langman CB, et al: Effects of therapy with recombinant human growth hormone on insulin-like growth factor system components and serum levels of biochemical markers of bone formation in children after severe burn injury. J Clin Endocrinol Metab 1998;83:21-24. 119. Humbel RE: Insulin-like growth factors I and II. Eur J Biochem 1990;190:445-462.
SECTION V • Disease Specific
120. Baxter RC: Circulating levels and molecular distribution of the acid-labile (alpha) subunit of the high molecular weight insulinlike growth factor-binding protein complex. J Clin Endocrinol Metab 1990;70:1347-1353. 121. Baxter RC, Dai 1: Purification and characterization of the acid-labile subunit of rat serum insulin-like growth factor binding protein complex. Endocrinology 1994;134:848--852. 122. BaxterRC, Martin JL: Binding proteins for the insulin-like growth factors: Structure, regulation and function. Prog Growth Factor Res 1989;1:49-68. 123. Cioffi WG, Gore DC, Rue LW 3rd, et al: Insulin-like growthfactor-1 lowersprotein oxidation in patients with thermal injury. AnnSurg 1994;220:310-316. 124. Lewitt MS, Saunders H, Phuyal JL, et al: Complex formation by human insulin-like growth factor-binding protein-3 and human acid-labile subunitin growth hormone-deficient rats. Endocrinology 1994;134:2404-2409. 125. Herndon ON, Ramzy PI, DebRoy MA, et al: Muscle protein catabolism after severe burn: Effects of IGF-1/IGFBP-3 treatment. Ann Surg 1999;229:713-720. 126. Debroy MA, Wolf SE, ZhangXI, et al:Anabolic effects of insulin-like growth factor in combination with insulin-like growth factor bindingprotein-3 in severely burned adults.J Trauma 1999;47:904-910. 127. Spies M, Wolf SE, Barrow RE, et al: Modulation of types I and II acute phase reactants with insulin-like growth factor-I/binding protein-3 complex in severely burned children. Crit Care Med 2002;30:83-88. 128. Wolfe SE, Woodside KJ, Ramirez RJ, et al: Insulin-like growth factorI/insulin-like growth factor binding protein-3 alters lymphocyte responsiveness following severe bum. J SurgRes2004;117:255-261. 129. Thomas SJ, Morimoto K, Herndon ON, et al: The effect of prolonged euglycemichyperinsulinemia on lean body mass after severe bum. Surgery 2002;132:341-347. 130. Ferrando AA, Sheffield-Moore M, Wolf SE, et al: Testosterone administration in severe bums ameliorates muscle catabolism. CritCare Med2001;29:1936-1942.
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131. Hart OW, Wolf SE, Ramzy PI, et al: Anabolic effects of oxandrolone aftersevere bum. Ann Surg2001 ;233:556-564. 132. Dernling RH, DeSanti L: Oxandrolone, an anabolic steroid, significantly increases the rate of weight gain in the recovery phase after major bums. J Trauma 1997;43:47-51. 133. Demling RH: Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe bum injury. Bums 1999;25:215-221. 134. Minifee PK, Barrow RE, Abston S, et a1: Improved myocardial oxygen utilization following propranolol infusion in adolescents with postburn hypermetabolism. J PediatrSurg 1989;24:806-810. 135. Honeycutt 0, Barrow R, Herndon 0: Cold stress response in patients with severe bums after beta-blockade. J Bum Care Rehabil 1992;13(2 part 1):181-186. 136. Herndon ON, Hart OW, Wolf SE, et al: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345: 1223-1229. 137. Hart OW, Wolf SE, Chinkes DL, et al: Beta-blockade and growth hormone after bum. Ann Surg 2002;236:450-456. 138. Aarsland A, Chinkes 0, Wolfe RR, et a1: Beta-blockade lowers peripheral lipolysis in bum patients receiving growth hormone. Rateof hepatic very low density lipoprotein triglyceride secretion remains unchanged. Ann Surg 1996;223:777-787. 139. Morio B, Irtun 0, Herndon ON, et al: Propranolol decreases splanchnic triacylglycerol storage in burn patients receiving a high-earbohydrate diet. Ann Surg2002;236:218-225. 140. BarretJP, Jeschke MG, Herndon ON: Fattyinfiltration of the liver in severely burned pediatric patients:Autopsyfindings and clinical implications. J Trauma 2001;51:736-739. 141. Fang CH, James HJ, Ogle C, et al: Influence of bum injury on protein metabolism in different types of skeletal muscle and the role of glucocorticoids.J Am ColiSurg 1995;180:33-42. 142. Lang CH, Nystrom GJ, Frost RA: Burn-induced changes in IGF-I and IGF-binding proteins are partially glucocorticoid dependent. Am J Physiol Regul Integr Comp Physiol 2002;282: R207-R215.
Trauma Rosemary A. Kozar, MD, PhD Margaret M. McQuiggan, MS, RD, CSM FrederickA. Moore, MD
CHAPTER OUTLINE
ENTERAL ROUTE PREFERRED
Introduction Enteral Route Preferred Role of Immune-Enhancing Diets in Trauma Patients Enteral Nutrition Protocol
Three single institutional prospective, randomized, controlled trials (PRCTs) and one meta-analysis published in the late 1980s and early 1990s have had a significant impact on clinical practice in trauma ICUS.l-4 The first single institutional trial included trauma patients who required an emergency laparotomy and had an abdominal trauma index (ATI) score greater than 15.1 The study group (n =31) received early total enteral nutrition (fEN) beginning 12 hours postoperatively via needle catheter jejunostomy (NCJ), and the control group (n = 32) received delayed total parenteral nutrition (fPN) , starting on day 6 if oral intake was inadequate (30% received TPN). Those who received early TEN had better nitrogen balance, higher lymphocyte counts, and fewer major infections. In a follow-up study by the same group published in 1989, patients having an ATI of 15 to 40 were randomly assigned to receive early TEN via NCJ (n =29) or early TPN (n = 30), formulated to be comparable to the enteral diet.- Despite a slight advantage in proteincaloric intake with TPN, there was no significant difference in nitrogen balance. With respect to clinical outcome, a significant decrease was seen in the incidence of major infections (one [3%] patient in the TENgroup vs. six [20%] in the TPN group). A different group of investigators subsequently confirmed these observations, by randomly assigning patients with an ATI greater than 15 to receive early TEN via jejunostomy «24 hours, n = 51) or early TPN (n =45) with a comparably formulated TPN solution.' Patients randomly assigned to receive TEN experienced significantly fewer major septic complications than those receiving TPN (14% with TEN vs. 38% with TPN). Additionally, patients receiving TPN experienced a significantly higher incidence of catheter-related sepsis (2% with TEN vs. 14% with TPN). In the same year Moore and co-workers' published a meta-analysis of combined data from eight PRCTs (six published and two not published) conducted to assess the nutritional equivalence of TEN
Rationale Patient Selection Enteral Access Formula Selection Administration of Feedings Gastric Feeding Monitoring Tolerance and Managing Intolerance Results of Protocol Nutritional Assessment Patient-Specific Goals Acute Renal Failure Monitoring Response to Support
Anticipated Complications Comorbid Conditions Refeeding Syndrome Hyperglycemia Jejunostomy-Related Complications Nonocclusive Bowel Necrosis Anabolic Compounds
INTRODUCTION The purpose of this chapter is to review (1) the evidence for the early use of the enteral route for nutrition, (2) the use of immune-enhancing diets, (3) an enteral nutrition protocol in trauma patients, and (4) the complications and controversies related to trauma patients in intensive care units (lCUs). 364
SECTION V • Disease Specific
compared with TPN in high-risk trauma and/or postoperative patients.' The same enteral formula was compared with similar TPN formulations, and septic complications were recorded prospectively by similar definitions. In the eight studies from which data were collected, 230 patients were enrolled; 118 were randomly assigned to receive TEN and 112 to receive TPN. One or more infections developed in twice as many patients receiving TPN as TEN (35% with TPN vs. 16% with TEN). When patients with catheter-related sepsis were removed from the analysis, a significant difference in the number of infections between groups remained (16% with TEN vs. 35% with TPN). Taken together, the above PRCTs provided convincing evidence that TENis preferred to TPN in patients sustaining major torso trauma. Although these studies have shown improved outcome in patients with major torso trauma undergoing emergency laparotomy, reluctance may be seen to feeding above a fresh bowel anastomosis. Laboratory studies have indicated that this is not a legitimate concern. In fact, enteral feeding has been shown to increase anastomotic strength, decrease cytokine profiles,and enhance wound healing. 5•6
ROLE OF IMMUNE·ENHANCING DIETS IN TRAUMA PATIENTS In the above-described PRCTs documenting improved outcomes with enteral nutrition, elemental formulas were used. Results of more recent trials suggested that additional benefits can be achieved by using polymeric immune-enhancing diets (IEDs). For general information on IEDs see Chapter 19. In numerous published PRCTs the efficacy and safety of IEDshave been tested in a variety of clinical settings," with the majority demonstrating improved patient outcome with the use of IEDs. These data have also been analyzed by meta-analysis, and overall demonstrate improved patient outcome.t '? Five of these studies were performed specifically in trauma patients (fable 29-1).11-13 The first study by Brown and colleagues!' documented that patients who received IEDs had fewer nosocomial infections (16% vs. 56%, P < 0.05) than those receiving standard enteral diets
365
(SEDs). This study, however, had several methodologic flaws including the following: (l) entry criteria were nonspecific; (2) TEN was started late (3.5 days for lED and 5.0 days for SED); and (3) more patients who received the lED had jejunostomy tubes and were fed earlier. The second study, a multicenter study conducted by Moore and associates.P a reduction in intra-abdominal abscesses (0% with lED vs. 11 % with SED, P < 0.05) and multiorgan failure (0% with lED vs. 11 % with SED, P < 0.05) in patients receiving the lED. This study has been criticized because the control group received an elemental diet that had a lower nitrogen content than the lED. This concern was addressed in a follow-up by Kudsk and colleagues" who used the same lED, but their control diet was isonitrogenous and polymeric. Their results showed a similar reduction in intra-abdominal abscess (5% with lED vs. 35% with SED) as well as a decrease in days of therapeutic antibiotic usage and decreased length of hospital stay. In the fourth study, Mendez and co-workers" failed to demonstrate any outcome improvement and suggested that the lED may exacerbate organ failure. This study had several methodologic flaws including the following: (l) TEN was started late; (2) the dropout rate was 25%; and (3) the lED and SED groups were not comparable. The lED patients were a decade younger (25 years for lED vs. 35 years for SED) and before starting TEN, they had a higher incidence of acute respiratory distress syndrome (31% for lEDvs. 14% for SED). In the last study, Weimann and associates" demonstrated a decrease in the number of days of systemic inflammatory response syndrome and a decrease in the incidence of multiorgan failure. Analysis of these individual studies provides convincing evidence that IEDs provide additional benefits compared with SEDs in patients sustaining major torso trauma. Although a benefit has been seen in trials enrolling only patients with blunt and penetrating torso trauma, improved outcome has been difficult to prove in trials enrolling ICU patients with less homogenous injuries. In addition, subset analysis suggests that IEDsmay be harmful in ICU patients with sepsis." A review of the potential immunomodulating effects of the key ingredients in IEDs has led some authorities to hypothesize that arginine,
_ _ Prospective, Randomize Studies of Immun.Enhancing OMts In Trauma Author
Result
Improvement
Critique of Study
Brown et ai, 199415
,J. Nosocomial infections
Yes?
Moore et ai, 199416
,J. Intra-abdominal abscesses ,J.MOF Intra-abdominal abscesses ,J. Antibiotics ,J. Length of stay t ARDS
Yes
Nonspecific entry criteria TEN started late Control diet ,J. protein than lED
Yes
Control diet and lED nitrogenous
No?
TEN started late Groups not comparable t ARDS before lED
,J. SIRS ,J.MOF
Yes
Kudsk et al, 199617 Mendez et ai, 199718 Weimann et ai, 199819
ARDS, acute respiratory distress syndrome; lED, immune-enhancing diet; MOF, multiple organ failure; SIRS, systemic inflammatory response syndrome; TEN,total enteral nutrition.
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29 • Trauma
one of the immune-enhancing agents in a number of commercially available IEDs is harmful in the patient withsepsis.Sepsis increases levelsof inducible nitric oxide synthetase. Arginine is a substrate for inducible nitric oxide synthetase. Arginine combines with molecular oxygen to produce citrulline and nitric oxide. The resulting nitric oxide could have numerous adverse effects in sepsis including vasodilation, cardiac dysfunction, and direct cytotoxic injury by generating potent reactive oxygen species. Unfortunately, there are few data to support or refute this hypothesis at this time.
ENTERAL NUTRITION PROTOCOL Rationale Although trauma patients benefit from receiving early TEN, many clinicians lack specific training and experience in administering TEN. Current feeding protocols were empirically developed in centers to perform studies in specific subgroups of high-risk patients. When clinicians apply these protocols to broader groups of patients, not surprisingly they are less successful. More disturbingly, there are case reports of nonocclusive bowel necrosis suggesting that caution is warranted when TEN is administered early to certain patients. The clinical presentation of this devastating complication is similar to that of neonatal necrotizing enterocolitis, and its pathogenesis is undoubtedly multifactorial. However, the consistent association with TEN indicates that the inappropriate administration of nutrients into a dysfunctional gut plays a pathogenic role. To provide a systematic, evidencebased approach to enteral nutrition and minimize complications, an enteral protocol for use in patients with torso trauma was devised with multidisciplinary contribution in 1997. 17 The protocol markedly streamlines the decision-making process related to enteral feeding, accelerates initiation and advancement of feedings, and serves as a multidisciplinary learning tool.
Patient Selection Identification of patients as candidates for nutritional support is based on American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines." Potential candidates are identified within the first day of ICU admission, and early enteral nutrition is begun in high-risk patients.
Enteral Access Clinical experience and experimental evidence demonstrate that gastric motility is often attenuated after severe injury, particularly neurologic injury.'? The number of studies specifically addressing the optimal site for enteral feedings in trauma patients is limited." Based on a review of the literature and clinical experience, early TEN is best delivered into the proximal small intestine. However,
recent results have demonstrated that erythromycin improves gastric emptying in the critically ilpl Thus, gastric feeding may be an achievable goal in a subset of trauma patients. For patients to be fed intragastrically, a nonsump 12- or 14-F nasogastric tube should be placed. For patients known to require long-term feeding access, a percutaneous gastrostomy can be obtained. Enteral feeding access should be obtained at the time of initial laparotomy or subsequent laparotomy if damage control is initially performed. The NCJ is the preferred method of access and a commercially available kit containing a Silastic 7-F catheter is available. For critically injured patients who do not undergo immediate laparotomy a nasojejunal (N]) tube should be placed, preferably in the first 24 hours after injury. This procedure is first attempted by the bedside nurse who makes one try to blindly place a "push" NJ tube (Corpak Medsystems, Wheeling, IL). This is successful in approximately one half of patients. In the remaining patients an NJ tube is placed endoscopically by the ICU procedure team in a lO-minute bedside procedure.F The technique involves passage of an 8-F nasobiliary drainage catheter (Wilson, Winston-Salem, NC) through the biopsy channel of a flexible endoscope that has been advanced into the duodenum.P NJ tube feeding may be done indefinitely, but if the need for long-term access becomes apparent, the NJ tube can be converted into a jejunal extension tube through a percutaneous endoscopic gastrostomy.
Formula Selection The selection criteria for enteral formulas are shown in Table 29-2. 24
Polymeric High-Protein Formultl Patients who do not meet the criteria for IEDs and who have normal gut function are believed to have increased nitrogen requirements due to major torso and/or head injuries. A modular protein component may be used in addition to the polymeric high-protein formula in the morbidly obese patient. Approximately 65% of enterally fed patients receive a polymeric highprotein formula.
Immune-Enhtlncing Diet Patients who have sustained major torso trauma and who have a known risk for septic complications and multiple organ failure should receive an lED. Approximately 15% of patients in the level I trauma center ICU receive IEDs.
Elementtll Formultl Patients who cannot tolerate a polymeric formula or who have not received enteral feedings for the firstweek postinjury are candidates for an elemental formula. Approximately 10% of patients meet these criteria.
SECTION V • Disease Specific
367
_ _ Formula Selection in an Enteral Nutrition Protocol A. Polymeric high-protein fonnula: These formulas should be used In patients who do not meet the criteria for immune-enhancing diets but have normal digestive and absorptive capacity of the gastrointestinal (GI) tract and are believed to have increased nitrogen requirements due to the presence of I. Major torso trauma 2. Major head injuries 3. Major upper GI tract surgery 4. Obese patients with moderate caloric but high-protein needs B. Immune enhancing diet: These formulas should be used in patients sustaining major torso trauma who are at known risk for major septic complications and MOF: I. Combined flail chest/pulmonary contusion anticipated to require prolonged mechanical ventilation 2. Major abdominal trauma defined by an abdominal trauma Index> 18 3. Two or more of the following: a. >6 unit transfusion requirement b. Major pelvic fracture c. Two or more long bone fractures 4. Nontrauma patients at risk for major septic morbidity a. Moderately malnourished patients (albumin <3.5 g/dL) undergoing major elective procedures of the esophagus, stomach, pancreas (with or without duodenum), hepatobiliary tree, or abdominal perineal resection h. Severely malnourished patients (albumin <2.8 g/dL) undergoing colonic or proximal rectal anastomosis C. Elemental fonnulas: These should be used in patients who have I. Proven intolerance to the first formula used 2. Not been fed enterally starting hospital day 7 3. Pancreatitis 4. Short gut 5. High output distal colonic or ileal fistula 6. Persistent, severe diarrhea >48 hours while receiving polymeric formula 7. Moderate distention >24 hours and/or girth increase >2 inches 8. Maintain elemental feeding minimum 72 hours D. Renal fallure fonnula: Renal failure requiring intermittent hemodialysis degree of injury may merit dilution of formula to strength to reduce viscosity and the addition of Promod (protein powder) to meet protein needs.
t
Renal Failure Formula A concentrated, reduced electrolyte formulation is selected for use only in patients requiring intermittent hemodialysis. Often a modular protein component is used in addition to the commercially available renal formula to meet the increased nitrogen demands of the critically injured patient.
Administration of Feedings When resuscitation is judged to be complete (generally 24 hours after admission) and enteral access has been obtained, infusion of 15 mUhr of full-strength formula is started and advanced by 15 mUhr every 12 hours, if no moderate or severe symptoms of intolerance exist, to a set goal of 60 mUhr. To assure tolerance, this rate is maintained for 24 hours and then advanced by 15 mUhr every 12 hours to a patient-specific targeted goal if more than 60 mUhr is required.
Gastric Feeding Consider patients for gastric feeding if they have a functioning gastrointestinal tract and no evidence of delayed gastric emptying as defined by history or radiologically. Nasogastric output should be less than 500 mU12 hr at the initiation of feeds. Sepsis and hyperglycemia should be well controlled before gastric feedings are started, because these factors have been shown to decrease
gastric emptying. Maintaining the head of the bed at an elevation of at least 30 degrees is essential for minimizing aspiration of stomach contents and oropharyngeal secretions. Feedings should be held for 4 hours before administration of an anesthetic for an operative procedure but may be restarted immediately after the procedure at the previous rate. Feedings are held for 4 hours before endotracheal extubation. Historically, practices for checking gastric residual volumes and cessation of feedings have varied greatly. Because salivary and gastric secretions proximal to the pylorus normally approach 200 mUhr, there is no need to respond to a gastric residual volume less than 200 mL. Feedings should be discontinued for a gastric residual volume greater than 500 mL and postpyloric feeding should be started."
Monitoring Tolerance and Managing Intolerance Tolerance parameters are assessed and documented on an enteral tolerance flow sheet by the bedside ICU nurse every 12 hours and are reviewed by the ICU team daily. The decision to advance feeding is based on objective data. Current indicators of intolerance are vomiting, abdominal distention or cramping/tenderness, diarrhea, and high nasogastric tube output. Symptoms are graded as mild, moderate, or severe. Mildsymptoms of intolerance, such as mild abdominal distention or diarrhea (one to two diarrheal stools per 12-hour shift)
368
29 • Trauma
are monitored by performing a physical examination at the onset of symptoms and in 6 hours, with the current rate of feeding being maintained. Moderate symptoms are managed on the basis of the particular symptom. For distention, enteral feedings are stopped, and the patient is assessed for evidence of small bowel obstruction. If distention remains moderate, an elemental formula is begun. Moderate diarrhea (three to four diarrheal stools per shift) is managed by maintaining (but not increasing) the current feeding rate and a repeat examination in 6 hours. Severe distention is managed by stopping all enteral feedings, increasing intravenous fluid administration, and evaluating the patient for possible nonocclusive bowel necrosis. For severe diarrhea (more than four diarrheal stools per shift), the patient is evaluated for Clostridium difficile infection and if found, tube feedings are reduced by 50%. Vomiting is managed by ensuring adequate gastric decompression and decreasing the tube feeding infusion rate by one half for jejunal feeding and' totally stopping gastric feeding. For jejunal feeding, high nasogastric output (>1200 mU12 hr) is treated by verifying postpyloric placement of the feeding tube and checking the nasogastric aspirate for glucose. Any amount of glucose is considered abnormal and enteral feedings are held. Finally, feedings are discontinued if treatment with any inotropic agents, paralytic agents, or vasopressors is instituted.
Results of Protocol The incidence of tolerance to enteral feeding with the protocol was analyzed in a prospective multi-institutional study." Early tolerance (during advancement of enteral feedings to a goal of 60 mUhr) was good in 84% (41 of 49) of patients and moderate in 16% (8 of 49). No patients experienced poor tolerance or complete intolerance. Late tolerance (after the standard goal rate was met) was good in 80% (39 of 49), moderate in 16% (8 of 49), and poor in 4% (2 of 49) of patients. The site of feeding (gastric vs. jejunal) was not dictated by the protocol. Moderate intolerance was primarily due to high gastric output in patients fed via the stomach. All patients with torso trauma were successfully maintained on early enteral nutrition using this standardized protocol.
Nutritional Assessment A nutritional assessment is performed within 72 hours of admission. Physical assessment of the patient includes
BEll
evaluation of body composition, edema, wound healing, nutrient composition of fluid losses through wounds or drains, indirect calorimetry, and review of the laboratory and medication profile. Height and preadmission weight are obtained, and information on chronic disease, medications, previous dietary restrictions, and drug and tobacco use patterns is elicited.
Patient-Specific Goals Patient-specific nutritional goals are initially based on body weight (Table 29-3). Actual body weight (ABW) is used when the patient weighs less than or equal to 120% of ideal body weight (lBW) and an adjusted body weight is used for patients weighing more than 120% of IBW, using the formula: Adjusted weight = [(ABW- IBW) x 25%]
+ IBW.
Initially, protein is provided at 1.5 to 1.75 g/kg actual or adjusted body weight.
Acute Renal Failure Approximately 1% of trauma patients will have underlying chronic renal insufficiency" and, for a variety of reasons, trauma places patients at high risk for acute renal failure. Nutritional support of trauma patients with hypermetabolism and renal failure is challenging. Increasingly, these patients are treated with continuous venous-venous hemofiltration, hemodialysis (CWHD) , or a combination of these, hemodiafiltration (CWHDF). Intermittent hemodialysis is generally reserved for those whose hypermetabolism has resolved and in whom hemodynamic stability has been achieved. Although more labor-intensive, CWHD/CWHDF is better tolerated from a hemodynamic perspective and allows for greater volume and urea and electrolyte clearance. As a result, standard enteral formulas with high protein loads and normal electrolyte concentrations are used. High-volume postfilter dextrose-containing replacement solutions deliver a considerable amount of dextrose calories (approaching 300 g daily), which should be considered as part of the total kilocalories.P Hyperglycemia often results, and, thus, the use of sterile water for injection as the vehicle to deliver replacement fluids should be coordinated with the nephrologist." Standard nutritional assessment parameters are of limited utility in acute renal failure. Measurements of urine urea nitrogen (UUN)
Nutritional Goals In Trauma Patients
Admit Weight
Total Amount
Underweight: BMI <18; <80% IBW Normal weight: BMI 18-25; 80%-120% IBW Overweight/obesity: BMI25-40; >120% IBW Morbid obesity: BMI ~ 40; >200% IBW
40 kcal/kg 30 kcal/kg 20-25 kcal/kg adjusted weight 10-20 kcal/kg adjusted weight
BMl, body mass index; IBW. ideal body weight; REE, resting energy expenditure.
Indirect Calorimetry REE x 1.2 REE x 1.0 REE x 0.85 REE xO.75
Protein 1.75 gfkg 1.75 gfkg 1.75 gfkg adjusted weight 1.75 gJkg adjusted weight
SECTION V • Disease Specific
become less reliable when creatinine clearance is less than 50 mUmin, whereas measurements of prealbumin and transferrin can be misleading in the acute stages of renal failure. Additionally, renal failure has variable effects on energy expenditure. Indirect calorimetry, if feasible, is recommended. The kilocalorie level should match needs and increasing kilocalorie loads are associated with a decreased protein catabolic rate." An estimate of protein catabolic rate can be obtained during intermittent dialysis by urea kinetic modeling. Generally 30 kcallkg in normal weight and 25 kcallkg adjusted weight in obesity and 1.6 to 1.8 g of protein/kg in the patient with continuous dialysis are appropriate. When the transition to intermittent hemodialysis occurs, a specialty renal enteral formula is used with the addition of a modular protein component.
Monitoring Response to Support A weekly 12-hour UUN measurement is obtained in all patients with creatinine clearance greater than 50 mUmin and without cirrhosis or acute spinal cord injury. A UUN value is not obtained in patients with spinal cord injury and paralysis because obligatory losses are generally extraordinary regardless of the level of support and persist for up to 7 weeks after injury." One may estimate the protein dose needed to achieve optimal nitrogen balance by [24-hr UUN (g) + 2 g N insensible losses + 5] x 6.25 = amount of protein (g) A C-reactive protein measurement must be obtained within 72 hours of admission and then weekly along with the serum prealbumin level. C-reactive protein is a sensitive acute-phase reactant that increases from a normal level near zero to up to 20 to 30 mg/dL within 48 to 72 hours of injury. It can be used as an indicator of the severity of injury, inflammation, and sepsis. Only when this level begins to decline, can the liver begin to synthesize constitutive proteins such as albumin, prealbumin, and transferrin. When the level falls to less than 10 to IS mg/dL, a prompt increase in prealbumin level typically occurs. If not, the clinician should reevaluate the adequacy of the support regimen or investigate other factors that may thwart anabolism. The prealbumin level is an accessible and inexpensive indicator of anabolic activity. Its half-life of 2 to 4 days increases its utility in the critical care setting. When the acute-phase response has subsided, increases in prealbumin level are typically 0.5 to 1.0 mg/dL daily in the patient with adequate support. Indirect calorimetry is obtained on an as-needed basis and may be performed on the mechanically ventilated patient with fractional inspired oxygen (Fi0 2) less than 60% and positive end-expiratory pressure less than 10. Studies are helpful when (1) overfeeding would be undesirable (as in diabetes, obesity, or chronic obstructive pulmonary disease), (2) underfeeding would be especially detrimental (as in renal failure or large wounds), (3) patients whose physical or clinical factors promote energy expenditure that deviates from normal, (4) drugs
369
are used that may significantly alter energy expenditure (e.g., paralytic agents, ~blockers, and corticosteroids), (5) patients do not show the expected response to calculated regimens, and (6) body habitus makes energy expenditure predictions challenging (morbid obesity or quadriplegial.P
ANTICIPATED COMPLICATIONS Comorbid Diseases Comorbid conditions may be present in up to 20% of severely injured patients'" and will influence the patient's specific nutritional goal. Obesity and morbid obesity are increasingly encountered in the trauma patient and may also increase risk for morbidity and mortality. Trauma patients with a body mass index greater than 31 were found to have an eightfold higher rate of mortality after blunt trauma, often due to pulmonary compllcations." Adjusted rather than actual weight is used in calculating energy and protein requirements for patients with a body mass index greater than or equal to 30 or whose weight exceeds 120% of IBW. Adjusted body weight is calculated by determining the patient's ABW and the IBW based on height-weight tables. Twenty-five percent of the difference between these numbers is added to the IBW: (ABW - IBW) (0.25) + IBW = Adjusted body weight Although controversial, hypocaloric feeding in the obese patient has also been suggested to lessen infectious complications due to hyperglycemia. Comparable nitrogen balance is achieved in this patient population when hypocaloric feedings are administered." General recommendations are to provide a high-protein (2 g/kg IBW/day) but low-ealoric (10 to 20 kcallkg adjusted weight/day in morbid obesity; 20 to 25 kcallkg adjusted weight in obesity) diet. Monitoring for clinical evidence of overfeeding (hypercapnia, hyperglycemia, insulin resistance, hypertriglyceridemia, diarrhea, and distention) is used to refine predictions.
Refeeding Syndrome Refeeding syndrome can occur with rapid and excessive feeding of patients with severe malnutrition due to starvation, alcoholism, delayed support, anorexia nervosa, and insufficientintracellular ions." As a result of ion fluxes into the cell with refeeding, serum phosphate, magnesium, potassium, and calcium levels can drop precipitously. Because of blunted basal insulin secretion, severe hyperglycemia may arise. Symptoms include cardiac arrhythmias, confusion, respiratory failure, and even death. This can be prevented by initiating nutritional replacement, whether it is TPN or enteral feeding, at no more than about two thirds of the required goal. Caloric intake can then be gradually increased over the next 5 to 7 days while electrolyte abnormalities are anticipated and corrected. Exogenous insulin may be required.
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HypergIycemia Critical illness is accompanied by increased plasma counter-regulatory hormone levels that have multiple effects on glucose homeostasis. The end result is hyperglycemia with resistance to insulin, a common entity in critically ill patients. Other factors that contribute to "stress diabetes" include obesity, systemic inflammatory response syndrome, advanced age, exogenous steroids or catecholamines, increased free fatty acids, and nutritional support. The resulting hyperglycemia can adversely affect outcome through several mechanisms including glycosuria and inappropriate diuresis, increased risk of infection (by impairing neutrophil and immunoglobulin function), and exacerbation of cerebral edema. Van den Berghe and colleagues" demonstrated in a prospective, randomized fashion that mortality decreased from 8% to 4.6% in critically ill surgical patients when glucose levels were strictly controlled between 80 and 110 mg/dL versus 120 to 180 mg/dL with conventional therapy. In a follow-up analysis, the same investigators demonstrated that the reduction in polyneuropathy, bacteremia, inflammation, and mortality in critically ill patients was related to the lowering of blood glucose levels and not the amount of infused insulin per se. 38 These data support the value of maintenance of normoglycemia.
of 50%. Marvin and associates" reported 13 cases of NOBN from among 4311 patients admitted to surgical or neurologic ICUs from 1993through 1998, for an incidence of 0.3%. No specific gastrointestinal symptoms associated with this entity were identified, although distention was common and occurred late in the course. Additional symptoms associated with NOBN are abdominal pain and tenderness, vomiting, and high nasogastric output, all commonly encountered indicators of intolerance. No accurate predictors of impending bowel necrosis have been identified. The precise etiology of NOBN remains unclear. Although a number of hypotheses have been proposed to explain its development, all focus on the role of secondary gut mucosal hypoperfusion. Hypotheses have included an increase in the metabolic demand (imposed by the administration of nutrients to an already metabolically stressed gut) and abdominal distention (from either hyperosmolar formulas or bacterial overgrowth). Signs and symptoms can range from mild abdominal distention, vomiting, or diarrhea to full-thickness necrosis and death if not promptly recognized. The premise for NOBN may be set early in the patient's postinjury course but only after exposure to escalating volumes of enteral nutrients can such an extreme example of injury become manifest.
Anabolic Compounds Jejunostomy-Related Complications The largest study examining the safety of NCJs in patients undergoing major elective and emergency abdominal operations documented a 1% incidence of major complications and a 1.7% incidence of minor complications.P When feeding jejunostomy-related complications in trauma patients were reviewed by Holmes and co-workers," the overall major complication rate was 4% (9 of 122). However, the majority of complications (10%) occurred in patients with a standard, open jejunostomy (typically a I4-F catheter) with only a 2% rate with 5- to 7-F needle catheter jejunostomy. In fact, the only difference between patients with and without major complications was the type of feeding access. Major complications included small bowel perforation, volvulus with infarction, intraperitoneal leaks, and nonocclusive small bowel necrosis. The first three of these complications can be minimized by improved technique and the latter by more judicious feeding.
Nonocclusive Bowel Necrosis Failure to recognize and appropriately manage intolerance can lead to a rare but often fatal condition known as nonocclusive bowel necrosis (NOBN). Although clinical reports are derived from retrospective case reports, the consistent association of NOBN with enteral nutrition implicates the inappropriate administration of nutrients into a dysfunctional gut. The incidence ranges from less than 1%to more than 5%,with a mortality often in excess
Trauma and immobilization are associated with a progressive loss of body cell mass that may become extraordinary in prolonged illness, despite aggressive nutrition care. Interest in anticatabolic strategies has included trials of anabolic compounds. The four major classes of anabolic compounds include recombinant human growth hormone, insulin-like growth factor-I, anabolic steroids, and high-dose insulin. These drugs have been tested most extensively in burn patients. Recombinant human growth hormone is the most tested compound and has powerful anabolic effects on most body cells, either directly or by stimulating insulin-like growth factor-I secretion. Relatively small trials have demonstrated accelerated donor site healing, improved muscle protein synthesis, decreased length of hospital stay, and decreased mortality in trauma patients.f In a recent large, multicenter European trial growth hormone was used early after cardiac or abdominal surgery, multiple trauma (8% of the subjects), or respiratory failure; significantly higher morbidity and mortality were seen in the treated group." Although there is no explanation for this increased mortality, enthusiasm for using recombinant human growth hormone in nonbum ICU patients has been tempered. In fact, current A.S.P.E.N. practice guidelines recommend against the routine use of anabolic agents (growth hormone or oxandrolone) in burn
patients." Oxandrolone is a synthetic testosterone analog with high anabolic and relatively low androgenic potential. It preserves body cell mass in burn patients, restores muscle mass in patients with acquired immunodeficiency
SECTION V • Disease Specific
syndrome, and accelerates wound healing. Gervasio and co-workers'? administered 10 mg twice daily to trauma patients with injury severity scores greater than or equal to 25 beginning within 5 days of admission and lasting up to 28 days. There was no significant difference in length of hospital stay, length of leU stay, or incidence of pneumonia, sepsis, acute respiratory distress syndrome, or multiorgan failure. No studies evaluating the use of oxandrolone in patients who are no longer in the acutephase response but demonstrate failure to become anabolic have been reported.
REFERENCES 1. Moore EE, Jones TN: Benefits of immediate jejunal feeding after major abdominal trauma-A prospective randomized study. J Trauma 1986;26:874--881. 2. Moore FA, Moore EE, Jones TN: TEN versus TPN following major abdominal trauma-Reduced septic morbidity. J Trauma 1989;29: 916-922. 3. Kudsk KA, Croce MA, Fabian TC, et al: Enteral versus parenteral feeding: Effects on septic morbidity following blunt and penetrating abdominal trauma. Ann Surg 1992;215:503-511. 4. Moore FA, Feliciano DV, Andrassy RJ, et al: Early enteral feeding, compared with parenteral, reduces postoperative septic complications-The results of a meta-analysis. Ann Surg 1992;216: 172-183. 5. Khalili TM, Navarro RA, Middleton Y, et al: Early postoperative feeding increases anastomotic strength in a peritonitis model. Am J Surg 2001;182:621--624. 6. Kiyama T, Witte MB, Thornton FJ, et al: The route of nutrition' support affects the early phase of wound healing. JPEN J Parenter Enteral Nutr 1998;22:276-279. 7. Moore FA: Effects of immune-enhancing diets on infectious morbidity and multiple organ failure. JPENJ Parenter Enteral Nutr 2001;25:S36-S42. 8. Heys SD, Walker LG, Smith I, Eremin 0: Enteral nutrition supplementation with key nutrients in patients with critical illness and cancer. Ann Surg 1999;229:467-477. 9. Beale RJ, Bryg DJ, Bihari DJ: Immunonutrition in the critically ill: A systematic review of clinical outcome. Crit Care Med 1999;27: 2799-2805. 10. Heyland DK, Novak F, Drover JW, et al: Should immunonutrition become routine in the critically ill patient? JAMA 2001;286: 944-953. 11. Brown RO, Hunt H, Mowatt-Larssen CA, et al: Comparison of specialized and standard enteral formulas in trauma patients. Pharmacotherapy 1994;14:314-320. 12. Moore FA, Moore EE, Kudsk KA, et al: Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding. J Trauma 1994;37:607-615. 13. Kudsk KA, Minard G, Croce MA, et al: A randomized trial of isonitrogenous diets after severe trauma: An immune-enhancing diet reduces septic complications. Ann Surg 1996;224:531-540. 14. Mendez C, Jurkovich GJ, Garcia, et al: Effects of an immuneenhancing diet in critically injured patients. J Trauma 1997;42: 933-940. 15. Weimann A, Bastian L, Bischoff WE, et al: Influence of arginine, omega-3-fatty acids and nucleotide-supplemented enteral support on systemic inflammatory response syndrome and multiple organ failure in patients after severe trauma. Nutrition 1998;14: 165-172. 16. Suchner U, Heyland DK, Peter K: Immune-modulatory actions of arginine in the critically ill. Br J Nutr 2002;87(suppl 1):SI21-S132. 17. McQuiggan MM, Marvin RG, McKinley BA, et al: Enteral feeding following major torso trauma: from theory to practice. New Horiz 1999;7:131-146. 18. A.S.P.E.N. Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002;26(suppl)75A--85A.
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19. Ott L, Young B, Phillips R, et al: Altered gastric emptying in the head-injured patient: Relationship to feeding intolerance. J Neurosurg 1991;74:738-742. 20. Kortbeek JB, Haigh PI, Doig C: Duodenal versus gastric feeding in ventilated blunt trauma patients: A randomized controlled trial. J Trauma 1999;46:992-996. 21. Boivin MA, Levy H: Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill. Crit Care Med 2001; 29:1916-1919. 22. Marvin RO, Moore FA, Cocanour CS, et al: Implementation of a procedure team improves utilization and reduces cost for critically ill patients in the ICU [abstract]. J Trauma 1998;44:425. 23. Reed RL, Eachempati SR, Russell MK, Fahkry C: Endoscopic placement of jejunal feeding catheters in critically ill patients by a "push" technique. J Trauma 1998;45:388-393. 24. Kozar RA, McQuiigan MM, Moore FA: Nutritional support of trauma patients. In Chicora SA, Martindale RG, Schweitzer SD (eds): Nutritional Considerations in the Intensive Care Unit. Science, Rationale, and Practice. Dubuque, lA, Kendall/Hunt, 2002, p 229. 25. Mentec H, Dupont H. Bocchetti M: Upper digestive intolerance during enteral nutrition in critically ill patients: frequency, risk factors, and complications. Crit Care Med 2001;29:1955-1961. 26. Kozar RA, McQuiggan MM, Moore EE, et al: Postinjury enteral tolerance is reliably achieved by a standardized protocol. J Surg Res 2002;104:70-75. 27. Cachecho R, Millham FH, Wedel S: Management of the trauma patient with preexisting renal disease. Crit Care Clin 1994;10: 523-536. 28. Monaghan R, Watters JM, Clancey SM: Uptake of glucose during continuous arteriovenous hemofiltration. Crit Care Med 1993;21: 1159-1163. 29. Frankenfield DC, Reynolds HN, Badellino MM: Glucose dynamics during continuous hemodiafiltration and total parenteral nutrition. Intensive Care Med 1995;21:1016-1022. 30. Macias WL, Alaka KJ, Murphy MH: Impact of the nutritional regimen on protein catabolism and nitrogen balance in patients with acute renal failure. JPEN J Parenter Enteral Nutr 1996;20: 56--62. 31. Rodriguez DJ, Clevenger fW, Osler TM, et al: Obligatory negative nitrogen balance following spinal cord injury. JPEN J Parenter Enteral Nutr 1991;15:319-322. 32. McClave SA, Snider HL: Understanding the metabolic response to critical illness: Factors that cause patients to deviate from the expected pattern of hypermetabolism. New Horiz 1994;2: 139-146. 33. Sauaia A, Moore FA, Moore EE, et al: Multiple organ failure can be predicted as early as 12 hours after injury. J Trauma 1998;45: 291-301. 34. Smith-Choban P, Weireter U, Maynes C: Obesity and increased mortality in blunt trauma. J Trauma 1991;31:1253-1257. 35. Smith-Choban P, Burge JC, Scales D: Hypoenergetic nutrition support in hospitalized obese patients: A simplified method for clinical application. Am J Clin Nutr 1997;66:546-550. 36. Crook MA, Hally V, Panteli JV: The importance of the refeeding syndrome. Nutrition 2001;17:632--637. 37. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345: 1359-1367. 38. Van den Berghe G, Wouters PJ, Boullion R, et al: Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med 2003;31:359-366. 39. Myers JG, Page CP, Stewart RM, et al: Complications of needle catheter jejunostomy in 2022 consecutive applications. Am J Surg 1995;170:547-551. 40. Holmes JH, Brundage SI, Hall RA, et al: Complications of surgical feeding jejunostomy in trauma patients. J Trauma 1999;47: 1009-1012. 41. Marvin RG, McKinley B, McQuiggan M, et al: Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition manifests on reliable signs for early detection. Am J Surg 2000;179:7-12. 42. Petersen SR, Holaday NJ, Jeevanandam M: Enhancement of protein synthesis efficiency in parenterally fed trauma victims
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by adjuvant recombinant human growth hormone. J Trauma 1994;36:726-733. 43. TakalaJ, Ruokonen E,WebsterNR: Increased mortality associated with growth hormone treatmentin critically ill adults. NEngl J Med 1999;341:785-792.
44. A.S.P.E.N. Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr2002;26(1 suppl):88SA-89SA. 45. Gervasio JM, Dickerson RN, Swearingen J, et al: Oxandrolone in trauma patients. Pharmacotherapy2000;20:1328-1334.
Nutritional Support in Patients with Sepsis Paul E. Marik, MD, FCCM, FCCP
CHAPTER OUTLINE Introduction Route of Feeding Timing of Feeding Nutrient Composition Role of Immunomodulating Diets in Patients with Sepsis Role of "Nutritional" Antioxidants in Sepsis Role of Permissive Underfeeding in Sepsis Conclusion
INTRODUCTION Sepsis is a major cause of morbidity and mortality worldwide and is the leading cause of death in noncoronary intensive care units. In the United States, approximately 750,000 cases of sepsis occur each year, at least 225,000 of which are fatal.' Despite the use of antimicrobial agents and advanced life supportive care, the case fatality rate for patients with sepsis has remained consistently between 30% and 40% over the last three decades," A marked increase in the incidence of sepsis can be expected in the next decade, primarily due to the increasing age of the population as well as to advances in medical technologies and the increasing use of immunosuppressive agents.' Over the last two decades nutritional support has emerged as a vital component of the management of critically ill patients. Nutrition supplies vital cell substrates, antioxidants, vitamins, and minerals, which optimize recovery from illness. Nutritional support is an important component of the multimodality management of patients with sepsis. It is likely that optimal nutritional support will reduce the morbidity and mortality of patients with severe sepsis. Despite the increasing incidence of sepsis and recognition of the importance of nutritional support in the critically ill, few studies have specifically investigated the role of nutrition in patients with sepsis. Consequently, the recommendations made
in this chapter are based on the synthesis of the best evidence from basic research, extrapolations from critically ill patients without sepsis and limited data from clinical studies of patients with sepsis. The key elements to consider in initiation of nutritional support in any patient are the route of feeding, the timing, the nutrient composition, and the dose/quantity. Each of these elements will be reviewed as they apply to the patient with sepsis.
ROUTE OF FEEDING In critically ill patients, the use of total parenteral nutrition (TPN) is associated with immune compromise, increased incidence of infections and complications, and increased mortality compared with the use of enteral nutrition.' It is likely that the risks associated with TPN are compounded in critically ill patients with sepsis. These patients should therefore be fed enterally unless the lack of functional bowel or safe access to it precludes use of enteral nutrition. Many patients with severe sepsis are treated with vasopressor agents in an attempt to maintain adequate arterial pressure and to improve tissue pertusion.! and many clinicians mistakenly believe that patients receiving vasopressors should not receive enteral nutrition. This assumption is based on the premise that enteral nutrition may cause bowel ischemia or infarction in these patients. Consequently, enteral nutritional support is often withheld until the vasopressor agents are discontinued or alternatively until TPN is initiated. Clinical and experimental data, however, strongly support the concept that enteral. nutrition increases splanchnic blood flow and nutrient utilization and may prevent bowel ischemia. In a canine model of lung injury, Purcell and colleagues' demonstrated that continuous enteral nutrition restored depressed splanchnic blood flow and increased splanchnic oxygen utilization. Kazamias and colleagues" studied the effects of enteral nutrition in a canine Escherichia coli endotoxin model. In this study, enteral nutrition restored depressed hepatic and superior mesenteric arterial and portal venous blood flow with normalization of intestinal mucosal and hepatic microcirculation and restoration of tissue oxygenation and hepatic adenosine
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triphosphate (ATP) stores. Revelly and colleagues" confirmed these findings in patients who received vasopressor agents after cardiac surgery. In this study, continuous enteral nutrition increased cardiac index, splanchnic blood flow, insulin secretion, and glucose utilization. The blood flow redistribution noted with enteral nutrition may be affected by the nutrient composition of the diet. Immune-enhancing nutritional formulations have been demonstrated to increase splanchnic blood flow to a greater degree than standard formulations in animal models.I" Although these data suggest that enteral nutrition may restore splanchnic blood flow and tissue oxygenation in patients with severe sepsis, it is probably prudent to delay the initiation of feeding until the patient has received volume resuscitation and an adequate mean arterial blood pressure has been achieved (this goal should be attained within 6 hours of presentation to the hospitalj.s" This approach does not apply to patients who have obstructive splanchnic vascular disease in whom enteral nutrition may cause further bowel ischemia. Many clinicians advocate postpyloric rather than gastric feeding on the basis that critically ill patients often have gastroparesis and that gastric feeding may predispose them to emesis and aspiration. Although Mentec and colleagues'? demonstrated some degree of upper digestive intolerance in 79% of nasogastrically fed patients, only 4.5% were unable to tolerate gastric feeding." In a meta-analysis of nine published studies we demonstrated no significant difference in the incidence of pneumonia (odds ratio [OR] 1.44; 95% confidence interval [CI] 0.84 to 2.46), percentage of caloric goal achieved (-5.2%; 95% CI -18.0 to 7.5%), mean total caloric intake (-169 calories; 95% CI -320 to 34 calories), length of ICU stay (-1.4 days, 95% CI -3.7 to 0.85), or mortality (OR 1.08; 95% CI 0.69 to 1.68) between patients fed gastrically compared with patients who received postpyloric tube feeding. II Based on these data we recommend that critically ill patients with sepsis who are not at a high risk for aspiration have a nasogastric or orogastric tube placed on admission to the ICU for the early initiation of enteral nutrition. The use of promotility agents should be considered in patients with high gastric residual volumes." Patients who remain intolerant of gastric tube feeding despite the use of promotility agents, patients with clinically significant reflux, and patients with documented aspiration should have a small intestinal feeding tube inserted for continuation of enteral nutritional support.
TIMING OF FEEDING Because many critically ill patients have gastroparesis and many of these patients have diminished or absent bowel sounds, enteral nutrition is often withheld for 5 to 7 days until the return of gastric emptying and bowel sounds. In addition, many clinicians believe that patients can tolerate 5 to 7 days of starvation without detrimental clinical effects. However, early enteral nutrition (as opposed to delayed enteral nutrition) has been demonstrated to improve nitrogen balance, wound healing,
and host immune function, augment cellular antioxidant systems, decrease the hypermetabolic response to tissue injury, and preserve intestinal mucosal integrity.I3-20 A number of studies have demonstrated that starvation for as short a time as 12 hours after injury depletes tissue antioxidant systems whereas early feeding after injury helps to maintain antioxidant levels.21-25 We performed a meta-analysis of 15 prospective, randomized clinical trials in which early versus delayed enteral nutritional support was compared in critically ill patients." This meta-analysis, which included patients with sepsis, demonstrated that early feeding decreases infectious complications and length of ICU stay. Based on the results of this meta-analysis and the experimental data presented earlier, we believe that enteral nutrition should be initiated within 12 hours of admission to the ICU in all critically ill patients. No benefit from delaying the initiation of nutritional support has been demonstrated.
NUTRIENT COMPOSITION Role of Immunomodulating Diets in Patients with Sepsis For a discussion of general concepts about these diets see Chapter 19. It has recently been recognized that a number of specific nutritional supplements are able to modulate the biologic response to injury, inflammation and infection. The addition of these specific nutrients to standard enteral formulations has resulted in a new generation of enteral nutritional formulas and the concept of immunomodulating nutritional support. In general these immunomodulating nutritional formulas contain supplemented glutamine, arginine, omega-3 fattyacids, and anti-oxidants, Experimental data has demonstrated that each of these nutritional supplements have favorable biological and clinical effects.27-33 Glutamine is a non-essential amino acid which is synthesized and released from skeletal muscle into the circulation, where it acts as an interorgan nitrogen and carbon transporter for intracellular glutamate. 29. 3o It is a precursor for the synthesis of the major antioxidant glutathione. Most importantly glutamine is a primary nutrient for enterocytes and the gut associated lymphoid tissue. In the critically ill, glutamine synthesis may be unable to keep pace with demand and a deficiency state ensures." This may have profound effects on the integrity of the gastrointestinal tract and lymphoid tissue. Arginine is traditionally regarded as a non-essential amino-acid. In the critically ill, however, arginine may become essential. Arginine has diverse biological actions including the stimulation of growth hormone, prolactin and insulin-like growth factor, is the precursor of nitric oxide (NO), is required for the synthesis of hydroxy-proline, and is required for lymphocyte function. 28,32,34 The omega-S fatty acids eicosapentaenoic acid and docosahexaenoic acid, which are derived from fish oil, are usually added to immuno-modulating nutritional lormulas." An incrase in the proportion of omega-3 as apposed to omega-6 fatty acids has numerous
SECTION V • Disease Specific
biological effects, however, in the critically ill its effects on leukotriene and prostaglandin production may be most important. Overall, inflammatory mediatiors derived from omega-3 fatty acids are less inflammatory and less immunosuppressive. 31,35,36 To date more than 20 randomized clinical trials evaluating the role of immunomodulating enteral formulas predominantly in critically ill patients have been performed. Although the results of these studies have been widely debated, most have demonstrated a clinical benefit in terms of reduced occurrence of infectious complications and reduced length of ICU and hospital stay.37-39 The effect of these formulations on organ failure and mortality is less clear. The effects of individual nutrients in subsets of critically ill patients have been less well evaluated. Because the composition of many of these formulas differs, it is likely that they do not have equivalent biologic and clinical effects. The use of argininesupplemented immunomodulating diets in patients with sepsis is controversial. It has been suggested that arginine is an "imrnunostirnulating nutrient" that increases the proinflammatory response in patients with sepsis and "adds fuel to the fire."4Q-42 This argument is based on the fact that arginine is the precursor for nitric oxide (NO) synthesis and that the generation of NO appears to be a fundamental finding in sepsis. Plasma and tissue levels of nitrite and nitrate (bioreaction products of NO) increase significantlyin experimental models of sepsis and in patients with sepsis. 43-48 NO binds to heme-containing proteins such as guanylate cyclase, which it activates to release guanosine 3',5'-cyclic monophosphate (cGMP).49 cGMP-mediated actions include smooth muscle relaxation and inhibition of platelet aggregation. 49,50 In addition to mediating vasodilation, NO has been implicated as a cause of the myocardial depression characteristic of sepsis. 51,52 In the cardiac myocyte, cGMP inhibits the j3-adrenergic stimulated increase in the slow inward calcium current and reduces the calcium affinity of the contractile apparatus. In addition to increasing cellular cGMP, NO may directly cause cellular injury via the formation of oxygen radicals. In the presence of superoxide anion, NO leads to the formation of peroxynttrtte.P'" Peroxynitrite is a potent oxidant with toxic effects on many molecules including nucleic acids, lipids, and proteins. Peroxynitrite impairs mitochondrial respiration and activates the poly(ADP) ribose synthase enzyme, resulting in reduced nicotinic acid dinucleotide (NAD), slowing the rate of glycolysis, electron transport, and ATP generation. 55-57 Furthermore, peroxynitrite and peroxynitrous acid cause nitrosylation of tyrosine groups on proteins forming nltrosotyrosine." NO synthesis requires the oxidation of a single guanidino nitrogen atom of L-arginine, a process involving the oxidation of nicotinamide adenosine dinucleotide phosphate (NADPH) and the reduction of molecular oxygen. Three major NO synthase (NOS) isoforms have been identified, which can be grouped together as constitutive NOS (cNOS) and inducible NOS (iNOS). iNOS is not normally active in the noninjured state. Various inflammatory mediators released during sepsis, but particularly interleukin (IL)-I, tumor necrosis factor-a, interferon, and
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platelet activating factor, alone or synergistically initiate the transcription and translation of iNOS. Arginine supplementation increases NO generation in sepsis," whereas arginine depletion reduces NO production/" It has therefore been suggested that arginine supplementation will increase NO-mediated tissue damage in sepsis and increase mortality.P'" The notion that arginine is proinflammatory and increases tissue inflammation and injury in patients with sepsis may not be correct given the incomplete knowledge at the present time. Although arginine is required for the synthesis of the T-cell receptor and for lymphocyte proliferation and function,61-63 arginine may limit the inflammatory response and associated tissue injury in sepsis by increasing NO production. Emerging data suggest that NO may be an important antiinflammatory mediator and regulator of microvascular blood flow in sepsis. NO has been demonstrated to downregulate the expression of endothelial cell adhesion molecules as well as the proinflammatory cytokines.64-68 In an endotoxin acute lung injury model, Walley and colleagues'" demonstrated that NO decreased pulmonary macrophage tumor necrosis factor-a and IL-6 protein and messenger RNA (mRNA) expression.f Fowler and co-workers'? demonstrated that NOsignificantly reduced IL-8 mRNA in cytokine-activated endothelial cells. Sundrani and colleagues" demonstrated that NOS inhibition increases venular leukocyte rolling and adhesion in septic rats, an effect that was partially reversed by the administration of i-arginine." De Caterina and colleagues" demonstrated that NO inhibited IL-I<xstimulated vascular cell adhesion molecule-I expression in a concentration-dependent manner. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers. Furthermore, these authors demonstrated that NO decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and intercellular adhesion molecule-I) and secretable cytokines (IL-6 and IL-8). These studies demonstrate that NO down-regulates the expression of endothelial cell adhesion molecules, the secretion of chemokines, and the transendothelial migration of inflammatory cells." While the anti-inflammatory effects of NO have not been fullydelineated, it is thought that NO inhibits the activation of nuclear transcription factor kappa-B (NF-lCB). NO may inhibit the activation of NF-lCB by: (1) scavenging reactive oxygen species thought to be important in the signalling events upstream of NF-lCB activation; (2) enhancing expression and/or stabilization of its inhibitor I-lCB and/or by inhibiting the binding of the pSO/p65 heterodimer to its DNA binding domains. 64,66,73-75 dela Torre and colleagues have demonstrated that NO Snitrosylates are a key thiol group in the DNA binding domain of p50 and that this is associated with decreased binding of NF-lCB to the promotor/enhancing sites with decreased gene transcription." In addition to decreasing neutrophil adhesion, activation, and degranulation in the microcirculation, NO has been demonstrated to decrease tissue factor expression.P'" Furthermore, NO inhibits platelet adhesion and aggregation to the endotheliurn.Pf" Recently Grimm and colleagues" demonstrated that NO
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inhibits the gene transcription and expression of major histocompatibility complex class II (MHC-II) molecules on vascular endothelial cells. The expression of MCH-II plays an important role in endothelial activation, and the inhibition of MCH-I1 may partly explain the antiinflammatory action of NO.82 Paradoxically, arginine supplementation may decrease oxidant damage. NOS has the ability to produce superoxide in addition to NO.83 Superoxide production is increased in the absence of t-arginine whereas the presence of i-arginine inhibits superoxide formation. Furthermore, NO may act as a superoxide radical scavenger." The most persuasive evidence to support the notion that L-arginine may be an anti-inflammatory agent is the effect of arginine supplementation on the microvascular reperfusion injury and allograft survival in both experimental transplantation models and in patients receiving transplants. Numerous experimental studies have demonstrated that L-arginine reduces the reperfusion injury in transplanted organs with attenuation of leukocyte infiltration and tissue injury and improved microvascular perfusion.85-88 Inhibition of NO production increases the reperfusion injury and decreases graft and recipient survival." Dietary arginine supplementation potentiates the immunosuppressive efficacy of standard immunosuppressive agents and has been demonstrated to enhance long-term allograft survival in both experimental animal models and clinical studies.90·91 In a murine renal allograft model, L-arginine supplementation after transplantation reduced vascular inflammation, endothelial injury, and vascular thrombosis.P Furthermore, L-arginine decreased tubulitis, interstitial cell infiltration, and interstitial injury. In a prospective, randomized clinical trial in patients undergoing kidney transplantation, Alexander'" demonstrated a reduction in the number of rejection episodes from 37% in the control group to 7% in the group of patients receiving a nutritional supplement containing arginine and canola oil. In addition to its anti-inflammatory properties, NO may play an important role in regulating blood flow in sepsis. A number of models of sepsis have demonstrated that NOS inhibition decreases microvascular flow and increases tissue injury in a number of organs including the intestines, liver, lung, and kidney, changes that are partially reversed by the administration of L-arginine. 43,94-96 These data suggest that NO may be important for maintaining microcapillary blood flow and decreasing the microvascular injury of sepsis. The effect of arginine supplementation and NOS inhibition has been investigated in a number of experimental models of sepsis. L-Arginine has been demonstrated to increase cardiac output in endotoxic shock models, whereas NOS inhibition decreases cardiac output, contractility, oxygen delivery,and oxygen utilization.97,98 Price and colleagues'P' demonstrated that L-arginine reversed the myocardial depression seen in endotoxic shock. Madden and colleagues'?' demonstrated that arginine supplementation increased the survival times of rats with peritonitis induced by cecal ligation and puncture. Similarly, Gianotti and colleagues'S demonstrated a
survival rate of 56% after cecal ligation and puncture in arginine-supplemented mice compared with 20% in those receiving standard nutrition. This survival advantage was reversed with the arginine inhibitor N-ro-nitro-L-arginine. Minnard and colleagues'P' demonstrated that inhibition of NO synthesis decreased survival in a murine endotoxin model. Similarly in an awake canine endotoxin model, Cobb and co-workers'?' demonstrated that inhibition of NOS decreased cardiac index and oxygen consumption and increased mortality. In a murine endotoxin model, Park and colleagues" demonstrated increased mortality with NOS inhibition that was associated with an increase in tissue damage in the lung, liver, and kidney. The benefits of L-arginine (and NO) supplementation in critically ill patients with sepsis can be inferred from two complementary clinical studies. The first investigated the impact of supplemental i-arginine, and the second studied the outcome of a NOS inhibitor in patients with sepsis. Galban and colleagues'P demonstrated a significant reduction in all-eause mortality in ICU patients with sepsis fed an enteral formula enriched with arginine. IOS Recently, a randomized, placebo-eontroIled, clinical trial of a nonselective NOS inhibitor in patients with sepsis was stopped prematurely because of a significantly higher mortality in the treatment arm. 106 In summary, these data suggest that i-arginine supplementation may be beneficial in patients with sepsis. The importance of i-arginine supplementation is underscored by the fact that sepsis may be an i-argininedeficient state. i-Arginine levels may become critically reduced in patients with sepsis due to decreased intake, increased metabolism, and diversion of L-arginine through the urea cycle as a consequence of increased arginase expression.Fr!!' Studies to confirm this concept and to define an appropriate arginine dose are still required.
Role of "Nutritional" Antioxidants in Sepsis The release of free radicals with damage to host cell membranes and other cell components plays an important role in tissue damage in sepsis. Endogenous antioxidants are rapidly depleted in patients with sepsis, and low levels of antioxidants are associated with organ dysfunction and increased mortality.II2-114 One of the main scavenger systems responsible for cleavage of free radicals is selenium-dependent glutathione peroxidase.!" Patients with sepsis have low levels of circulating selenium.114 In a small randomized, controlled trial in patients with sepsis, Angstwurm and colleagues!" demonstrated that selenium replacement reduced organ dysfunction and improved clinical outcome. Selenium is safe and cheap and appears to be a very promising agent in the management of sepsis. Flavonoids are a large group of naturally occurring antioxidants ubiquitously distributed in the plant kingdom further subdivided into several classes. Flavonols, such as quercetin, are predominantly found in onions, broccoli, apples, tea, and red wine.116.117 Many biologic effects of the f1avonoids have been
SECTION V • Disease Specific
described in addition to their antioxidant properties including anti-inflammatory, antiallergic, and antimutagenic effects. II8- 121 The anti-inflammatory action is mediated in part by inhibition of cytokine action.!" In addition, flavonoids have been reported to inhibit the catalytic activities of a variety of enzymes involved in the inflammatory cascade, including phospholipase C, cyclooxygenase, lipoxygenase, and myeloperoxidase. 118- 121 Quercetin, one of the predominant flavonoids in red wine has been shown to be a selective inhibitor of phospholipase Az.123 Flavonoids are particularly appealing in the treatment of patients with sepsis; however, this therapeutic intervention is currently untested.
Role of Permissive Underfeeding in Sepsis A caloric intake of 25 to 30 kcal/kg/day and a protein intake of 1 to 1.5 g/kg/day is the nutrient intake currently recommended in critically ill patients based on estimated energy expenditure. There are no data to suggest that matching caloric intake to energy expenditure measured by indirect calorimetry is beneficial. Indeed, experimental studies suggest that administration of nutrients at metabolic expenditure can exacerbate inflammation and increase mortality.124This may have particular relevance in patients with sepsis. Anorexia is a component of the stress response. Animals and humans decrease nutrient intake during illness and after injury. There is debate regarding the significance of decreased nutrient intake after injury. Clearly, long-term starvation leads to loss of lean body mass, cellular and organ dysfunction, and increased mortality. However, there are no data available to suggest that short-term underfeeding (as opposed to complete starvation) has any detrimental effects on recovery from critical illness. Although full nutrient intake may optimally support protein synthesis and growth, it may also stimulate detrimental processes such as bacterial virulence, autoimmune processes, cytokine release, inflammation, and energy consumption.P' This has lead to the concept of permissive underfeeding. 124 Animal studies clearly indicate that overfeeding (administering nutrients at levels that exceed energy consumption) is detrimental. Yamazaki and associates'" fed rats either a normal diet or a high-ealorie/ protein diet. After 6 days of feeding, the animals were subjected to cecal ligation and perforation. Although the high-ealorie/protein diet resulted in better nitrogen balance, 4-day mortality was increased from 14% to 53%. Alexander and co-workers!" induced peritonitis in guinea pigs by infusing Escherichia coli and Staphylococcus aureus. Overfeeding decreased survival rates (10% vs. 38%). Many animal studies of critical illness suggest that moderate underfeeding (administering nutrients at less than metabolic expenditure) improves outcome. Alexander and co-workers'< reported improved survival with underfeeding in a model of E. coli/S. aureus sepsis (57% vs. 38%). Survival was improved despite greater
377
weight loss. Peck and colleagues!" studied calorie and protein restriction in mice with Salmonella peritonitis.!" Calorie restriction (50% of normal) improved survival. On the other hand, severe protein restriction decreased survival. These authors further studied dietary restriction during guinea pig peritonitis produced with E. coli/S. aureus infection. 128 Moderate protein restriction improved survival despite worsening of nitrogen balance. Other studies have demonstrated improved survival with restricted diets in mice infected with Salmonella typhimurium and in rats after endotoxin administration.P'P" In experimental models of sepsis, severe dietary restriction (as opposed to moderate restriction) has been reported to increase mortality.'!' Overall, these studies suggest that severe dietary restriction is associated with increased mortality during infection. However, moderate restriction may improve survival after infection. There has been only one prospective, randomized, controlled clinical trial of hypocaloric nutrition in humans. McCowen and associates'" randomly assigned 40 adult hospitalized patients to hypocaloric parenteral nutrition (1000 kcal/day; 70 g of protein/day) or standard parenteral nutrition (25 kcal/kg/day and 1.5 g of proteinlkg/day). As expected, nitrogen balance was worse in the hypocaloric nutrition group. Overall, there were no significant differences in noninfective complications, length of hospital stay, and mortality. However, the standard feeding group had more infections (11 of 20 vs. 7 of 20). In summary, animal studies and one human clinical trial of hypocaloric nutrition during critical illness suggest that underfeeding may improve outcome. Clearly overfeeding critically ill patients with sepsis is associated with increased morbidity. The role of permissive underfeeding requires further study. However, until additional data are available, it may be reasonable to limit the caloric intake of patients with sepsis to approximately 20 kcal/kg/day and protein intake to 1 g/kg/day.
CONCLUSION The nutritional management of patients with sepsis is best summarized by the following dictum: do it early, do it gastrically, do it with an immune-enhancing diet (although this is not fully supported yet in the absence of specific substrate and dosing), and do it slowly. REFERENCES 1. Angus DC, Unde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and associated costs of care. Crit Care Med 2001;29: 1303-1310. 2. Marik PE,Varon J: Sepsis: State 01 the art. Dis Mon 2001;47:463-532. 3. Heyland DK, MacDonald S, Keefe L, Drover JW: Total parenteral nutrition in the critically ill patient: A meta-analysis. JAMA 1998;280:2013-2019. 4. Purcell PN, Davis K Jr, Branson RD, Johnson DJ: Continuous duodenal feeding restores gut blood flow and increases gut oxygen utilization during PEEP ventilation lor lung injury. Am J Surg 1993;165:188-193. 5. Kazamias P, Kotzampassi K, Koufogiannis D, Eleftheriadis E: Influence of enteral nutrition-induced splanchnic hyperemia on
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peritonitis by modulating bacterial clearance. The role of nitric oxide. Ann Surg 1993;217:644-653. 103. Minnard EA, Shou J, Naama H, et al: Inhibition of nitric oxide synthesis is detrimental during endotoxemia. Arch Surg 1994;129: 142-147. 104. Cobb JP, Natanson C, Hoffman WD, et al: N-ro-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 1992;176:1175-1182. 105. Galban C, Montejo JC, Mesejo A, et al: An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med 2000;28:643-648. 106. Grover R, Lopez A, Lorente J, et al: Multicenter, randomized, placebo-controlled, double blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock [abstract). Crit Care Med 1999;27(suppl):A33. 107. Klasen S, Hammermann R, Fuhrmann M, et al: Glucocorticoids inhibit lipopolysaccharide-induced up-regulation of arginase in rat alveolar macrophages. Br J PharmacoI2oo1;132:1349--1357. 108. Bernard AC, MistrySK, Morris SM Jr, et al: Alterations in arginine metabolic enzymes in trauma. Shock 2001;15:215-219. 109. Ochoa JB, Bernard AC, O'Brien WE, et al: Arginase I expression and activity in human mononuclear cells after injury. Ann Surg 2001;233:393-399. 110. Tsuei BJ, Bernard AC, Shane MD, et al: Surgery induces human mononuclear cell arginase I expression. J Trauma 2001;51:497-502. Ill. Ochoa JB, Bernard AC, Mistry SK, et al: Trauma increases extrahepatic arginase activity. Surgery 2000;127:419--426. 112. Cowley HC, Bacon PJ, Goode HF,et al: Plasma antioxidant potential in severe sepsis: A comparison of survivors and nonsurvivors. Crit Care Med 1996;24:1179--1183. 113. Goode HF,Cowley HC,Walker BE,et al: Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 1995;23:646-651. 114. Goode HF, Webster NR: Free radicals and antioxidants in sepsis. Crit Care Med 1993;21:1770-1775. 115. Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R: Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care Med 1999;27:1807-1813. 116. Hertog MG, Hollman PC, Katan MB: Content of potentially anticarcinogenic f1avonoids of 28 vegetables and 9 fruits commonly consumed in The Netherlands. J Agric Food Chem 1992;40: 2379--2383.
117. Hertog MG, Hollman PC, van de Putte B: Content of potentially anticarcinogenic f1avonoids in tea infusions, wines and fruit juices. J Agric Food Chern 1993;41:1242-1246. 118. Cotelle N, Bernier JL, Catteau JP, et al: Antioxidant properties of hydroxy-f1avones. Free Radic Bioi Med 1996;20:35-43. 119. Husain SR, Cillard J, Cillard P: Hydroxyl radical scavenging activity of f1avonoids. Phytochemistry 1987;26:2489--2492. 120. Kandaswami C, Middleton E Jr: Free radical scavenging and antioxidant activity of plant f1avonoids. Adv Exp Med Bioi 1994; 366:351-376. 121. Panes J, Gerritsen ME, Anderson DC, et al: Apigenin inhibits tumor necrosis factor-induced intercellular adhesion molecule-1 upregulation in vivo. Microcirculation 1996;3:279--286. 122. Gerritsen ME: Flavonoids: Inhibitors of cytokine induced gene expression. Adv Exp Med Bioi 1998;439:183-190. 123. Lindahl M, Tagesson C: Selective inhibition of group II phospholipase ~ by quercetin. Inflammation 1993;17:573-582. 124. Zaloga GP, Roberts P: Permissive underfeeding. New Horiz 1994;2:257-263. 125. Yamazaki K,Maiz A, Moldawer LL, et al: Complications associated with the overfeeding of infected animals. J Surg Res 1986;40: 152-158. 126. Alexander JW, Gonce SJ, Miskell PW, et al: A new model for studying nutrition in peritonitis. The adverse effect of overfeeding. Ann Surg 1989;209:334-340. 127. Peck MD, Babcock GF, Alexander JW: The role of protein and calorie restriction in outcome from Salmonella infection in mice. JPEN J Parenter Enteral Nutr 1992;16:561-565. 128. Peck MD, Alexander JW, Gonce SJ, Miskell PW: Low protein diets improve survival from peritonitis in guinea pigs. Ann Surg 1989;209:448-454. 129. Gauthier Y, Isoard P: Increased resistance to Salmonella infection of hypoferremic mice fed a low-protein diet. Microbiol Immunol 1986;30:425-435. 130. Yelch MR: Effects of naloxone on glucose and insulin regulation during endotoxicosis in fed and fasted rats. Circ Shock 1988;26:273-285. 131. Bhuyan UN, Ramalingaswami V: Responses of the proteindeficient rabbit to staphylococcal bacteremia. Am J Pathol 1972;69:359--368. 132. McCowen KC, Friel C, Sternberg J, et al: Hypocaloric total parenteral nutrition: Effectiveness in prevention of hyperglycemia and infectious complications-A randomized clinical trial. Crit Care Med 2000;28:3606-3611.
III Brain and Spinal Cord Injuries M. Bonnie Rosbolt, PharmD Jimmi Hatton, PharmD, BCNSP
Chapter Outline Introduction Traumatic Brain Injury Nutrition Assessment Nutrition Management Patient Monitoring Spinal Cord Injury Nutrition Assessment Nutrition Management Patient Monitoring
INTRODUCTION Patients with trauma to the central nervous system (CNS) are a complex population with multiple factors influencing nutritional support decisions. Traumatic brain injury (TBI) and acute spinal cord injury (ASCI) are most common in young adults, primarily men. There is significant morbidity and mortality associated with the primary injury, resulting from head and spinal cord trauma. Although the mortality rate appears to be decreasing, the rate of impaired individuals surviving with significant disability is increasing. The health care delivery system has improved the outcome of individuals who sustain these injuries. Immediate acute resuscitative measures, life support practices, quality of life rehabilitative care, and pharmaceutical advances have produced survivors with a "redesigned lifestyle"-a lifestyle with varying levels of daily independent living and productivity. Survivors of TBI and spinal cord injury often have significant cognitive or physical impairments, requiring life-long assistance, and are unable to return to the productivity levels of uninjured agematched counterparts. Early, aggressive nutritional support may limit initial muscle losses in both groups and sustained nutritional support during the chronic phase of recovery is a pivotal component of treatment. The impact of the initial insult to either the brain or spinal cord will result in an acute metabolic response, the stress response, mediated by endogenous hormonal changes influencing substrate metabolism.
Nutritional support is an important factor in management of the stress response. A change in the metabolic demands of the body isassociated with this stress response because a cascade of endogenous physiologic mediators are released. In addition to elevations in peripheral and central cytokines and other inflammatory mediators, increases in norepinephrine and epinephrine, adrenocorticotropic hormone, growth hormone, prolactin, vasopressin, and endorphins lead to significant metabolic alterations.V The relationship between the stress-related effects on organ and endocrine systems and immunologic competence leads to increased calorie and protein requirements. The magnitude of the systemic metabolic response after CNS injury is influenced by injury severity and location. The increased metabolic demand requires early intervention to limit functional loss of muscle and to lower the risk of complications from malnutrition that occurs sooner in this setting. The enteral route for provision of calories is preferred because of the potential advantages of less exacerbation of hyperglycemia, a theoretical reduction in the risk of infection, and the lower costs. Changes in gastric motility occur in both TBI and spinal cord injury, with the latter influenced dramatically by the site of primary insult. These effects contribute to the rationale for decisions about the route of specialized nutritional support for a given patient. Nutritional support is recognized as a critical component of care for patients with CNS trauma. Guidelines for nutritional support decisions have been developed by the Brain Trauma Foundation (BTF), the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), and the Section on Disorders of the Spine and Peripheral Nerves of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons.r" Throughout this chapter the specific clinical factors and significant publications contributing to nutritional support decisions for each of these populations will be outlined.
TRAUMATIC BRAIN INJURY Although TBI represents greater than 33% of all injuryrelated deaths in the United States, the extensive rehabilitation and long-term care requirements of survivors 381
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are also consequences that affect society.'' Financial implications of this injury in 1995 were estimated to be $56 billion. TBI is a condition affecting young adults. Increased awareness of the importance of immediate resuscitative measures has led to an increase in patient survival.The patient's chance for survival with better outcome is improved by minimizing the effects of hypoxemia, hypotension, and elevated intracranial pressure. Nutritional intervention during the acute phase of injury is a key factor contributing to survival after TBI and is recognized as important for optimal rehabilitation.
Nutrition Assessment Early nutritional intervention has a substantial impact on outcome. Systemic manifestations of the hypermetabolic state include increased protein breakdown (hypercatabolism), increased energy expenditure (hypermetabolism), and increased glucose production along with increased tissue resistance to insulin, leading to hyperglycemia." The stress response associated with the hypermetabolism is also responsible for an acute-phase response, illustrated by an increased production of fibrinogen, C-reactive protein and (X,I-acid glycoprotein. The liver's production of visceral proteins such as albumin, prealbumin, and transferrin declines. These changes affect monitoring parameters traditionally used in patients receiving nutritional support. Under these conditions, patients with severe TBI may experience 10% to 15% loss of lean body mass within I week if no intervention is made. A 30% weight loss would most likely be seen within 2 to 3 weeks after injury without nutritional support. This magnitude of loss has been reported to increase morbidity and mortality Io-fold in patients undergoing gastric surgery.' Consequently, the BTF has concluded that nutritional support is indicated within the first week after severe TBP The A.S.P.E.N. guidelines recommend initiation of feeding within 48 hours to reduce risk of infection, improve survival, and reduce disability." Infectious complications remain a major factor contributing to poor outcome in this population. Immunocompetence and gastrointestinal motility along with endothelial integrity are adversely affected by the increased metabolic demand," In 14 men with severe TBls (Glasgow Coma Scale [GCS] score <8), immunologic status was depressed within 72 hours of injury," In particular, components of the innate (phagocytic) and acquired (humoral and cellular) response were significantly depressed compared with those in age- and sexmatched control subjects. Significant reductions in neutrophil superoxide release and in numbers of T cells, T helper cells, T suppressor cells, and natural killer cells were reported along with significant dysfunction in the humoral production of immunoglobulins G and M. Early implementation of nutritional support mitigates the impairment of immune function in the patient with TBI. Modifiable components of immune function are altered after early nutritional support compared with delayed nutritional support," Increased production of
CD4 lymphocytic cells and an increased C04-to-CD8 ratio are seen with nutritional support initiated within 24 hours of injury. Treatments used in managing intracranial hypertension and the systemic sequelae accompanying this injury can influence nutritional support decisions. When intracranial pressure (lCP) is greater than 20 mm Hg or when cerebral perfusion pressure (CPP) is less than 60 mm Hg, treatments that influence nutritional goals are used.' CPP is the calculated difference between mean arterial pressure and ICP; consequently, treatments may include vasopressors to elevate mean arterial pressure or specific therapy for ICP. High doses of vasopressors alter perfusion to the gastrointestinal tract and increase the risk of ischemic bowel with subsequent implications for enteral nutrition tolerance and safety. The treatment options for lowering ICP include cerebrospinal fluid drainage, hyperventilation, mannitol, and pentobarbital coma. These treatments affect acid-base status, blood chemistry, gastrointestinal motility, cardiac output, and metabolic rate. Pentobarbital is a barbiturate that has central and peripheral effects on gastrointestinal motility. Peripherally pentobarbital decreases the tone and force of peristaltic contractions and centrally it decreases neural outputs that affect gastrointestinal activity. Determining accurate energy expenditure while avoiding overfeeding and ensuring tolerance in patients with pharmacologically induced coma is a challenge. In a retrospective study of 32 patients placed into pentobarbital coma, 23 patients received at least 75% of their measured energy expenditure (1.3 times higher than the predicted energy expenditure) with enteral nutrition." In this subgroup of patients, enteral feeding is possible, although postpyloric feedings may be warranted to ensure tolerance and prevent complications. Phenytoin administration is another potential source of nutritional problems in patients with head injuries. The occurrence of post-traumatic seizures in patients with TBls is not uncommon and requires treatment with an anticonvulsant. Phenytoin administration complicates the ability to provide adequate nutrition enterally while maintaining therapeutic drug levels without recognizing a significant drug-nutrient interaction.l'r" It is recommended that tube feedings be held for I hour before and after the administration of phenytoin to minimize the absorption interference affecting both total and albumin adjusted phenytoin concentrations. This practice affects the volume of enteral nutrition and requires adjustments in delivery rates to enable caloric goals to be achieved. Systemic effects of TBI include electrolyte abnormalities due to altered pituitary function and vasopressin release, immunosuppression, high gastric acid production, deep vein thrombosis, and seizures. Depressed serum zinc concentrations and elevated urinary excretion of zinc have been reported. When patients with TBls received supplemental doses of zinc, improved outcome was reported." Drug therapy used in the management of these complications can influence nutrition recommendations, tolerance, and monitoring end points.
SECTION V • Disease Specific
Nutrition Management Route The BTF does not support any particular route as superior in this population based on the lack of class I studies confirming any benefit on outcome.' The general consensus regarding route of nutritional support, however, is that the enteral route is preferred because gastrointestinal function is considered to be intact, despite effects of the injury on this system. Even patients with milder injuries may have dysphagia that persists and limits oral intake. The occurrence of dysphagia reported in the literature from various studies ranges from 25%to 60%. A recent study reported dysphagia in 61% of 54 patients. 15 An aspiration rate of 41% was reported with the most common disturbances (occurring in up to almost 80% of those studied) being diminished lingual control and loss of bolus control. Sixty percent had an impaired tongue base retraction. Other swallowing abnormalities reported in patients with brain injuries include delayed or absent swallowing reflex, reduced peristalsis, and prolonged oral transit time." The extent of swallowing dysfunction mandates that other avenues for nutritional delivery be assessed early in patients with TBls. TBI treatment guidelines acknowledge the need to reach full nutritional goals within 7 days of injury. Access routes for initiating enteral nutrition after TBI include nasoenteric (nasogastric, nasoduodenal, and nasojejunal), percutaneous, or surgical. Placement of the feeding tube using the nasoenteric route may be challenging in this setting because of the presence of severe facial fractures or refractory ICPelevations. In 23 patients with brain injuries, increased ICP and low GSC scores were associated with gastric atony and lower esophageal sphincter incompetence, which delayed patients' abilities to tolerate full enteral feedings by nasogastric tube." Recently, patients receiving enteral nutrition delivered within 24 hours of injury directly to the small bowel demonstrated accelerated recovery and improved nutritional markers compared with patients in whom full feedings were titrated using the gastric route." In general, when enteral nutrition is used, small bowel feedings are preferred. However, in a recent review of parameters to consider in decisions about initiation of enteral feeding in critically ill patients, more information comparing routes was identified as a need for future studies.' Full goal feedings have been reportedly delayed for up to 14 days when gastric feedings are used. The risk of aspiration with gastric feeding along with the difficulty of tube placement warrants the use of endoscopy or fluoroscopy to assure accurate tube position. The observation that gastric feeding presents increased risk for aspiration and delay in nutrient delivery has been challenged." Regardless of tube location, nutritional support should be initiated within 72 hours of injury to permit time for achieving nutrient intake goals within the first week. Prokinetic agents may be useful in improving gastric tolerance or assisting with repositioning of the tube if it dislodges. Metoclopramide and erythromycin have been used clinically in this setting without problems;
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however, doses and seizure risks must be examined on a patient-by-patient basis." Depending on the recovery from the acute injury, long-term feeding access devices will be used, usually after the first 10 days of injury. Percutaneous endoscopically placed gastric or jejunal devices are often used in this population because of the chronic nature of the recovery and rehabilitation phase of the disease. Enteral feeding can be initiated through different routes and accesses. The approach to enteral feedings can be followed in a step-wise manner (Fig. 31-1).
Energy Establishing nutritional goals in this population requires an understanding of the patient's neurologic condition. The GCS score describes the functional capacity of the injured brain with lower scores reflecting the most severe injury. Depending on injury severity, caloric demands will vary; this relationship has been translated into general dosing guidelines for daily caloric intake (Table 31-1). Nonsedated patients with severe TBls have mean resting metabolic expenditures approximately 40% above predicted values. Equations for predicting initial calorie needs are considered unreliable, and indirect calorimetry is encouraged in this population. The HarrisBenedict equation reportedly predicted measured metabolic demand accurately only 50%of the time in patients with head injuries who were receiving enteral feedings." Another formula has been derived to predict energy
FIGURE 31-1. Stepwise approach to initiation of enteral feedings in patients with severe brain injuries. (From Pepe JL, Barba CA: The metabolic response to acute traumatic brain injury and implications for nutritional support. J Head Trauma Rehabil 1999;14:462-474.)
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-
Energy Predictions for Patients with eNS Injuries
Equations
GCS <8: %RME = 152 - 14(GCS) + O.4(HR) + 7(DSI) GCS 2:8: %RME =90 - 3(GCS) + 0.9(HR)
Clinical condition
Estimates
GCS 4-5 GCS 6-7 GCS 8-12 Paraplegic Quadriplegic
40-50 kcal/day 30-40 keel/day 30-35 keel/day 27 kcal/day 23 keel/day
DSI, days since injury; GCS, Glasgow Coma Scale score; HR, heart rate; RME = resting metabolic energy. From Clifton GL, Roberston CS, Choi SC: Assessment of nutritional requirements of head-injured patients. J Neurosurg 1986;64:895-901.
expenditure specifically for patients with head injuries on the basis of a study of 57 patients with TBlswithin the first 2 weeks after injury.22 The formula incorporates the GCS score, heart rate, and days since injury as the predictive determinants of resting metabolic expenditure. The formula is provided in Table 31-1; however, a large prospective study to confirm its validity has not been reported. Close monitoring of metabolic changes is especially important in patients with TBls because hyperglycemia has been associated with poor outcome. Inadequate oxygen delivery to the brain as a consequence of reduced CPP will generate increased lactic acid production from anaerobic metabolism of glucose within local brain tissues. Lactate production within the injured brain is often monitored as a clinical parameter indicating dynamic processes within the injured tissue. Glucose administration rates are now limited to 3.5 g/kg/day to account for the change in oxidative utilization seen in acute traurna.P In fact, the serum glucose level should be closely monitored to keep concentrations less than 180 mg/dL to reduce the risk of exacerbation of the underlying brain damage. Enteral products offer a blend of lipids containing varying lengths of fatty acids that may be beneficial compared with parenteral lipids (only long-chain triglycerides in the United States) for patients with TBls. Myelin sheaths within the CNS are composed of lipids. The longchain fatty acids are key functional components of cellular membranes in the CNS; yet, these serve as initiators of free radical production after TBI. The injured brain continues to experience secondary injury, and the contribution of exogenous long-ehain fatty acids to persistent free radical generation is unknown. Consequently, a formula offering a blend of short-, medium- and long-chain triglycerides as lipid sources is preferred over parenteral emulsions. This may be a contributing factor in enteral nutrition blunting the acute phase response, along with the role of short-ehain fatty acids on gastrointestinal integrity. Medium-ehain triglycerides are rapidly metabolized and are readily available as a calorie source, in contrast to long-ehain triglycerides, which function primarily as
structural components within the body." The rapid metabolism of medium-chain triglycerides, however, can lead to ketosis in some patients. In the injured brain, glucose remains the fuel of choice; however, ketones can be an important readily available substrate too. Patients undergoing hyperventilation for management of ICP will develop laboratory changes reflecting a compensatory mechanism for the iatrogenic respiratory alkalosis. Therefore, arterial blood gases in addition to urinary ketones should be evaluated routinely to determine the etiology of the metabolic acidosis. Symptoms of ketosis would not be readily apparent in the patient with a TBI.
Protein Hypercatabolism is evidenced by the large protein losses reported in this population. Lean body mass losses, hypoalbuminemia, and altered visceral proteins are seen very early after TBI. Urine nitrogen losses exceeding 20 g/day have been reported. The amount of insulinlike growth factor-l, the mediator of growth hormone anabolic effects, is reduced after TBJ.25 The imbalance between anabolic and catabolic hormones contributes significantly to the persistent loss of nitrogen even with aggressive protein supplementation. Consequently, the nutritional regimen should include approximately 15% to 20% of total calories as protein replacement. Initial protein doses of 1.5 g/kg/day are reasonable with adjustments made on the basis of nitrogen balance, when available. Each of the above issues will affect the selection of product. When a formula for enteral nutrition is being considered in this setting, products with concentrated calorie sources and high protein are generally preferred. A list of formulas commonly used in the neurosurgical intensive care unit is provided in Table 31-2. The individual components of the formula, including the amount required for delivery of the Recommended Daily Allowance for vitamins and trace elements, should be evaluated on the basis of the patient's specific needs. Total volume, free water, and vitamin K concentrations differamong products and need to be considered as well.
Special Considerations Immunonutritional formulas have not been extensively studied prospectively compared to standard formulas in this population. However, use of an immune-enhancing nutritional formula was studied in 30 severely head injured patients (GCS between 4 and 10) investigating the effects of early versus delayed immune-enhancing enteral feedings." The immune-enhancing formula contained supplemental arginine, nucleic acids, omega-S fatty acids, and fiber. This study did not demonstrate any differences in length of stay or infectious complications between early and delayed feeding with the immuneenhancing formula. Therefore, the literature does not support routine use of immune-enhancing formula. Therefore, the literature does not support routine use of immune-enhancing formulas in this patient population.
SECTION V • Disease Specific
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_ _ Options for Enteral Tube Feeding Formulas Commonly Used In Head and Spinal Cord Injuries Product Name
Deliver 2.0 TraumaCal HN Boost Plus
lsocal HN
Administration Rate (mL/hr)
25 50 75 25 50 75 25 50 75 25 50 75
The increased delivery of glutamine may not be appropriate after TBI owing to the unknown contribution this amino acid may make to persistent glutamate production. The anti-inflammatory properties of c.o-3 fatty acids, although seemingly beneficial in this hyperdynamic state, still are long-chain fatty acids, and their contribution to free radical production is untested in this setting. Arginine is involved in the nitric oxide cascade, another system affected by TBI with unknown consequences of additional supplementation. A recent review of evidence for these products in critically ill patients suggested no favorable effect on mortality."
Patient Monitoring Many of the metabolic abnormalities associated with TBI will persist for the first 2 weeks after injury as the brain attempts to recover. Close monitoring of serum glucose and electrolyte levels is essential during this period. Baseline information before initiation of nutritional support should be collected. A decision about protein monitoring should be made; measurements of either prealbumin level or nitrogen balance or both should be obtained. The BTF states that class I data from this population show earlier improvement in visceral protein recovery rates with enteral than with parenteral nutrition, yet in another class I study, no difference in these rates was seen.' More investigations are needed in this area. Although the doses of protein are aggressive, monitoring of blood urea nitrogen to avoid azotemia or hyperammonemia is important. Any factor that can contribute to CNS changes must be considered and avoided. Sodium concentrations will be influenced by the injury to the brain. Attention to daily fluid balance, blood urea nitrogen and serum creatinine, free water orders related to nutrition, and parenteral fluid therapy is essential. Pituitary function after TBI may fluctuate, leading to cerebral salt wasting or frank diabetes insipidus or syndrome or inappropriate anti-diuretic hormone secretion. Hence, close monitoring of free water is indicated. Vasopressin is used in this population whenever diabetes insipidus is diagnosed or urine output is excessive. Free water supplementation will change drastically as
Nonprotein Calories (kcaljday)
Protein (gfday)
1020 2040 3060 702
45 90 135 50
1404
100
2106
149 35.5 71
756 1512 2268 530 1060 1590
106 26 53 78
adjustments are made with vasopressin and once it is discontinued, any recommendations for free water require reevaluation. Hypokalemia, hypophosphatemia, hypocalcemia, and hypomagnesemia are common and will probably be managed by standing orders for electrolyte replacement. If electrolytes are replaced intermittently by parenteral infusions, less chance exists for enteral nutrition to complicate these abnormalities. Cerebrospinal fluid drainage can produce losses that are clinically relevant to these assessments. As always, careful monitoring of any drugs administered, either through the feeding tube or other routes, is essential. Liquid pharmaceutical formulations should be examined for sorbitol content and pH because of the effect on tolerance to nutritional regimens. After the first 18 days of injury, metabolic demand has not been well defined. When patients' conditions are stabilized and extent of recovery appears evident, those with a persistent neurologic deficit will continue to require nutritional support. The hypermetabolic component to their injury is thought to subside over time, and adjustment in calorie provision will be necessary to prevent hyperglycemia. Although catabolism may continue, it will be at a much slower rate so a reduction in protein intake may also be indicated. Increases in blood urea nitrogen should be assessed in combination with other serum markers such as sodium or serum creatinine levels to determine whether the increase is related to hydration status. Upon discharge to rehabilitation or another care program, serum chemistry values should be monitored every 2 weeks initially and then at least monthly if chronic nutritional support is indicated. Careful attention to drug therapy is especially important during this phase of care because of the potential for clinically important interactions. The greatest potential for complications exists when the dynamic endogenous milieu of acute TBI is not reconsidered during the latter period of recovery. A prime example is hyperglycemia, an issue in most patients during the first 2 weeks after injury. The mediators of secondary injury after TBI contribute significantly to hyperglycemia and with time their production will decline. This will affect glucose concentrations and insulin doses derived from earlier metabolic profiles.
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Nasoenteric tubes can be cumbersome and are often dislodged with manipulations that are needed in critical care. Translocation or coiling of the feeding tube into the stomach may lead to a significant gastric residual volume of the enteral formula. The patient with a TBI who is immunosuppressed has a high risk for pneumonia. The additional risk of aspiration of tube feedings is substantial and should be avoided. Increased risk of sinusitis and aspiration due to obstruction of the swallowing reflex and interference with the lower esophageal sphincter has also been reported.s" Costs associated with enteral nutrition may be increased if sophisticated methods are required for routine placement of feeding tubes, replacement of tubes, and/or securing of tubes to prevent inadvertent removal."
an ASCI at or above the T61evel. This can be precipitated by full bladder or bowel, infections, severe constipation, or pressure sores. This condition leads to a rapid increase in blood pressure to potentially dangerous levels. Symptoms include headache, visual spots, blurred vision, and goose bumps. The primary risk of this condition is stroke; it is potentially life-threatening and must be recognized quickly. Patients are instructed about this condition and know to immediately empty bowels and bladder and seek medical help. Nutrition support personnel should be acutely aware of these symptoms and consider any dietary or nutritional component such as fiber as a contributing factor.
Nutrition Assessment SPINAL CORD INJURY Although ASCls can accompany up to 20% of TBls, the patient with an isolated ASCI has remarkably distinct nutritional support requirements. The physiologic reaction is similar in brain injury and spinal cord injury. The focal damage initiates the stress response and production of inflammatory mediators and cytokines, contributing to secondary injury. As in TBI, the extent of the secondary injury is proportional to the extent of the primary injury. When nutritional support is considered, a comprehensive approach focusing on spine injury level, extent of cord injury, and interrupted cord function is necessary. Patients with ASCls can develop ischemic pressure ulcers from prolonged placement on rigid spine backboards. They can also exhibit spinal shock and acute respiratory muscle failure if injuries are in the upper thoracic or cervical spine. The shock syndrome is unusual because of the overriding parasympathetic input to the vasculature, and patients will have hypotension accompanied by bradycardia. During the acute resuscitative period, patients will receive fluids, atropine, vasopressors, and high doses of the corticosteroid, methylprednisolone." The latter will begin within 8 hours of injury and may continue for up to 48 hours in some situations. In clinical trials, higher rates of sepsis and pneumonia have been reported with steroid treatment. The most recent guidelines for ASCls accepted by the AANS and Congress of Neurological Surgeons do not recommend this as a treatment standard but rather as an option, taking into consideration risk of infections. S Regardless, the steroid therapy and the endogenous milieu create a catabolic environment that rapidly depletes muscle mass. The hypercatabolic cascade seen in ASCls also leads to changes in mucosal and skin integrity and compromised immune function. These factors combined with the immobility, denervation, and muscle atrophy that accompany the disease provide the ultimate rationale for implementing adequate, safe nutritional support. Other systemic complications include pancreatitis, pulmonary dysfunction, and urinary and intestinal dysfunction with risks of autonomic dysreflexia syndrome. Autonomic dysreflexia can occur when patients have
The optimal composition of the nutrient formula for patients with ASCls has not been determined. The AANS and Congress of Neurological Surgeons guidelines suggest use of a high-nitrogen formula with at least 15% of the calories as protein and with no more than 15% glucose and a minimum of 4% total calories as essential fatty acids," Patients with ASCls are not uniformly hypermetabolic, especially beyond the first week of injury. Initially, increased metabolic demand may be seen; however, this rapidly declines with paralysis and indirect calorimetry assessments suggest that calorie requirements may be only 94% of those predicted using HarrisBenedict formulas." Reported weight losses of up to 10% have been observed within the first week of injury; however, aggressive replacement of calories may not be indicated. Caution must be used with determining caloric need for this population because of the risk of overfeeding. Indirect calorimetry is preferred when available; general guidelines are provided in Table 31-1. The metabolic demand is influenced by the amount of remaining neuronal connectivity after the injury. Patients with higher cord injuries have lower energy expenditure than those with incomplete injury or thoracic level paraplegia.P-" A recent study indicated that the stress and activity factors of 1.6 and 1.2, respectively, calculated using the Harris-Benedict equation, overestimated resting energy expenditure determined by indirect calorimetry." By eliminating the activity factor and reducing the stress factor to 1.1 to 1.3, the Harris Benedict equation may be a better predictor of energy expenditure. In contrast to the distinct metabolic profile, nitrogen loss in patients with ASCls remains increased over the first 2 to 3 weeks of injury and may last up to 7 weeks.P When 10 patients with ASCls were compared with age-, sex-, and injury severity-matched patients with nonspinal cord injuries, nitrogen balance remained negative at the seventh week despite aggressive nutritional support of 2.4 g of protein/kg of ideal body weight and 120% predicted energy expenditure. In another study by these investigators, 12 patients with ASCls received nutritional support based on predicted energy requirements using the Harris-Benedict equation with a stress factor of 1.6 and activity factor of 1.2 and 2 g/kg of protein." Several
SECTION V • Disease Specific
patients did not suffer a negative nitrogen balance until week 2 to 3, but overall 11 of the 12 experienced a negative nitrogen balance. The obligatory negative nitrogen balance persisted up to 7 weeks postinjury. As the disease progresses to the chronic phase, the metabolic demand continues to be lower than that of age matched control subjects, and muscle begins to be replaced with fat. Exercise programs have positive effects on the metabolic profile of patients with chronic injury; however, overall calorie needs remain reduced compared with those of age- and sex-matched control subjects. Consequently, indirect calorimetry isstillneeded to design an optimal nutritional regimen for this population. This biphasic metabolic response needs to be considered when nutritional needs of patients with spinal cord injuries are assessed and treatment protocols are determined. Patients with chronic spinal cord injuries experience uniquely different symptoms resulting from the loss of nervous tissue and its intimate relationship with the endocrine and immune system. These patients have a higher risk for cardiovascular disease than their ablebodied counterparts. They experience glucose intolerance accompanied by peripheral insulin resistance and hyperinsulinemia. Results of oral glucose tolerance tests in 100 patients with spinal cord injuries (all levels) compared with those in control patients showed that 38% of patients with tetraplegia and 50% of patients with paraplegia had higher mean plasma glucose and insulin values." In another study, subjects with complete tetraplegia had significantly worse carbohydrate tolerance with significantly greater peak and sum plasma insulin concentrations.f Further analysis revealed that peak serum glucose concentrations were significantly associated with increased total body percent fat, complete tetraplegia, older age, and male sex. Individuals with tetraplegia were found to have a marked reduction in whole body glucose transport that appeared to be due to a proportional reduction in muscle mass.
Nutrition Management There are no studies presenting evidence of either parenteral or enteral routes being superior in the patients with ASCls. Evidence supporting various options for an enteral feeding route, gastric administration versus small bowel administration, or early versus late nutritional initiation, as published for patients with TBls is lacking for patients with ASCls. The approach to assessing this patient population is much like that for other individuals with neurologic and critical injuries. For short-term feeding, use of a nasoenteric or nasogastric tube will be sufficient; however, when adequate oral feeding cannot be achieved, a more permanent alternative must be considered. In a retrospective review of 158 patients, the majority of which had a cervical spine injury or an ASCI, who received gastric feeding tubes by either the percutaneous endoscopic route or open surgical gastrostomy, the authors observed a 30.2% reduction in risk of complications with endoscopically placed tubes." The MNS and Congress of Neurological Surgeons guidelines for
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ASCls favor small bowel feeding, either nasoduodenal or nasojejunal acutely, with permanent devices not being addressed.' In patients with high cervical spine injuries, the risk of aspiration continues; therefore, small bowel placement may be the preferred route.
Patient Monitoring Assessment of nutritional status in patients with both acute and chronic spinal cord injuries remains an important step in ensuring improvements and identifying deficiencies in nutritional support that have an impact on morbidity and mortality. A thorough evaluation relies on monitoring laboratory studies of visceral proteins, minerals, and trace elements, daily estimates of dietary intake, and anthropometrics.v-" A study of 51 patients with ASCls over an 8-week period from the time of injury reported that nutrient deficiencies were most prominent within the first 2 weeks of injury." Of these patients, 100% had hypoalbuminemia, 62% had a carotene deficiency, 37% had a transferrin deficiency, 25% had an ascorbic acid deficiency, 24% had a thiamin deficiency, and 20% had a folate deficiency on the basis of serum markers. Albumin and transferrin levels remained low throughout the study period. A statisticallysignificant correlation between nutrient levels of albumin, ascorbate, and carotene and maximal inspiratory and expiratory pressure was reported. Factors predicting length of stay in a rehabilitation care facility for patients with ASCls include hypoalbuminemia and anemia in addition to the level and extent of the spinal cord lesion." In 28 patients with injuries between C3 and C7,86% developed anemia. The majority (71%) had normochromic, normocytic anemia, and the remaining 14% had normochromic, microcytic anemia. Optimization of nutritional status will help decrease the number of hospital days, reduce the incidence of complications, and improve functional outcome. 36-39 Other studies confirm the presence of hematologic derangements of patients with spinal cord injuries. Perkash and Brown" reported that decubitus ulcers and urinary tract infections were associated with the development of anemia of chronic disease. Nutritional support also plays an important preventative role in reducing the incidence of gastric stress ulcerations. In a retrospective study of 166 patients with spinal cord injuries divided into two groups, patients assigned to receive oral diets had a statistically significant increase in acid peptic ulceration leading to bleeding and perforation than those assigned to receive total parenteral nutrition after 5 days of enteral nutrition attempts." This investigation preceded the routine implementation of high-dose steroid treatment immediately after injury, which may increase the risk of mucosal ulceration. Some special factors should be considered when one anticipates potential complications that nutritional supplementation can modify or cause. Constipation, fecal incontinence, and obstructed defecation are common complications of spinal cord injuries. 42•43
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Constipation is the most common gastrointestinal complaint of these patients with spinal cord injuries.42,43 Constipation generally results from the slowed transit time that occurs in both acute and chronic spinal cord injuries in addition to the absent defecation reflex. The alteration in bowel function depends on the level of the spinal cord injury. Two different types of motility dysfunction can cause fecal incompetence: either the decrease of peristaltic contractions or the increase in nonperistaltic contractions in the sigmoid colon." The risk of autonomic dysreflexia must be recognized, and formula adjustments, such as a high-residue diet and adequate fluid intake, should be implemented when indicated. REFERENCES 1. Epstein J, Breslow MJ: The stress response of critical illness. Crit Care Clin 1999;15:17-33. 2. Pepe JL, Barba CA: The metabolic response to acute traumatic brain injury and implications for nutritional support. J Head Trauma RehabilI999;14:462-474. 3. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2000;17:453-547. 4. A.S.P.E.N. Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. Neurologic impairment. JPEN J Parenter Enteral Nutr 2oo2;26:80SA-81SA. 5. Section on Disorders of the Spine and Peripheral Nerves, The American Association of Neurological Surgeons: Nutrition support after spinal cord injuries. Neurosurgery 2OO2;50:S81-584. 6. Centers for Disease Control and Prevention. Surveillance for traumatic brain injury deaths-United States, 1989-1998. MMWR Morb Mortality Wkly Rep 2002;51:1-14. 7. Young B, Ott L, Yingling B, McClain C: Nutrition and brain injury. J Neurotrauma 1992;9:S375-S385. 8. Wolach B, Sazbon L, Gavrielli R, et al: Early immunological defects in comatose patients after acute brain injury. J Neurosurg 2001;94:706-711. 9. Sacks GS, Brown RO, Teague D, et al: Early nutrition support modifies immune function in patients sustaining severe head injury. JPEN J Parenter Enteral Nutr 1995;19:387-392. 10. Magnuson B, Hatton J, Williams S, Loan T: Tolerance and efficacy of enteral nutrition for neurosurgical patients in pentobarbital coma. Nutr Clin Pract 1999;14:131-134. 11. Kitchen D, Smith D: Problems with phenytoin administration in neurology/neurosurgery ITU patients receiving enteral feeding. Seizure 200I;10:265-268. 12. Markowsky SJ, Skaar DJ, Christie JM, et al: Phenytoin protein binding and dosage requirements during acute and convalescent phases following brain injury. Ann Pharmacother 1996;30:443-448. 13. Faraji B, Yu P: Serum phenytoin levels of patients on gastrostomy tube feeding. J Neurosci Nurs 1998;30:55-59. 14. Young B, Ott L, Kasarskis E, Rapp R, et al: Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma 1996;13:25-34. 15. Mackay LE, Morgan AS, Bernstein BA: Swallowing disorders in severe brain injury: Risk factors affecting return to oral intake. Arch Phys Med Rehabil 1999;80:365-371. 16. Mackay LE,Morgan AS,Bernstein BA: Factors affecting oral feeding with severe traumatic brain injury. J Head Trauma Rehabil 1999; 14:435-447. 17. Norton JA, Ott LG, McClain C, et al: Intolerance to enteral feeding in the brain-injured patient. J Neurosurg 1988;68:62-66. 18. Taylor SJ, Fettes SB,Jewkes C, Nelson RJ: Prospective, randomized, controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. Crit Care Med 1999;27:2525-2531.
19. Klodell CT, Carroll M, Carrillo EH, Spain DA: Routine intragastric feeding following traumatic brain injury is safe and well tolerated. Am J Surg 2000;179:168-171. 20. Silva CCR,Saconato H, Atallah AN: Metoclopramide for migration of naso-enteral tube [Cochrane Review]. In The Cochrane Library, Oxford, UK, Update Software, 2003, issue 1. 21. Weekes E, Elia M: Observations on the patterns of 24-hour energy expenditure changes in body composition and gastric emptying in head-injured patients receiving nasogastric tube feedings. JPEN J Parenter Enteral Nutr 1996;20:31-37. 22. Clifton GL, Roberston CS, Choi SC: Assessment of nutritional requirements of head-injured patients. J Neurosurg 1986;64:895-901. 23. Suchner U: Enteral versus parenteral nutrition: Effects on gastrointestinal function and metabolism: Background. Nutrition 1998;14: 76-81. 24. Hatton J, Record KE, Bivins BA, et al: Safety and efficacy of a lipid emulsion containing medium-chain triglycerides. Clin Pharm 1990;9:366-371. 25. Hatton J, Rapp RP, Kudsk KA, et al: Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: A phase II safety and efficacy trial. J Neurosurg 1997;86:779-786. 26. Minard G, Kudsk MA, Melton S, et al: Early versus delayed feeding with an immune-enhancing diet in patients with severe head injuries. JPEN 2000;24:145-149. 27. Heyland DK, Novak F, Drover JW, et al: Should immunonutrition becorne routine in critically ill patients? A systematic review of the evidence. JAMA 2001;286:944-953. 28. Ott L, Annis K, Hatton J, et al: Postpyloric enteral feeding costs for patients with severe head injury: Endoscopy, blind placement, and PEG/J vs. TPN. J Neurotrauma 1999;16:233-242. 29. Kearns PJ, Thompson 10, Werner PC, et al: Nutritional and metabolic response to acute spinal cord injury. JPEN J Parenter Enteral Nutr 1992;16:11-15. 30. Cox SA, Weiss SM, Posuniak EA, et al: Energy expenditure after spinal cord injury: An evaluation of stable rehabilitating patients. J Trauma 1985;25:419-423. 31. Rodriguez DJ, Benzel EC, Clevenger FW: The metabolic response to spinal cord injury. Spinal Cord 1997;35:599-604. 32. Rodriguez DJ, Clevenger FW, Osler TM, et al: Obligatory negative nitrogen balance following spinal cord injury. JPEN J Parenter Enteral Nutr 1991;15:319-322. 33. Bauman WA, Spungen AM: Disorders of carbohydrate and lipid metabolism in veterans with paraplegia or quadriplegia: A model of premature aging. Metabolism 1994:43:749-756. 34. Bauman WA, Adkins RH, Spungen AM, Waters RL: The effect of residual neurological deficit on oral glucose tolerance in persons with chronic spinal cord injury. Spinal Cord 1999;37:765-771. 35. Dwyer KM, Watts DD, Thurber JS, et al: Percutaneous endoscopic gastrostomy: The preferred method of elective feeding tube placement in trauma patients. J Trauma 2002;52:26-32. 36. Houda B: Evaluation of nutritional status in persons with spinal cord injury: A prerequisite for successful rehabilitation. SCI Nurs 1993;10:4-7. 37. Laven GT, Huang CT, DeVivo MJ, Stover SL, Kuhlemeier KY, Fine PR: Nutritional status during the acute stage of spinal cord injury. Arch Phys Med Rehabil 1989;70:277-282. 38. Burr RG, Clift-Peace L, Nuseibeh I: Haemoglobin and albumin as predictors of length of stay of spinal injured patients in a rehabilitation centre. Paraplegia 1993;31:473-478. 39. Huang CT, DeVivo MJ,Stover SL: Anemia in acute phase of spinal cord injury. Arch Phys Med Rehabil 1990;71:3-7. 40. Perkash A, Brown M:Anemia in patients with traumatic spinal cord injury. J Am Paraplegia Soc 1986;9:10--15. 41. Kuric J, Lucas CE, Ledgerwood AM, et al: Nutritional support: A prophylaxis against stress bleeding after spinal cord injury. Paraplegia 1989;27:140--145. 42. Krogh K, Mosdal C, Laurberg S: Gastrointestinal and segmental colonic transit times in patients with acute and chronic spinal cord lesions. Spinal Cord 2000;38:615-621. 43. Badiali D, Bracci F, Castellano V, et al: Sequential treatment of chronic constipation in paraplegic subjects. Spinal Cord 1997;35: 116-120.
II Cardiac Surgery Mette M. Berger, MD, PhD Rene L. Chiolero, MD
CHAPTER OUTLINE Introduction Nutritional Status of the Cardiac Patient The Gastrointestinal Tract after Cardiac Surgery and during Hemodynamic Failure Nutritional and Metabolic Management Metabolic Support Nutritional Support-Indications and Requirements
Conclusion
INTRODUCTION Cardiovascular disease is one of the most significant causes of morbidity and mortality in Western countries. A large number of admissions to intensive care units (lCUs) are generated by cardiovascular events, such as cardiac surgery, acute myocardial infarction, and acute cardiomyopathies. Even when the primary cause of lCU admission is not related to a cardiac cause, cardiovascular diseases may complicate the clinical evolution of the condition, owing to the growing number of ICU patients who are older than 65 years of age. Chronic heart failure is common in persons in this age category, with a prevalence of 30 to 130 individuals per 1000; in the general population, the prevalence is 3 to 20 individuals per 1000. 1 Patients with surgical and medical cardiac conditions have many of the same problems and characteristics: all have basal chronic metabolic alterations involvingmainly carbohydrate and lipid metabolism and also may have acute organ dysfunction due to ischemia. Cardiovascular system failure with a variable degree of systemic inflammatory response syndrome is present in both categories of patients. Cardiac surgical procedures in adults include mainly coronary artery bypass grafting (CABG), valve replacement or repair, thoracic aorta surgery, heart and cardiopulmonary transplantation, and surgery for repair of the various types of congenital heart diseases. Stay in the ICU is less than 2 days for a large proportion of these
patients; such patients do not require nutritional support. For other patients, complications and cardiac failure develop, which prolong their stay in the ICU. Prior nutritional status and the severity of the organ failure will have a direct influence on the length of ICU stay and hence on nutritional requirements and management. Cardiac failure has been classified by the New York Heart Association (NYHA) into four classes, from the lowest degree (I) of disease to the most severe forms (IV); patients with NHYA classes III and IV cardiac failure are considered to be at risk of postoperative complications.' These patients will eventually require nutritional support.
NUTRITIONAL STATUS OF THE CARDIAC PATIENT The relationship between cardiovascular disease and nutrition is obvious because atherosclerosis is associated with nutrition-related disorders, generally of the overfeeding type (e.g., diabetes, obesity, and dyslipidemias). In contrast, malnutrition is present in up to 50% of patients with severe congestive heart failure.' Such patients are particularly prone to acute worsening of their malnutrition. Cardiac cachexia has been recognized as an independent predictor of higher mortality in patients with chronic heart failure," whereas moderate overweight appears to be protective. The association between chronic heart failure and wasting has been known since antiquity. Cardiac cachexia follows two patterns: (1) the classic type that occurs in some patients with advanced heart failure (i.e., NYHA classes III and IV) or (2) the nosocomial type that develops in the postoperative period.V Cardiac cachexia is due both to a decrease in nutrient intake caused by anorexia and malabsorption and to specific metabolic alterations observed in the critically ill patient. After surgery, the vast majority of patients develop hypermetabolism and hypercatabolism as a consequence of the acute-phase response triggered by surgery and circulating endotoxins." The acute phase with its endocrine and metabolic consequences' contributes to the development of the second type of malnutrition.
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The mechanisms behind cardiac cachexia are complex and include decreased blood flow to organs and tissues and decreased substrate supply to the cells. In the presence of hypoxia, other mechanisms contribute, e.g., cellular energetics are altered. Cardiac cachexia involves depletion of lean body mass (including that of vital organs such as the heart), leading to a decline in organ and system performance and immune function. Malnutrition worsens cardiac function; a trial in rats comparing ad libitum chow feeding or restriction to 50% of this amount for 90 days showed that malnutrition was associated with a reduction in left ventricular systolic function and with lower contractility and compliance.' Hence, malnutrition and cardiac surgery constitute a deleterious spiral. Cardiac cachexia is also associated with poor outcome after heart transplantation, with an increase in 3Q-day mortality (13%vs. 7% in normal weight recipients) and a doubling of the 5-year mortality." A trial involving 5168 patients undergoing CABGlO showed that the operative mortality was highest among those with both low body mass index (BMI <20 kg/m") and albumin level less than 25 giL. Hypoalbuminemia was independently associated with increased risk of reoperation for bleeding, postoperative renal failure, prolonged ventilatory support, length of ICU stay, and total length of stay. A BMI >30 kg/m2 was associated with increased sternal wound infection. Nutritional assessment is particularly challenging after surgery in patients with cardiac failure. The frequent presence of pre- and postoperative edema alters the validity of weight and calculated BMI. Fluid resuscitation during and after surgery further increases edema. In preoperative settings, when an accurate assessment is required, lean body mass determination by anthropometric measurements such as skin fold thickness or armmuscle circumference may be used; bioimpedance analysis enables an acceptable estimation of total body water. In postoperative settings, such determinations produce inaccurate results. 11 Plasma protein levels corrected for inflammatory status (C-reactive protein, albumin, and prealbumin) are also an indication of the patient's status. Practically, the clinician should consider actual weight, recent weight loss, and clinical presentation of the patient; an unintentional weight loss of more than 7.5% of previous normal weight is an independent risk factor of mortality in chronic heart failure.' Among preoperative laboratory determinations, albumin level is the most reliable indicator, especially if the concentration is less than 25 giL,lO as in other surgical patients.
THE GASTROINTESTINAL TRACT AFTER CARDIAC SURGERY AND DURING HEMODYNAMIC FAILURE Gastrointestinal complications and particularly bowel ischemia are a serious threat after cardiopulmonary bypass (CPB). A trial enrolling 11,202 patients undergoing cardiac surgery with CPB (overall mortality rate of 3%and a 95% autopsy rate) showed a 0.49% incidence of acute mesenteric ischemia." In another trial enrolling 2,054
cardiac surgery patients, postoperative gastrointestinal complications were even more common with a 1.4% incidence.' Mortality associated with intestinal ischemia is high, from 11 %and Up.2.12 The need for gastrointestinal surgical intervention increased greatly the mortality rate compared with patients not requiring surgery (44% vs. 0%; P< 0.01). In both trials, gastrointestinal complications were significantly associated with the presence of symptoms of unstable angina, peripheral vascular disease, duration of CPB and cross-clamp time, pre- and postoperative intra-aortic balloon pump (lABP) support, the development of postoperative renal failure, and operation type and priority.s" Ischemic complications explain the recommendations for cautious use of enteral nutrition; the guidelines of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) state with a C level of evidence that enteral nutrition should be deferred after cardiac surgery until the patient's condition is hemodynamically stable." Indeed, cardiac surgery with CPBand associated periods of aortic cross-clamping and of non pulsatile blood flow affect both systemic and regional perfusion patterns. These predispose the splanchnic region to inadequate perfusion and increase gut permeability. The circulating endotoxin level rises during cardiac surgery and may contribute to cytokine activation, high oxygen consumption, and fever (postperfusion syndrome)," Splanchnic blood flow (SBF) does not necessarily decrease during CPB or after surgery as shown by two recent trials enrolling 10 patients each. In the first study, SBF was measured using infusion of indocyanine green dye and low-dose ethanol from induction of anesthesia through hypothermic CPBuntil 4 hours after surgery; SBF and oxygenation parameters did not change significantly.P The second confirmed the absence of local or global splanchnic ischemia using intestinal laser Doppler flowmetry, gastric tonometry, and measurements of splanchnic lactate extraction.l" Nevertheless, a mismatch between splanchnic oxygen delivery and demand was seen in the latter trial, particularly during rewarming. Bowel ischemia may also result from the deleterious effects of increasing intra-abdominal pressure such as those observed during abdominal compartment syndrome; this complication occasionally occurs after cardiac surgery but is more common after descending thoracic and abdominal aortic surgery. Its occurrence should nevertheless be considered. 15 In addition, the use of vasoactive drugs causes unpredictable effects on splanchnic perfusion." Although dopexamine seems to improve splanchnic perfusion and gastric mucosal perfusion (as reflected by intracellular pH [pHi]), all the other vasoactive drugs including dopamine and norepinephrine have unpredictable effects. Cardiac surgery for CABG using the off-pumptechnique is also associated with hemodynamic alterations, but there are very few data yet. In our experience, this technique is preferred for high-risk patients. A complicated postoperative course is therefore not uncommon, and the systemic inflammatory response syndrome may be intense.
SECTION V • Disease Specific
Gastrointestinal motility is affected by a series of factors in cardiac surgery patients, and gastric emptying is significantly reduced in the postoperative perlod.F:" Anesthesia, opioids, mechanical ventilation, vasoactive drugs, and sedatives reduce intestinal and gastric motility, which may contribute to difficulties with enteral feeding.
NUTRITIONAL AND METABOLIC MANAGEMENT Cardiac surgery patients rarely require artificial nutritional support, but in those who do it is particularly difficult to manage because these patients generally have combined failure of many systems and organs. The aims of nutritional support are many. The most traditional are to provide energy and substrate for body function and lean body mass maintenance and to prevent malnutrition and nutrient deficiencies. Metabolic and nutritional management during cardiac failure has recently been reviewed.7 New aims for nutritional and metabolic support have appeared: to improve organ function by metabolic support, to improve antioxidant status and immunity, and to down-regulate the inflammatory response to surgery. With enteral nutrition most of these aims can be accomplished, but a combination with intravenous support may be required.
Metabolic Support Metabolic support and nutritional support form a continuum. Metabolic support is generally provided early after an insult and consists of supporting the failing organ using specific substrates (electrolytes, glucose, glutamine, and antioxidants), whereas nutritional support (feeding) provides the complete range of nutrients (glucose, proteins, lipids, and micronutrients). Feeding is generally only considered after 3 to 5 days of fasting.' Alterations in myocardial substrate metabolism are involved in the pathogenesis of contractile dysfunction and heart failure. In particular, metabolism of myocardial fatty acids and glucose is altered, the changes being particularly prominent in patients with idiopathic dilated cardiomyopathy and ischemic heart disease.Pr" Myocardial ischemia induces changes in substrate utilization, with increased anaerobic glycolysis and reduced pyruvate oxidation. The reduction in coronary blood flow is followed by lactate production and accumulation in tissues and glycogen breakdown." The goal of manipulation of metabolism therefore is mainly to cause a shift in substrate utilization from fatty acid to glucose, which constitutes a new approach in the management of the failing myocardium.
Perioperative Glucose-Insulin-Potassium Infusion Early provision of substrate to the failing heart was first considered in 1962, when Sodi-Pallares and associates"
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showed that the administration of a glucose-insulinpotassium (GIK) solution improved outcome after myocardial infarction and reduced the occurrence of ventricular arrhythmias. After a few years of neglect, the GIK infusion has been recently reintroduced in clinical practice owing to a series of trials showing improved recovery of the ischemic myocardium in diabetic patients undergoing cardiac surgery.23 The positive results are explained by the direct effect of the GIKinfusion on cell energetics and other actions on cell membranes. Moreover, it was recently shown that tight glycemic control is a determinant of outcome in an ICU population including a large proportion of cardiac surgery patients." The issue is of utmost importance, because glycemic control is a major problem encountered during GIK infusions. In our surgical ICU, we have repeatedly observed that cardiac surgery patients in cardiogenic shock with prior diabetes mellitus develop severe hyperglycemia very easily during the initiation of such therapy. Due to major insulin resistance, glucose infusion at rates of 1 to 3 g/kg/day may result in glycemias >20 mmol/L and may require the simultaneous infusion of up to 60 units of insulin/hr. without achievement of glycemic control, as shown in Figure 32-1. Diabetic patients with high surgical risk have been particularly Investigated." In a prospective, randomized, controlled trial (PRCT) 40 patients with diabetes mellitus undergoing CABG were assigned to either a GIK group (500 mL of 5% dextrose in water + 80 units of regular insulin + 40 mmol KCI infused at 30 mUhr) or to a noGIK group (5% dextrose in water at 30 mUhr). GIK infusion was begun at induction of anesthesia and continued for
~... o S
o E E
Time (hours) FIGURE 32-1. Postoperative evolution of glycemia, glucose and insulin delivery in a 73-year-old patient with insulindependent diabetes mellitus before surgery (weight 67 kg, height 169 em, BMI 23.4 kg/m 2) . The patient was admitted with severe postoperative heart failure due to a perioperative myocardial infarct along with hemorrhagic shock (4100-mL blood loss in 24 hours) and vasoplegia. Over the first 24 hours he required a blood transfusion (1800 mL), massive fluid resuscitation (7900 mL in 24 hours), and vasopressor treatment with epinephrine and norepinephrine. GIK was initiated at 0.1 g/kg/hr (6 g of glucose/hr) and 10 units of insulin/hr. The dose of insulin was increased up to 60 units/hr, but glycemic control was not achieved; total insulin delivery in 24 hours was 1265 U for 225 g of glucose.
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12 hours postoperatively. The GIK group had higher postoperative cardiac indices (P< .0001), lower inotrope scores (P= .05), less weight gain (P< .0001), and shorter duration of mechanical ventilation (P = .0128). A significantly lower prevalence of atrial fibrillation (15% vs. 60%; P = .003) and shorter hospital stay were also observed. In this study the glucose dose of 36 g over 24 hours was low, whereas the insulin dose was large, amounting to 115units over the same period. These results suggest that beneficial results might be attributed to insulin itself and not to the GIK combination. Results of trials in cardiac surgery with CBP in nondiabetic patients have been more disappointing. A PRCT enrolling 46 patients who were undergoing off-pump CABG and receiving GIK infusion or saline from induction of anesthesia through the first 12 hours of ICU stay showed no difference in indicators of myocardial cell damage (similar increases in troponin I and creatine kinase MB).25 The lack of benefit may have resulted from the fact that the population consisted of low-risk patients and from the lack of glycemic control in the intervention group. Another PRCT of 42 patients who were undergoing CABG and receiving either GIK or glucose 5%infusion during the CPB throughout surgery showed no difference in myocardial cell damage (reflected by troponin 1)26. In this tria.l too, gl.ycemic control was poor in the GIK group. GIK IS considered to be purely a metabolic support. However, one should not forget that glucose infusion results in delivery of significant amounts of "glucose" calories, similar to the glucose infusions that had the goal of protein sparing in the 1980s.27 Indeed, the classical GIK infusion delivers 240 g of glucose/day for about 48 hours (Le., 960 kcal/day in a 8Q-kg patient receiving 3 g of glucose/kg/day); this corresponds to 48% of a 25 kcal/kg energy target, during a period when fasting is the usual choice for most patients.
Glutamine Glutamine has specific metabolic and immune functions in critically ill patients. This conditionally essential amino acid has been shown to be a preferential fuel for various cells during acute conditions. Glutamine enhances myocardial recovery after ischemia. A recent animal trial showed that glutamine supplementation resulted in the full recovery of cardiac output and restoration of adenosine triphosphate-ta-adenosine diphosphate ratios in an isolated rat heart model.P In another animal trial in chickens, glutamine significantly increased survival of cardiomyocytes and recovery of contractile function after ischemia-reperfusion injury; this protection was associated with enhanced heat shock protein 72 expression.P A trial including 10 patients with chronic stable angina provided in a randomized design a single oral dose of glutamine (80 mg/kg) or placebo. The patients were su?jected to an exercise test, and glutamine supplementatIon delayed ST segment alterations after supplementation." These observations suggested that glutamine may be beneficial as a protective therapy in patients at risk for cardiac ischemia and reperfusion injury, such as cardiac surgery patients.
Antioxidant Vitamins and Trace Elements and Other Micronutrients The nonpharmacologic management of cardiac conditions has been shown to include provision of micronutrients with antioxidant functions." Selective deficiencies of selenium, calcium, and thiamine can lead directly to heart failure. Plasma vitamin C levels are lower in patients with chronic heart failure." Vitamins B6, B12, and folate all tend to reduce levels of homocysteine." which is associated with increased oxidative stress. During ischemia-reperfusion the antioxidant endogenous defenses, including vitamin E and selenium, have also been shown to be reduced in congestive heart failure. 33 Coenzyme QlO, called ubiquinone, is also an endogenous antioxidant protecting the membranes. Reduction of up to 50% of myocardial levels have been documented in both animal and human models of heart failure. In a PRCT enrolling 41 patients who were undergoing CABG with left ventricular dysfunction the impact of oral supplements enriched with camitine, coenzyme QlO, and taurine was investigated. Results showed a significant increase in the myocardial levels determined in biopsy studies of these three nutrients in the intervention group." The supplementation was also associated with a significant reduction in left ventricular end-diastolic volume (P = .037), reflecting improved cardiac function. Thiamine (vitamin BI ) deficiency is common in patients who abuse alcohol" and in critically ill patients." The former group includes a significant proportion of the population. Vitamin BI deficiency typically causes cardiac .f~ilure (wet beri-beri) with an enlarged heart, nonspecific electric alterations, profound vasodilation, and peripheral neuritis. The presenting picture is high output cardiac failure. Typically, it responds to thiamine supplementation (100 to 200 mg/day for a week). The micronutrient requirements after the early phase have been shown not to be different from those for other conditions. Early antioxidant micronutrient supplementation should probably be considered' it is a potentially simple treatment that deserves f~rther research. Micronutrients to supplement according to actual evidence include vitamin C, vitamin E, vitamin B, selenium, glutamine, and possibly coenzyme Q.34.35
Nutritional Support-Indications and Requirements In patients with chronic cardiac failure, appetite is often suppressed, which contributes to cachexia." Nutritional support may therefore be required in patients with more chro~ic conditions, especially if surgery is anticipated; the risk of complications is increased if patients have been ma.lnourished previously.'? After cardiac surgery, most patients do well and do not require any form of artificial nutrition in the absence of prior malnutrition. Ho~ever, the presence of severe hemodynamic and respiratory failure in lCU patients with unstable conditions compromises spontaneous feeding and makes
SECTION V • Disease Specific
these patients dependent on artificial nutritional support. The general recommendations of avoiding prolonged starvation prevail in such patients; although 3 to 5 days without nutrition is considered tolerable, this period should be used for hemodynamic stabilization and for assessment of nutritional status and provision of early metabolic support. In patients whose conditions remain unstable, nutritional support should be considered from day 3 on and increased to target doses over 3 to 5 days. There are as yet no definitive guidelines on the optimal time for initiation of metabolic and nutritional support in this category of patients.
Energy and Substrate Requirements The levels of energy requirements in critically ill patients are highly variable: hypermetabolism is common, but in the presence of cachexia, the requirements are difficult to predict. In our experience, when nutritional support is initiated in cardiac surgery patients, the energy requirements can be set at 25 kcal/kg/day.38.39 Requirements may be lower in patients with severe persistent cardiogenic shock. Such patients may benefit from determination of resting energy expenditure by indirect calorimetry. Protein requirements do not differ from those of other patients and should be set at 1.3 g/kg/day, whether feeding is delivered by the enteral or intravenous route.
Route: Enteral, Intravenous, or Combined? The enteral route is the first choice in the majority of patients, whether during chronic or critical illness. However, there are a few caveats and contraindications to this approach because of the risk of bowel ischemia mentioned earlier in this chapter.v" The recently revised A.S.P.E.N. guidelines for nutritional support recommend caution in the introduction of enteral feeding." In circulatory compromise, enteral nutrition is considered relativelycontraindicated, because it may aggravate gut ischemia by a steal mechanism. This is why many authors recommend the use of parenteral nutrition in acute conditions and especially after surgery; these recommendations are based on expert opinions, with only limited and contradictory data to support the fact that enteral nutrition contributes to this type of complication. The normal hemodynamic response to feeding is complex, including an increase in cardiac output and vasodilation of mesenteric arteries and a decrease in peripheral resistance. In healthy subjects, enteral feeding induces significant increases in flow parameters in the superior mesenteric artery and portal vein in both sexes." A study enrolling 44 healthy subjects showed splanchnic postprandial hyperemia in response to intraduodenal feeding using echo-Doppler technology. Postprandially, diastolic blood pressure fell, and flow in the portal vein (not significant) and mean velocity in the superior mesenteric artery increased significantly. These changes were paralleled by alterations in systemic hemodynamics.
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On the benefit side, continuous enteric feeding has been shown to minimize oxygen consumption (\02) and myocardial V02 in patients with congestive heart failure, compared with intermittent feeding. Therefore, enteral nutrition can be provided safely from the cardiac function aspect." The combination of oral food and parenteral nutrition to achieve 20 to 30 kcal/kg/day for 2 to 3 weeks in patients with cardiac cachexia (severe mitral valve disease and congestive heart failure) was also associated with stable hemodynamics, unchanged whole body \02 and CO2 production." Our team has repeatedly shown that enteral nutrition can be used with caution during severe cardiac compromise, including patients requiring IABP and high doses of vasopressor support. Paracetamol (acetaminophen) absorption, which is very similar to that of protein absorption, is maintained postoperatively in cardiac surgery patients during low output states." In a series of 23 patients with hemodynamic failure (cardiac index between 2 and 2.5 Um 2/min), jejunal absorption was maintained compared with that in patients without cardiac failure (Fig. 32-2). Such patients can be fed with caution by either the gastric or jejunal route according to their clinical tolerance of enteral feedings. The introduction of enteral nutrition in patients with inotropic support after cardiopulmonary bypass causes increases in cardiac index and splanchnic blood flow, whereas the metabolic responses (endocrine profile) indicate that nutrients are used." The data from this trial also suggest that the hemodynamic response to early enteral nutrition is adequate after cardiac surgery. Another recent observational study in 70 patients with circulatory compromise admitted to our ICU showed that the enteral feeding volume was limited in the presence of severe hemodynamic compromtse'"; as a mean, a maximum of 1000 mL could be delivered by the gastric route and 1500 mL by the postpyloric route. Among these 70 patients, 18 were dependent on IABP support. The analysis of this subset of patients with extremely severe hemodynamic failure showed similar results, enabling the delivery of 1000 to 1500 kcal/day by the enteral route (15 to 20 kcal/kg/day) in 16 of the 18 patients (Fig. 32-3). Nevertheless, we have repeatedly observed that although enteral nutrition is possible, the total energy delivery remains between 50% and 75% of the target determined by indirect calorimetry, owing to limited feeding volume tolerance. Dailyenergy delivery should therefore be monitored, especially ifthe enteral route is used alone, to avoid the development of energy deficits. Combined enteral and parenteral nutrition should be used to achieve energy targets in patients with ICU stays longer than 7 days to avoid the deleterious effects of negative energy balances.r' Another relative contraindication to enteral nutrition is the development of chylothorax after CABG45; this complication may also occur in other types of cardiothoracic procedures in adults and children." In most patients, conservative treatment consisting of avoidance of enteral nutrition (total parenteral nutrition) and pleural drainage is successful; the average duration of lymph leak is 14 days. In some patients (less than 20% in the literature) a low-fatenteral diet can be used as the initial treatment.
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32 • Cardiac Surgery
FIGURE 32-2. Paracetamol absorption on days 1 and 3 after cardiac surgery: the four figures show the paracetamol kinetics after administration of 1 g of paracetamol. The patients were grouped according to their hemodynamic status (with or without hemodynamic failure) and compared to six healthy control subjects. Between days 1 and 3, patients recovered their gastrointestinal function independently of hemodynamic status. pp, postpyloric paracetamol; ga, gastric paracetamol. (From Berger MM, Berger-Gryllaki M, Wiesel PH, et al: Gastrointestinal absorption after cardiac surgery. Crit Care Med 2000;28:2217-2223.)
Enteral Access Enteral nutrition should be initiated by the gastric route in absence of a contraindication. Alas, gastric feeding may be difficult to carry out in patients in cardiogenic shock. Indeed because of the use of sedatives, opiates, mechanical ventilation, cardiac assistdevices, and vasoactive drugs, the pylorus is often closed," rendering gastric
Daysafter surgery FIGURE 32-3. Enteral energy delivery in 18 patients with severe circulatory compromise requiring major hemodynamic support including IABP. Except in two patients, enteral nutrition could be initiated on day 2 after surgery and steadily increased over 5 to 6 days to a mean delivery of about 1100 kcal/day. EN covered SO% to 70% of energetic requirements of the majority of patients but required additional TPN to reach target.
feeding inefficient. Gaining of postpyloric access may solve this problem; various techniques may be used such as blind manual placement, endoscopic placement, or fluoroscopic positioning. The two latter techniques involve additional costs and increase the patient's risk with the performance of additional procedures and movement to the radiology department. Endoscopic placement of the feeding tubes is considered a safe method of providing enteral nutrition, as shown by a retrospective study including 15 critically ill cardiothoracic surgery patients's; no complications of the procedure were observed. Mean duration of tube function was 8.5 days and mean duration of tube feeding was 16days. However, the authors questioned the benefits of nasoenteral tubes, because frequent repositioning of these types of tubes was required. Blind placement of a feeding tube in the ICU is worth attempting, and various placement techniques and types of feeding tubes have been advocated. In our experience a specially designed self-propelled feeding tube progresses into pylorus in approximately 60% of ICU patients." The study enrolled 105 unselected critically ill patients; organ failures were assessed using Sequential Organ Failure Assessment (SOFA) score, which assigns o(no failure) to 4 points (maximal failure) to six organs and systems including the cardiovascular, respiratory, and renal systems. The study showed that the poorest tube progression rate was seen in patients with the most severe cardiac compromise, grades 3 and 4 (Fig. 32-4); a delay in progression, which reflects altered gastrointestinal motility, was proportional to the dose of vasopressor
SECTION V • Disease Specific
395
surgery investigated the effect of an oral supplement containing a mixture of immune-enhancing nutrients (arginine, 0)-3 fatty acids, and nucleotidesj.P This trial showed that 5 days or more of supplementation improved the general immune response (stronger delayed-type hypersensitivity response) and was associated with a lower infection rate (4 of 23 vs. 12 of 22, P = 0.013), a reduction of the requirement for inotropic drugs, lower interleukin-6 concentrations, and better preservation of renal function. These data suggest that routine preoperative nutritional intervention should be considered in patients undergoing elective cardiac surgery. As yet no data are available to support the systematic use of immuno-modulating diets in the early postoperative period after cardiac surgery, but based on results of the previous trial, this premise certainly deserves further investigation. Hence, with actual knowledge to date, the only diets that should be considered are standard polymeric diets. Fibers are not contraindicated and can be used according to local feeding protocols.
Patient Monitoring Days FIGURE 32-4. Feeding tube progression according to levels of hemodynamic compromise. The figure shows the cardiovascular SOFA scores of patients with placement failure, gastric and postpyloric positions. The scores on placement were significantly lower in the patients in whom tube migration occurred (P = 0.03). (From Berger MM, Bollmann MD, Revelly JP, et al: Progression rate of self-propelled feeding tubes in critically ill patients. Intensive Care Med 2002;28:1768-1774.)
drugs required for hemodynamic support as shown in the figure. Other types of accesses, such as percutaneous gastric feeding tubes and surgical jejunostomies, can be used in cardiac surgery patients for the same indications as those in other patients with conditions requiring prolonged enteral feeding.
Timing and Diets: Preoperative, Early,
or Conventional Feeding According to international guidelines, cardiac surgery patients do not benefit from early enteral feeding" nor are they candidates for use of immuno-modulating diets." These guidelines require some discussion though. Manipulation of the inflammatory response to surgery by an immuno-modulating diet is a promising tool both preoperatively and in critically ill cardiac patients. Fish oil 0)-3 fatty acids have beneficial anti-inflammatory properties, which make them candidates for nutritional intervention at the various stages of cardiac disease. Cardiac surgery typically elicits an inflammatory response.t which might be down-regulated by fish oil. Preventing such responses may require preoperative intervention. A PRCT enrolling 50 patients aged 70 years or older with poor ventricular function before cardiac
A very severe complication after cardiac surgery is splanchnic ischemia, which may result in bowel necrosis and eventually death. 2.12 Therefore, clinical follow-up of these patients includes a careful examination of the abdomen, monitoring for distension or other signs of ileus. Some diagnostic tools can assist the clinician (fable 32-1): (1) Splanchnic ischemia may be monitored by gastric tonometry and the determination of pHi, which consists of determining gastric mucosal partial CO2 pressure (Pcoj) using a nasogastric tube equipped with a special balloon tip for gas collection, and by calculation of mucosal pH.16 (2) Monitoring intra-abdominal pressure by means of a urinary bladder catheter is also a helpful tool. Any increase in pressure greater than 20 mm Hg puts the gut at risk of ischemia from abdominal compartment syndrome. (3) Monitoring of arterial pH by blood gas analysis and determination of arterial blood lactate can be used to confirm intestinal ischemia: decreasing pH and increasing lactate levels usually herald the development of clinically relevant intestinal ischemia, but these are late signs. The second most serious problem is poor control of glycemia." Every effort should be made to maintain euglycemia, using insulin up to 50 units/hr whenever required. The third most serious problem is the development of malnutrition; the most common cause after surgery is the delivery of insufficient amounts of energy. Therefore, daily monitoring of energy delivery should be part of clinical management. Daily targets should be set at 25 kcal/kg/day. If this target is not reached within 4 to 5 days, a combination of enteral feeding with intravenous nutrition should be introduced rapidly to avoid the deleterious effects of negative energy balances.f Table 32-1 shows the most common problems encountered during feeding and some practical solutions.
396
32 • Cardiac Surgery
-
Trouble Shooting: Common Problems Encountered during Feeding after cardiac Surgery and Proposed Management
Problem
Diagnostic Tool
Management
Target
Hyperglycemia Gastroparesis
Glycemia (>8 mrnol/l.) Gastric residue >300 mL
Glycemia 4-7 mrnol/L Residue <200 mL
Intolerance to feeding Nonocclusive bowel necrosis Bowel ischemia
Abdominal distension Abdominal distension Splanchnic acidosis: .,l. pHi t arterial lactate Abdominal distension, t PIA 1 PIA
Insulin Postpyloric feeding Cisapride (cave prolonged QD Metoclopramide TPN Surgical resection TPN improve hemodynamics Gastric decompression (aspiration) Diuretics Reduce fluid loading Diuretics gastric decompression Prophylaxis: anti H2 drugs Treatment: proton pump inhibitors Enteral nutrition (?) Fibers Neostigmine (continuous or intermittent) Lactulose Fibers Same as other pancreatitis Postpyloric enteral feeding
Abdominal compartment syndrome Gastrointestinal bleeding
Blood in nasogastric tube Endoscopic diagnosis
Diarrhea Constipation
>5 Liquid stools/day No stools for more than 5 days
Pancreatitis
lleus/sublleus, pain Laboratory: amylasemla and IIpasemia Cause: cold CPS Abdominal ultrasound Laboratory: t alkaline phosphatase Nonspecific as in other ICU patients Albumin <25 gil Prealbumin <0.15 mgfL.,l. weight Negative energy balance >10,000 kcal
Acalculous cholecystitis
Malnutrition
Normal abdomen No distension Normal pHi (>7.2) No distension Normal PIA PIA <20 mm Hg No bleeding
<3 Stools/day 1 Stool/S days
No pain Normal transit
Postpylorlc feeding Interventional radiology Surgery Feeding Monitor dally energy balance Calculated cumulated energy balance for ICUstay
Prealbumin >0.2 mg/L Total energy balance <8000 kcal
CPB, cardiopulmonary bypass; PIA, intra-abdominal pressure; pHi, intracellular pH; TPN, total parenteral nutrition.
CONCLUSION Using the enteral route to feed patients with cardiac failure is challenging. The targets and the tools do not differ significantly from those for patients with other diagnoses. Nevertheless, cardiac surgery patients with circulatory compromise have some unique characteristics: they have a higher risk of splanchnic ischemia and their outcome is adversely affected by poor glycemic control. The delivery of energy up to 25 kcal/kg/day is sufficient for maintaining nutritional status. Enteral nutrition is possible and safe under close clinical supervision, even during circulatory compromise, but may result in insufficient energy delivery, prompting the need for combined parenteral and enteral approaches. REFERENCES I. Cowie MR, Mosterd DA, Wood DA: The epidemiology of heart failure. Eur Heart J 1997;18:208-225. 2. Lazar HL, Hudson H, McCann J, et al: Gastrointestinal complications following cardiac surgery. Cardiovasc Surg 1995;3:341-344. 3. A.S.P.E.N. Board of Directors and the Clinical Guidelines Task Force: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002;26 (I suppl):ISA-138SA. 4. Anker SA, Ponikowski P, Varney S, et al: Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997;349: 1050-1053.
5. Mustafa I, Leverve X: Metabolic and nutritional disorders in cardiac cachexia. Nutrition 2001;17:756--760. 6. Bouter H, Schippers EF, Luelmo SA, et al: No effect of preoperative selective gut decontamination on endotoxemia and cytokine activation during cardiopulmonary bypass: A randomized, placebocontrolled study. Crit Care Med 2002;30:38-43. 7. Berger MM, Mustafa I: Metabolic and nutritional support in acute cardiac failure. Curr Opin Clin Nutr Metab Care 2003;6:195-201. 8. Okoshi K, Matsubara LS, Okoshi MP,et al: Food restriction-induced myocardial dysfunction demonstrated by the combination of in vivo and in vitro studies. Nutr Res 2002;22:1353-1364. 9. Lietz K,John R, Burke EA,et al: Pretransplant cachexia and morbid obesity are predictors of increased mortality after heart transplantation. Transplantation 2001;72:277-283. 10. Engelman DT, Adams DH, Byrne JG, et al: Impact of body mass index and albumin on morbidity and mortality after cardiac surgery. J Thorac Cardiovasc Surg 1999;118:866--873. 11. Bracco D, Berger MM, Revelly JP, et al: Segmental bioelectrical analysis to assess perioperative fluid changes. Crit Care Med 2000; 28:2390-2396. 12. Venkateswaran RV, Charman SC, Goddard M, Large SR: Lethal mesenteric ischaemia after cardiopulmonary bypass: A common complication? Eur J Cardio-Thor Surg 2002:22:534-538. 13. Gardeback M,Settergren G, Brodin LA, et al: Splanchnic blood flow and oxygen uptake during cardiopulmonary bypass. J Cardiothor Vasc Anesth 2002;16:308-315. 14. Thoren A, Elam M, Ricksten SE: Jejunal mucosal perfusion is well maintained during mild hypothermic cardiopulmonary bypass in humans. Anesth Analg 2001;92:5-11. 15. Cheatham ML: Intra-abdominal hypertension and abdominal compartment syndrome. New Horiz 1999;7:96-115. 16. Silva E, DeBacker D, Creteur J, Vincent JL:Effectsof vasoactive drugs on gastric intramucosal pH. Crit Care Med 1998;26: 1749-1758.
SECTION V • Disease Specific
17. Goldhill DR, Whelpton R, Winyard JA, Wilkinson KA: Gastric emptying in patients the day after cardiac surgery. Anaesthesia 1995;50:122-125. 18. Berger MM, Berger-Gryllaki M, Wiesel PH, et al: Gastrointestinal absorption after cardiac surgery.Crit Care Med2000;28:2217-2223. 19. Lopaschuk GO, Stanley WC: Glucose metabolism in the ischemic heart. Circulation 1997;95:313-315. 20. Davila-Roman VG, Vedala G, Herrero P, et al: Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J AmColiCardiol2002;40:271-277. 21. Marzilli M: Management of ischaemic heart disease in diabetic patients-Is there a role for cardiac metabolic agents? Curr Med ResOpin 2001 ;17:153-158. 22. Sodi-Pallares 0, Testelly M, Fishleder F, et al: Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. Am J Cardiol 1962;9:166-181. 23. LazarHL, ChipkinS, PhilippidesG,et at: Glucose-insulin-potassium solution improve outcomes in diabetics who have coronary artery operations. Ann Thorac Surg2000;70:145-150. 24. van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in criticallyill patients. N EnglJ Med2001;345:1359-1367. 25. Lell WA, Nielsen VG, McGiffin DC, et al: Glucose-insulin-potassium infusion formyocardial protection during off-pump coronary artery surgery. AnnThor Surg2002;73:1246-1251. 26. Bruemmer-Smith S,Avidan MS, HarrisB,et al: Glucose, insulinand potassiumfor heart protection during cardiac surgery. BrJ Anaesth 2002;88:489-495. 27. Wolfe RR, O'DonnellTFJr, Stone MD, et al: Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition. Metabolism 1980;29:892-900. 28. Khogali SE, PringleSO, Weryk BV, Rennie MJ: Is glutamine beneficial in ischemic heart disease? Nutrition 2002;18:123-126. 29. Wischmeyer PE, Vanden Hoek TL, Li C, et al: Glutamine preserves cardiomyocyteviability and enhances recoveryof contractile function after ischemia-reperfusion injury. JPEN J Parenter Enteral Nutr 2003;27:116-122. 30. Witte KK, ClarkAL, ClelandJG: Chronic heart failureand micronutrients. J AmColiCardioI2001;37:1765-1774. 31. Keith ME, Ball A, Jeejeebhoy KN, et al: Conditioned nutritional deficiencies in the cardiomyopathic hamster heart. Can J Cardiol 2001;17:449-458. 32. Stanger0: Physiology of folic acid in health and disease. CurrDrug Metab2002;3:211-223. 33. Keith M, GeranmayeganA,Sole MJ, et al: Increased oxidativestress in patients with congestiveheart failure. J AmColiCardioI1998;31: 1352-1356. 34. Jeejeebhoy F, Keith M, Freeman M, et al: Nutritional supplementation with MyoVive repletes essential cardiac myocyte nutrients and reduces left ventricular size in patients with left ventricular dysfunction. Am Heart J 2002;143:1092-1100.
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35. Jamieson CP, Obeid OA, Powell-Tuck J: The thiamine, riboflavin and pyridoxinstatus of patients on emergency admission to hospital. Clin Nutr 1999;18:87-91. 36. Cruickshank AM, Telfer ABM, Shenkin A: Thiamine deficiency in the critically ill. IntensiveCare Med 1988;14:384-387. 37. Heyrnsfield SB, Smith J, Redd S, Whitworth HB Jr: Nutritional support in cardiac failure. Surg Clin NorthAm 1981;61:635-652. 38. Revelly JP, BergerMM, Chiolero R:The hemodynamic response to enteral nutrition. In Vincent J (ed): Yearbook of IntensiveCare and EmergencyMedicine. Berlin,Springer-Verlag, 1999 pp. 105-114. 39. Revelly JP, Tappy L, Berger MM, et al: Metabolic, systemic and splanchnic hemodynamic responses to early enteral nutrition in postoperativepatients treated forcirculatorycompromise. Intensive Care Med 2001;27:540-547. 40. SzinnaiC, MottetC, Gutzwiller JP, et al: Role of gender upon basal and postprandial systemic and splanchnic haemodynamics in humans. Scand J GastroenteroI2001;36:540-544. 41. Heymsfield SB, Casper K: Congestive heart failure: Clinical management by use of continuous nasoenteric feeding. AmJ Clin Nutr 1989;50:539-544. 42. Paccagnella A, Calc M, Caenaro G, et al: Cardiac cachexia: Preoperative and postoperative nutrition management. JPEN J Parenter Enteral Nutr 1994;18:409-416. 43. BergerMM, CayeuxMC, Revelly JP, Chiolero R: Enteralnutrition in critically ill patients with severe hemodynamic failure. Clin Nutr 2002;21(suppl 1):7. 44. Bollmann MD, Berger MM, Revelly JP, et al: Impact of energy balance on clinical outcome in ICU patients-Preliminary results. Clin Nutr2oo1;20(suppl):260. 45. Brancaccio G, Prifti E, Cricco AM, et al: Chylothorax: A complication after internal thoracic artery harvesting. Ital Heart J 2001;2: 559-562. 46. Nguyen OM, Shum-Tim D, Dobell AR, Tchervenkov CI: The management of chylothoraxlchylopericardium following pediatric cardiac surgery: A IO-year experience. J Cardiac Surg 1995;10: 302-308. 47. Vaswani SK, Clarkston WK: Endoscopic nasoenteral feeding tube placement following cardiothoracic surgery. Am Surg 1996; 62:421-423. 48. Berger MM, Bollmann MD, Revelly JP, et al: Progression rate of self-propelled feeding tubes in critically ill patients. IntensiveCare Med2002;28:1768-1774. 49. Heyland DK, Novak F, Drover JW, et al: Should immunonutrition become routine in critically ill patients?Asystematic reviewof the evidence. JAMA 2001;286:944-953. 50. Tepaske R. te ElthuisH, Oudernans-van Straaten HM, et al: Effect of preoperative immune-enhancing nutritional supplement on patients at risk of infection after cardiac surgery: A randomised placebo-controlled trial. Lancet 2001;358:696-701.
Severe Obesity in Critically III Patients Trish Fuhrman, MS, RD, FADA, CNSD Karen McDaniel, MS, RD, CNSD
CHAPTER OUTLINE Introduction The Impact of Severe Obesity on Nutrition Support Nutrition Assessment Nutrition Management Hypocaloric Nutrition Support Options for Enteral and Tube Feeding Tube Placement Rationale for Initiating and Monitoring Enteral Nutrition Support Patient Monitoring Anticipated Complications Summary
INTRODUCTION Nutrition assessment and management of enteral feeding are often problematic for patients with critical illness and trauma. Delivery of adequate and effective nutrition can become even more challenging when obesity is superimposed on the metabolic derangements of injury and illness. Obese patients are at greater risk of having chronic diseases and conditions that can further complicate the delivery and management of enteral nutrition. Coronary artery disease, degenerative bone disease, diabetes mellitus, endocrine abnormalities, hepatobiliary disease, dyslipidemia, hypertension, physical disabilities and limitations, and respiratory difficulties increase the risk of morbidity and mortality in the critically ill obese patient. The occurrence of postinjury and postoperative complications, such as wound dehiscence, respiratory failure, and infectious complications, has also been reported to be increased in obese patients.!" 398
THE IMPACT OF SEVERE OBESITY ON NUTRITIONAL SUPPORT Obesity is described as an excess of fat mass compared with lean body mass.' Obesity is defined as a body mass index (BMI) greater than or equal to 30 kg/m" and less commonly as a weight greater than 130% of "ideal" body weight (IBW).4.5 The caveats to using BMI and percent IBW are that these methods do not detect altered distribution of body mass, such as an increase in fat mass or a decrease in lean body mass," Body composition can be determined with noninvasive methods such as dualenergy X-ray absorptiometry, bioelectrical impedance, and air displacement plethysmography. However, not every facility will have access to these technologies, their use may be limited to patients with a lower range of weights, and reference values are still being developed for critically ill and obese populations. Table 33-1 provides a breakdown of BMI and percent IBW because these numbers are used to define obesity." A BMI greater than or equal to 25 kg/m2 is associated with an increased risk of mortality and morbidity.s In 1999,61%of adults in the United States had a BMI greater than or equal to 25 kg/m2 and therefore were classified as being either overweight or obese." The health care costs for treatment of obesity and the diseases associated with obesity were
_ _ Classification of Obesity Degree of Obesity Overweight Class I obesity Class II obesity Class III obesity (morbid or extreme obesity)
8MI (kgfmZ)
% "Ideal" Body Weight
25-29.9 30-34.9 35-39.9
125-129.9 130-134.9 135-139.9
~40
~140
Adapted from National Institutes of Health: Clinical guidelines on the identification and treatment of overweight and obesity in adults-The evidence report. Obes Res 1998;6:515-2095.
SECTION V • Disease Specific _ _ Co-Morbidities Related to ObeSlty25.40
Arthritis Cancer Cardiomyopathy Cardiovascular disease Cerebrovascular accident Cholelithiasis Degenerative joint disease Type 2 diabetes mellitus Gastroesophageal reflux Hepatosteatosls Hypertension Hypercholesterolemia Obstructive sleep apnea Renal disease Respiratory impairment Urinary stress incontinence
in excess of 117 billion U.S. dollars in 2000.4 As the weight of the population continues to increase, associated health care costs are likely to continue to escalate. Obesity is not currently categorized as a disease state. However, the extent to which obesity contributes to mortality is astounding. Table 33-2 lists diseases and conditions in which obesity is a significant contributing factor. The risk of obesity contributing to these adverse conditions and diseases is determined by the degree of obesity, age of the patient, and distribution of body fat. As BMI increases, the associated risk for mortality and morbidity increases. Excess body weight is associated with increased risk of death by any cause in adults 30 to 74 years of age, but the relative risk associated with a greater body weight is higher in younger people." Although morbidity has not been shown to have the same effect in obese elderly patients, the study by Landi and colleagues? did not separately classify patients with a BMI greater than 40 kg/m 2 nor did the study differentiate patients by degree of illness and injury. This raises uncertainty about the mortality risk of severely (class lID obese patients regardless of age. The catabolic response after injury in the severely obese patient is similar to that of the normal weight patient." Obese patients are at risk for depletion of lean body mass if an exogenous source of energy and protein is not provided during the treatment and recovery period. However, the metabolic response may differ among severely obese and normal weight individuals.'? In obese patients more protein and less fat are mobilized after trauma than in nonobese individuals. I I Obesity itself may create a chronic inflammatory state that in turn contributes to insulin resistance, type 2 diabetes mellitus, and cardiovascular disease." This makes assessment and provision of nutrients to the critically ill obese patient a significant challenge.
NUTRITION ASSESSMENT Surprisingly the data available to aid clinicians in estimating nutrient requirements in the critically ill obese patient are limited. Obese patients have a greater fat,
399
fluid, and lean body mass than lean individuals. The proportion and distribution of the fat and lean mass is highly varied among obese patients. The obese patient will have increased lean body mass, which will affect calorie and protein requirements, but the excess adipose tissue is considered metabolically inactive relative to other tissue and therefore does not affect calorie and protein requirements. The utilization of fuel is also different among obese and lean patients. In obese patients reduced lipolysis and fat oxidation as a result of injury or critical illness is often seen. I I This reduction may interfere with the ability of the patient's body to utilize fat as a fuel, thus increasing reliance on carbohydrate, which in turn will increase the requirement for gluconeogenesis. The irony is that patients with an abundant source of adipose tissue for fuel are unable to utilize this fuel and are reliant on the breakdown of their lean body mass for survival. The bottom line is the patient should be fed to preserve lean body mass but allow for mobilization of fat stores. What is unknown is the optimal energy level needed to provide nourishment without further contributing to metabolic complications and lipogenesis. Body size as well as cornorbid disease and injury, age, genetics, sex, hormones, and nutritional status have an impact on the demand for energy. Energy requirements increase in proportion to weight gain and increased fatfree mass (FFM).13 Energy expenditure is related to FFM of the individual, but the energy expenditure will vary among obese individuals. The average energy expenditure for obese individuals, reported to be 1.7 to 1.9 kcal/kg of FFM, varies significantly among individuals." This poses a problem for clinicians because FFM is not easily determined in the clinical setting. This adds to the quandary clinicians face when they attempt to estimate energy requirements in obese patients. When the confounding variables of critical illness and injury are included, the potential for miscalculation of estimated energy needs is even greater. Indirect calorimetry has been proposed as the most efficacious means to determine energy requirements in the critically ill obese patient." However, not every facility has access to indirect calorimetry or trained personnel to perform the test and interpret the data. IS Furthermore, the accuracy of indirect calorimetry in measuring energy expenditure and fuel utilization has not been well studied in the critically ill obese patient. The modified Fick equation, circulatory indirect calorimetry, incorporates data from the thermodilution method and requires a pulmonary artery catheter. Although this method is relatively simple and available in most intensive care units, it has been shown to have a high rate of variability compared with indirect calorimetry measuring pulmonary gas exchange." There are several predictive equations that can be used to determine caloric needs. 17- 22 Table 33-3 lists some of the more common equations and adaptations currently used to predict energy expenditure in critically ill obese patients. There is ongoing controversy as to which weight the clinician should use in the equations in Table 33-3: IBW, actual body weight (ABW), or an adjusted body weight
400 _
33 • Severe Obesity in Critically III Patients
•.
Predictive Energy Equationl for Critically III Obese Patlentl
Harris-Benedict equation (BEE) x 1 - 1.4 Male: 65.5 + 13.8 (Jf) + 5 (H) - 6.8 (A) Female: 655 + 9.6 (Jf) + 1.9 (H) - 4.7 (A) Ireton-Jones equation Spontaneously breathing: 629 - 11 (A) - 25 (Jf) - 609 (0) Mechanically ventilated: 1784 - 11 (A) + 5 (Jf) + 244 (S) + 239 (T) + 804 (B) kcal/kg 14-22 kcal/kg A, age in years; B, burn (l =yes, 0 =no); H, height in centimeters; 0, obesity (l = yes, 0 = no); S, gender (1 = male, 0 = female); T, trauma (1 yes, 0 = no); W, weight in kg. Data from references 17 to 22.
=
(AdjBW). A survey of nutrition support practitioners found that 40%used AdjBW and 40%used ABW.1O AdjBW is proposed as a means to account for the patient's metabolically active tissue." The original equation, AdjBW = (ABW - IBW)(0.25) + IBW has undergone a permutation by substituting 0.25 with 0.38 for males and 0.32 for ternales." Despite refinement of the equation, its validity in critical care has not been demonstrated. An AdjBW is often recommended when the Harris-Benedict equation is used for patients with BMI greater than or equal to 30 or who weigh more than 130% IBW,25.26 whereas calculations using the IretonJones equation should use ABW.17.18,27 However, variability in body composition and degree of obesity limit the accuracy of all equations that estimate energy needs. It is more important to monitor the patient's tolerance to the initial empiric nutrition regimen and adjust it accordingly. Obese patients not only have greater fat mass, but also have greater lean body mass than their lean counterparts. This makes estimating protein requirements more challenging. Recommendations vary from 1.0 to 2.0 g/kg of IBW/day in patients with adequate renal and hepatic function. With the use of enteral formulas, it may be a challenge to provide this level of protein without overfeeding calories to the patient. It may be necessary to purchase high-protein formulas (25%protein) or modular proteins for the hospital enteral formulary. Riskswith the use of modular proteins include inaccuracy in measuring the protein powder and bacterial contamination." The goal is to provide enough protein to produce a positive nitrogen balance. However, the accuracy of a 24-hour urine collection as well as the variability of the use of 2 to 4 g to account for insensible losses can make it challenging to get more than an estimate of nitrogen balance. Fluid intake is often restricted in the critically ill obese patient because of increased risk of congestive heart failure and pulmonary edema. Fluid limitations can inhibit the ability to provide adequate enteral nutrition support, particularly with a 1 kcal/mL enteral formula. Calorically dense enteral formulas are used to provide nutrient requirements without compromising fluid status. In addition to changing the caloric density of enteral formulas, parenteral fluids provided to critically ill patients may
need to be adjusted or consolidated when enteral nutrition is initiated. There are no known differences in the requirements for micronutrients in obese patients compared with those of nonobese patients. The risk of providing a suboptimal intake of vitamins and minerals could occur when hypocaloric enteral feedings are given or when volume restriction is necessary. The reduced volume of formula given through the tube feeding may be insufficient to provide 100% of the Recommended Dietary Allowance (RDA) or Adequate Intake level (AI)29-32 for vitamins and minerals. When providing less than 100% of the RDNAI via the tube feeding, the clinician should consider giving a vitamin and mineral supplement either by mouth, through the feeding tube, or intravenously.
NUTRITION MANAGEMENT Hypocaloric Nutrition Support Short-term hypocaloric nutrition has been proposed as a means to avoid metabolic complications in critically ill nonobese 33.34 and severely obese35-39 patients. Hypocaloric, high-nitrogen feeding is not specifically defined, but usually involves giving 50% to 60% of estimated or measured energy requirements (<20 kcal/kg) and approximately 1.5 to 2.0 g of protein/kg of IBW.40 Many studies in which a hypocaloric, high-nitrogen feeding regimen was implemented in obese patients have included mild to moderately stressed patients and parenteral nutrition. 35.37 This is in part due to the ability to manipulate the components of parenteral formulations to provide the desired distribution of carbohydrate, fat, and protein. In general, these studies found no significant disadvantages with feeding of a hypocaloric, highnitrogen regimen and a conventional parenteral nutrition solution. Some of the studies reported achievement of positive nitrogen balance35.38.39 with hypocaloric feeding whereas others have not. 34,41 However, despite nitrogen balance, outcomes related to morbidity (other than fistula closure") and mortality were not reported, and most of the studies were small. When outcomes of patients receiving either enteral or parenteral nutrition are compared, the debate continues as to whether the route." nutrient composition (fat vs. total kilocalories)." or glycemic control":" of the feeding regimen is responsible for the beneficial effects of enteral feeding and adverse effects of parenteral feeding. Although enteral nutrition has been perceived as being better in many clinical settings, because it is associated with more problems related to consistent nutrient delivery, due to high gastric residual volumes and diarrhea, delivery of estimated nutrient needs may be impeded and in effect, create an underfed state. Dickerson and associates" retrospectively compared hypocaloric and eucaloric enteral feedings in 40 critically ill obese (125% IBW) patients in the ICU. Patients were stratified as to whether they received more than or equal to 20 kcal/kg ABW (n =12) or less than 20 kcal/kg ABW (n = 28). Both groups received 2 g of protein/kg
SECTION V • Disease Specific
of IBW/day. The hypocaloric group received fewer kilocalories and had a shorter length of stay in the lCU, a reduced number of days of antibiotic treatment, a trend toward fewer days receiving mechanical ventilation, and no significant difference in nitrogen balance, abscess development, or sepsis. The authors concluded that hypocaloric enteral nutrition was as effective as eucaloric enteral nutrition in critically ill obese patients and was a safe mode of providing adequate nutrition without the complications associated with excess substrates. It is important to remember that the goal of hypocaloric feeding is not weight loss. The goals are positive nitrogen balance and glycemic control. Caution has been advised when hypocaloric feeding is used in patients with severe injury because endogenous fuel stores may not be mobilized in obese patients" and underfeeding of nonobese patients can result in increased morbidity and mortality." Patients should be monitored for potential essential fatty acid deficiency if a very low-fat enteral formula is used or if a modular formula is prepared using no fat.
401
epistaxis, perforation and hemorrhage of the esophagus, insertion into the trachea or bronchus, and pneumothorax." A large body mass, insufficient muscle mass and strength to manipulate body positioning, and degenerative joint disease contribute to an inability to maintain the patient in a semirecumbent position during placement. Respiratory compromise may worsen with occlusion of one nostril with the feeding tube." After the tube is placed, verification of the placement cannot be done with auscultation because the adiposity of the abdominal cavity will muffle sounds within the stomach and bowel. The use of fluoroscopy can be beneficial for placement, especially postpyloric, of feeding tubes in obese patients. However, fluoroscopy may be prohibitive for patients whose weight exceeds 400 pounds (180 kg)." Successful blind placement of small bowel tubes in critically ill patients, including obese patients, has been reported. This technique may be necessary for the obese patient who cannot be placed on the fluoroscopy table."
Endoscopic Placement
Options for Enteral and Tube Feeding Obesity is associated with a greater risk of diabetes, cardiovascular disease, and hypertension. The sequelae from these obesity-associated comorbidities contribute to fluid retention, poor glycemic control, congestive heart failure, and pulmonary edema in the critically ill obese patient. In addition to these conditions making it difficult to provide adequate nutrition support, placement of an enteral feeding tube is complicated by body habitus and comorbid conditions often seen in the obese patient. The effect that obesity has on feeding should also be considered when the appropriate route of feeding is chosen. Gastric feeding can be problematic because of the increased risk for gastric reflux and potential aspiration in obese patients. Obesity is associated with increased gastric fluid volume in addition to high intra-abdominal pressure." Often it is difficult to maintain critically ill patients in the semirecumbent position. This trilogy of increased gastric volume, elevated intra-abdominal pressure, and supine positioning can increase the risk of regurgitation of gastric contents and subsequent aspiration. This risk would substantiate the use of small bowel feeding, but obtaining small bowel enteral access can be challenging and poses other risks as mentioned later.
Tube Placement Nasogastric Placement Many factors need to be considered when an enteral feeding tube is placed in the obese patient. Blind nasoenteric feeding tube placement is probably the safest way to gain enteral access, but there are risks associated with tube insertion. Fat deposition around the pharynx and palate can hinder blind placement of the feeding tube. Misplaced feeding tubes can cause
Although a more permanent feeding tube can be placed endoscopically, the risks of complications and adverse events are greater than with nasoenteric tube placement, especially in the obese patient. There are complications associated with the endoscopic procedure itself as well as complications related to the placement of an enterocutaneous tube. The obese patient may have difficulty lying flat for the procedure, which could increase respiratory distress. Obese patients may also have greater requirements for medications and a longer therapeutic effect from medications given during the procedure." The thickness of adipose tissue could interfere with transluminal identification of the abdominal wall and increase the risk of injury to the colon. Elevated intraabdominal pressure is often seen with obese patients and can contribute to increased tension on the enterostomy site, resulting in superficial infection, gastric wall necrosis, necrotizing fasciitis, and leakage of gastrointestinal contents into the peritoneal cavity." An overlong tube may be needed to avoid skin irritation of the external bumper. Surgical insertion of a feeding tube presents the greatest risk to the patient, in part due to the risk of thromboembolism associated with obesity as well as to the impact that obesity has on cardiovascular, pulmonary, and infectious complications." Table 33-4 provides a list of complications associated with nasoenteric, endoscopic, and surgical tube placement in obese patients.
Formula Selection No enteral formula has been specifically designed for the obese patient. Formula selection depends on the underlying disease and organ function. High-protein formulas (25% of kcal from protein) will be useful in the obese patient with adequate renal and hepatic function to provide adequate protein without excess calories. Respiratory compromise in the obese patient may tempt clinicians to use a high-fat, low-carbohydrate enteral formulation. However, a reduction in the proportion of
402 ' . •
33 • Severe Obesity in Critically III Patients
.
Potential Complications Associated with Enteral Feeding Tube Placement In Obese Patients
Nasoenterlc placement Tube misplacement Epistaxis, esophageal perforation or hemorrhage, tracheal Intubation, pneumothorax Respiratory insufficiency Gastroesophageal reflux and aspiration pneumonia Sinusitis Inability to achieve post pyloric positioning Endoscopic placement Endoscopy complications Aspiration, esophageal or gastric bleeding or perforation, respiratory Insufficiency Superficial skin or soft tissue infection Necrotizing fasclltls Gastric or intestinal bleeding Gastric or intestinal leakage with peritonitis Colonic Injury Tube migration with gastric or intestinal obstruction Fistulization Surgical placement Thromboembolism Respiratory insufficiency Cardiac events Superficial skin or soft tissue Infection Necrotizing fasclltls Gastric or Intestinal bleeding Gastric or intestinal leakage with peritonitis Tube migration with gastric or Intestinal obstruction Fistulization Complications associated with laparoscopy (hypercarbla, decreased venous return) Revised from ShikoraSA: Enteral feeding tube placement in obese patients: Considerations for nutrition support. NutrClin Prac 1997:12(1):59-513.
carbon dioxide to oxygen (respiratory quotient) is more responsive to overall energy provided rather than to the distribution of fuels." The selection of an enteral formula can be more challenging if hypocaloric, high-nitrogen enteral feeding is desired. This may require addition of modular protein to an existing enteral formula. The addition of additives to enteral formulations can increase the risk of contamination of the formula that in tum can contribute to the occurrence of infectious complications and diarrhea.f Fluid restriction because of volume overload may contribute to underfeeding even with a 2 kcallmL enteral formula to reduce the risk of congestive heart failure or pulmonary edema in the obese patient.
The guidelines for critically ill patients are adjusted to a 5- to lO-day window of inadequate intake because of the hypermetabolic and catabolic effects of stress and illness. Time for initiating nutritional intervention is not different for critically ill obese and nonobese patients. However, the risk of metabolic complications in the critically ill obese patient suggests the need for introducing nutrition support. particularly glucose, gradually and assessing tolerance while maintaining glycemic and metabolic control. As with any critically ill patient. levels of fluid. electrolytes. glucose, blood urea nitrogen. creatinine. magnesium, phosphorus. and calcium should be closely monitored until stable.
PATIENT MONITORING Anticipated Complications Metabolic aberrations as shown in Figure 33-1 are associated with severe obesity in critical illness and injury. These confounding factors can make the provision of nutrition support problematic and challenging. Although there have been reports that endogenous fat for energy cannot be effectively mobilized in critically ill patients.U:" other researchers have demonstrated positive nitrogen balance with hypocaloric, high-protein feeding, suggesting use of endogenous lipid as a fuel source. 35.37
Alterations in Lipid Metabolism Obesity can contribute to hyperlipidemia and hepatic steatosis. Critically ill patients have been reported to have hypertriglyceridemia, elevated low-density lipoprotein levels. and decreased high-density lipoprotein levels. When critical illness is superimposed on obesity, the potential for increased lipid abnormalities may be even
greater." Debate over whether endogenous fat for energy can be effectively mobilized and utilized in the critically ill
Rationale for Initiating and Monitoring Enteral Nutrition Support Critically ill patients should be fed whether obese or lean. If a patient cannot consume an adequate intake orally, enteral nutrition support should be considered. According to the guidelines of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) anyone who has not been adequately fed for 7 to 14 days or anyone who is anticipated not to be adequately fed for 7 to 14 days is a candidate for specialized nutritional support.P
FIGURE 33-1. Metabolic aberrations associated with severe obesity and critical illness. Data from references I, II, 12,25, 33, 40, 45, and 60.
SECTION V • Disease Specific
obese patient continues. A study by Jeevanadam and colleagues" suggested that stored fat for fuel was not effectively oxidized in fasted critically ill obese patients compared with critically ill nonobese patients. The inability to use endogenous fat stores could contribute to essential fatty acid deficiency in critically ill obese patients. However, another study by Dickerson and assoelates" estimated oxidation of fat in critically ill obese patients at 68% of nonprotein kilocalories using indirect calorimetry to identify fuel substrate use. The patients of Dickerson and associates were receiving hypocaloric parenteral nutrition that included lipids and were not compared to a control group.
Hyperglycemia Release of proinflammatory cytokines, including tumor necrosis factor (TNF)-a and interleukin (IL)-6 and IL-l, contributes to insulin resistance during inflammation and with metabolic diseases such as obesity-related diabetes." Hyperglycemia resulting from glucose intolerance and insulin resistance can occur in critically ill patients with a wide range of 8Mls. However, this is often problematic in the critically ill severely obese patient. There is strong evidence that obesity, insulin resistance, and diabetes produce a mild chronic state of inflammation with elevated levels of TNF, IL-6, IL-l, and C-reactive protein. 54-56 It is believed that insulin receptor signaling is disrupted by TNF, IL·6, and IL-l as well as by cytokineinduced insulin-resistant mediators.F-" Nitric oxide released from adipose cells may also be a factor in insulin resistance in skeletal muscle that has been infiltrated with fat in obese patients." Poor wound healing and impaired immune response have been associated with hyperglycemia.v'P Providing excess carbohydrate or glucose can also contribute to excess carbon dioxide production and promotes hepatic steatosis. Hyperglycemia increases insulin production and hyperinsulinemia contributes to sodium and fluid retention. Therefore, hyperglycemia can disrupt the functioning of the cardiovascular, pulmonary, immune, and hepatic systems.
Hypertension Obese subjects are three times more likely to have hypertension." Hypertension results from increased demand on the circulatory system with the increased vascular volume and cardiac output associated with obesity. Hypertension and left ventricular hypertrophy are often seen in the morbidly obese patient." Congestive heart failure can further exacerbate complications associated with vascular volume and cardiopulmonary circulation. (It is important to use a large cuff to measure blood pressure accurately in obese patients.)
Immune Dysfunction Immune dysfunction may be related to impaired protein synthesis seen in obese trauma patients, which is greater than that seen in nonobese trauma patients. II Obesity is
403
associated with hyperglycemia, which interferes with immune function and is associated with an increased risk of sepsis. This may be due, in part, to hyperglycemia resulting from insulin resistance and the effect of glucose on the immune system. An increased inflammatory response is seen due to an increased release of cytokines by adipose tissue. Surgical patients with a 8MI greater than 27 kg/m 2 are more likely to experience nosocomial infections postoperatively. I
Respiratory Compromise Respiratory compromise including a reduction in expiratory reserve volume and an increase in the forced expiratory volume-to-forced vital capacity ratio is related to the patient's age, fat distribution, and severity of obeSity.60 Vital capacity, total lung capacity, and functional residual volume can be reduced by 30% in the severely obese patient. 60,61 The mechanics of breathing are more difficult with increased body mass as is the increased requirement to expel carbon dioxide. Hypoxemia is a common finding in the severely obese patient. Sleep apnea has been reported to occur in 40% of men and 3% of women with a 8MI greater than 45.3 kg/m 2•62 Anesthesia contributes to a decrease in functional residual capacity. Obese patients receiving mechanical ventilation may be more difficult to wean from the ventilator, have a higher risk of aspiration, and a greater risk of pulmonary complications after surgery." McClaveand coworkers63 reported that overfeeding with enteral nutrition contributed to azotemia, increased minute ventilation, and higher costs of hospitalization.P On the other hand, the authors also caution that underfeeding can reduce diaphragmatic and intercostal muscle mass and function and thus contribute to increased minute ventilation.
Impaired Wound Healing Wound healing is an anabolic process and requires adequate calories. Endogenous energy may not be effectively mobilized for fuel in obese patients and, therefore, sufficient energy and protein to promote wound healing must be supplied." The large body mass of the obese patient hinders oxygenation to the injured tissues and makes repositioning the patient to reduce the development of pressure ulcers more difficult.
SUMMARY Nutrition assessment and enteral nutrition management of the critically ill obese patient often presents challenges for the clinician. It is important for the clinician to identify all comorbidities present and to avoid exacerbating metabolic complications when providing nutrition support. The optimal feeding regimen (hypocaloric vs. eucaloric) is still under investigation. However, shortterm hypocaloric nutrition support appears to be safe and well-tolerated in the severely critically ill obese patient. Enteral nutrition support should be considered for any patient with a functional gastrointestinal tract
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33 • Severe Obesity in Critically III Patients
who is unable to meet nutrient needs by oral intake. Selection of the enteral feeding formula should be based on the patient's metabolic condition and ability to tolerate fluid volume. Critically ill obese patients should be monitored closely for glycemic control, lipid tolerance, and adequacy of nutrient provision.
REFERENCES 1. Choban PS, Heckler R, Burge JC, et al: Increased incidence of nosocomial infections in obese surgical patients. Am Surg 1995;61: 1001-1005. 2. Pasulka PS, Bistrian BR, Benotti PN, et al: The risks of surgery in obese patients. Ann Intern Med 1986;104:540-546. 3. Printen KJ, Paulk SC, Mason EE: Acute postoperative wound complications after gastric surgery for morbid obesity. Am Surg 1975;41: 483-485. 4. Centers for Disease Control and Prevention: Obesity trends among U.S. adults between 1985and 2000.Available at http://www.cdc.gov. Accessed September 11, 2002. 5. National Institutes of Health: Clinical guidelines on the identification and treatment of overweight and obesity in adults-The evidence report. Obes Res 1998;6:515-209S. 6. Kyle UG, Genton L,Pichard C: Body composition: What's new. Curr Opin Clin Nutr Metab Care 2002;5:427-433. 7. Landi F, Onder G, Gambassi G, et al: Body mass index and mortality among hospitalized patients. Arch Intern Med 2000;160: 2641-2644. 8. Stevens J, Cai J, Pamuk ER, et al: The effect of age on the association between body-mass index and mortality. N Engl J Med 1998; 338:1-7. 9. Shikora SA, Muskat PC: Protein-sparing modified fast total parenteral nutrition formulation for a critically ill morbidly obese patient. Nutrition 1994;10:155-157. 10. Ireton-Jones CS, Francis C: Obesity: Nutrition support practice and application to critical care. Nutr Clin Prac 1995;10: 144-149. 11. Jeevanadam M,Young DH,Schiller WR:Obesity and the metabolic response to severe multiple trauma in man. J Clin Invest 1991;87: 262-269. 12. Marette A: Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr Opin Clin Nutr Metab Care 2002;5:377-383. 13. Pi-Sunyer FX: Overnutrition and undernutrition as modifiers of metabolic processes in disease states. Am J Clin Nutr 2000; 72(suppl):5335-537S. 14. Makk UK, McClave DSA, Creech PW, et al: Clinical application of the metabolic cart to the delivery of total parenteral nutrition. Crit Care Med 1990;18:1320-1327. 15. McClaveSA, McClain CJ,Snider HL:Should indirect calorimetry be used as part of nutritional assessment? J Clin Gastroenterol 2001;33:14-19. 16. Ogawa AM, Shikora SA, Burke LM, et al: The thermodilution technique does not agree with indirect calorimetry for the critically ill patient. J Parenter Enteral Nutr 1998;22:347-351. 17. Ireton-Jones CS,Turner WW, Liepa, et al: Equations for estimation of energy expenditures in patients with burns with special reference to ventilatory status. J Burn Care Rehabil 1992;13: 330-333. 18. Ireton-Jones CS,Jones JD: Why use predictive equations for energy expenditure assessment? J Am Diet Assoc 1997;97(suppl):A-44. 19. Harris JA, Benedict FG: A Biometric Study of Basal Metabolism. Publication No. 279. Washington, DC, Carnegie Institution of Washington, 1919. 20. Hunter DC, Jaksic T, Lewis D, et al: Resting energy expenditure in the critically ill: Estimates versus measurement. Br J Surg 1988;75: 875-878. 21. Glynn CC, Greene GW, Winkler MF, et al: Predictive versus measured energy expenditure using limits-of-agreement analysis in hospitalized, obese patients. J Parenter Enteral Nutr 1999;23: 147-154. 22. Trombley LE, Reinhard T, Klurfeld D: Energy expenditure in the critically ill obese patient. Support Line 2001;23(2):18-24.
23. Wilkens KG, Schiro KB (eds): Suggested Guidelines for Nutrition Care of Renal Patients, 2nd ed. Chicago, American Dietetic Association, 1992. 24. Schiro-Harvey K, ed: National Renal Diet Professional Guide, 2nd ed. Chicago, American Dietetic Association, 2002. 25. Burge JC: Obesity. In Matarese LE, Gottschlich MM (eds): Contemporary Nutrition Support Practice: A Clinical Guide. Philadelphia, WB Saunders, 2003, pp 546-551. 26. Cutts ME, Dowdy RP, Ellersieck MR, et al: Predicting energy needs in ventilator-dependent critically ill patients: Effect of adjusting weight for edema or adiposity. Am J Clin Nutr 1997;66:1250-1256. 27. Ireton-Jones CS,Turner WW Jr: Actual or ideal body weight: Which should be used to predict energy expenditure? J Am Diet Assoc 1991;91:193-195. 28. Vanek VW:Closed versus open enteral delivery systems: A quality improvement study. Nutr Clin Prac 2000;15:234-243. 29. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC, National Academy Press, 1997. 30. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC, National Academy Press, 1998. 31. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC, National Academy Press, 2000. 32. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC, National Academy Press, 2001. 33. Zaloga GP, Roberts P: Permissive underfeeding. New Horizons 1994;2(2):257-263. 34. Frankenfield DC, Smith JS, Cooney RN: Accelerated nitrogen loss after traumatic injury is not attenuated by achievement of energy balance. J Parenter Enteral Nutr 1997;21:324-329. 35. Burge JC, Good A, Choban PS, et al: Efficacy of hypocaloric total parenteral nutrition in hospitalized patients: A prospective, doubleblind randomized trial. J Parenter Enteral Nutr 1994;18:203-207. 36. Dickerson RN, Boschert KJ, Kudsk KA, et al: Hypocaloric enteral tube feeding in critically ill obese patients. Nutrition 2002;18: 241-246. 37. Dickerson RN, Rosato EF, Mullen JL: Net protein anabolism with hypocaloric parenteral nutrition in obese stressed patients. Am J Clin Nutr 1986;44:747-755. 38. Greenberg GR,Jeejeebhoy KN: Intravenous protein-sparing therapy with gastrointestinal disease. J Parenter Enteral Nutr 1979;3: 427-432. 39. Choban PS, Burge JC, Scales D, et al: Hypoenergetic nutrition support in hospitalized obese patients: A simplified method for clinical application. Am J Clin Nutr 1997;66:546-550. 40. Shikora SA, Naylor MJ: Nutritional support for the obese patient. In Shikora SA, Martindale RG, Schwaitzberg SD (eds): Nutritional Considerations in the Intensive Care Unit. Dubuque, lA, Kendall/Hunt, 2002, pp 325-334. 41. Liu K, Cho M, Allen M, et al: Hypocaloric parenteral nutrition support in elderly obese patients. Am Surg 2000;66:394-400. 42. Kudsk KA, Laulederkind A, Hanna MK: Most infectious complications in parenterally fed trauma patients are not due to elevated blood glucose levels. J Parenter Enteral Nutr 2001;25:174-179. 43. Battistella FD, Widergren IT, Anderson JT, et al: A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition. J Trauma 1997; 43:52-60. 44. McGowen KC, Friel C, Sternberg J, et al: Hypocaloric total parenteral nutrition: Effectiveness in prevention of hyperglycemia and infectious complications-A randomized clinical trial. Crit Care Med 2000;28:3606-3611. 45. Van den Berghe G, Wouters 0, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367. 46. Van den Berghe G, Wouters 0, Bouillon R, et al: Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med 2003;31:359-366. 47. Gottschlich MM, Mayes T, Khoury JC, et al: Significance of obesity on nutritional, immunologic, hormonal, and clinical outcome parameters in burns. J Am Diet Assoc 1993;93:1261-1268.
SECTION V • Disease Specific 48. Shikora SA: Enteral feeding tube placement in obese patients: Considerations for nutrition support. Nutr Clin Prac 1997;12(suppl): S9-S13. 49. Taylor B, Schallom L: Beside small bowel feeding tube placement in critically ill patients utilizing a dietitian/nurse team approach. Nutr Clin Prac 2001;16:258-262. 50. Trempy GA, Rock P: Anesthetic management of a morbidly obese woman with a massive ovarian cyst. J Clin Anesthesiol 1993;5: 62-68. 51. Talpers SS, Romberger DJ, Bunce SB, et al: Nutritionally associated increased carbon dioxide production. Chest 1992;102:551-555. 52. A.S.P.E.N. Board of Directors and the Clinical Guidelines Task Force: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002; 26(suppl):ISA-138SA. 53. Khovidhunkit W, Memon RA, Feingold KR, et al: Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis 2000;181(suppl 3):5462-5472. 54. Festa A, D'Agostino R Jr, Williams K, et al: The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Diord 2001;25:1407-1415. 55. Pannacciulli N, Cantatore FP, Minenna A, et al: C-reactive protein is independently associated with total body fat, central fat, and
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insulin resistance in adult women. Int JObes Relat Metab Diord 2001;25:1416-1420. 56. Pickup JC. Crook MA: Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 1998;41:1241-1248. 57. Hotamisligil OS, Murray DL, Choy LN, et al: Tumor necrosis factor a inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA 1994;91:4854-4858. 58. McMurray JK: Wound healing with diabetes mellitus. Better glucose control for better wound healing in diabetes. Surg Clin North Am 1984;64:769-778. 59. Kannel WB, Brand N, Skinner JJ: The relation of adiposity to blood pressure and development of hypertension: The Framingham Study. Ann Intern Med 1967;67:48-59. 60. Marik P, Varon J: The obese patient in the ICU. Chest 1998;113: 492-498. 61. Lazarus R, Sparrow D, Weiss ST: Effects of obesity and fat distribution on ventilatory function: The normative aging study. Chest 1997;111:891-898. 62. Vgontzas AN, Tan TL, Bixler EO, et al: Sleep apnea and sleep disruption in obese patients. Arch Intern Med 1994;154:1705-1711. 63. McClave SA, Lowen CC, Kleber MJ, et al: Are patients fed appropriately according to their caloric requirements? J Parenter Enteral Nutr 1998;22:375-381.
II Enteral Nutrition and the Neurologic Diseases Mark H. Del.egge, MD
CHAPTER OUTLINE Introduction Background Chronic Neurologic Diseases Dysphagia Gastrointestinal Dysfunction Enteral Feeding Considerations for Patients with Chronic Neurologic Disorders Conclusion
INTRODUCTION The spectrum of neurologic diseases can be quite diverse and can require different decisions on nutritional interventions. The patient with an acute brain injury may be well nourished before injury, but hypermetabolism may rapidly erode nutritional stores, especially protein, culminating in a death due to starvation.' Neurosurgical patients requiring either major spinal or cerebral interventions are subject to the same intense catabolism as other patients after major surgery. Other neurologic diseases may alter the patient's ability to initiate the complex swallowing reflex, resulting in gradual nutritional deterioration to a starvation state or death from repeated episodes of aspiration pneumonia. Because patients with neurologic diseases comprise 15% of patients in acute care hospitals, more than 30% of rehabilitation center inpatients, and 50% of nursing home patients, their early, effective nutritional management may help improve outcome and reduce medical costs. In this chapter the rationale, indications, and special physiologic challenges 406
presented by patients with chronic neurologic diseases are discussed.
BACKGROUND The acuteness of the need to feed patients with neurologic diseases aggressively seems to have lagged behind other areas in medicine. As early as 1947, rapid nutritional deterioration after craniotomy was noted by Drew and colleagues.! Patients with brain injury are the population having the most recognized-risk of nutritional deficiency of patients with neurologic injuries. However, the hypermetabolism associated with brain injury was not documented until 1975.3 Approaches to nutritional therapy involve a complex decision-making process. Rapp and co-workers" demonstrated in patients with head injury that total parenteral nutrition (TPN) was not only safe but was also associated with higher patient survival than attempts to provide intragastric feeding. This result was in contrast to previous beliefs that TPN, with its high fluid volumes and hyperosmolar solutions, would be deleterious in patients with brain injuries owing to the possible worsening of cerebral edema," However, the use of TPN must be weighed against its associated complications such as hyperglycemia and central line sepsis. Previous problems with intragastric feeding due to delayed gastric emptying, reflux, and aspiration complicated the decision of whether to use early enteral nutrition in many patients. In these patients a decision either to start TPN or to starve the patient until adequate gastrointestinal (GI) function returned was needed. Current technology and practice in nutrition have changed dramatically over the past 25 years, so that aggressive early enteral nutrition is a major consideration in the management of patients with brain injuries and in maintenance of patients with chronic neurologic disease requiring nutritional support.
SECTION V • Disease Specific
CHRONIC NEUROLOGIC DISEASES Many neurologic diseases can affect a patient's ability to eat independently. Depressed levels of consciousness are associated with a decreased ability to protect the upper airway from episodes of gastroesophageal reflux, vomiting, and even oropharyngeal secretions. Morbidity and mortality from aspiration pneumonia can be significant in this population. Some diseases may affect the neural or muscular coordination required for successful swallowing, whereas others may alter gastric or intestinal motility. A review of the signs and symptoms of these disorders can lead to a better understanding of rehabilitation techniques, when possible, and to alternate enteral access routes, when function is unlikely to return or may be significantly delayed. The importance of nutrition in chronic neurologic disease has been evaluated, but this still remains an area for which new research is needed. Britton and associates" reported on a significant decrease in subsequent infectious episodes in malnourished patients with chronic neurologic injuries who received a percutaneous endoscopic gastrostomy (PEG) tube and enteral feedings. Lewis and colleagues? examined the impact of neurologic injury on gastroesophageal reflux in a group of malnourished, neurologically debilitated patients. Reflux episodes improved in this group after adequate nutrition. Adequate nutrition appears to provide support for adequate muscle function of the esophagus, lower esophageal sphincter (LES), and diaphragm muscle groups, all important in preventing episodes of reflux.
Dysphagia Careful evaluation of the swallowing reflex is important in guiding decisions about whether the patient can eat orally or whether enteral access should be considered. Dysphagia is divided into two broad groups, esophageal dysphagia and oropharyngeal (transfer) dysphagia, and a careful history is important to determine which type is present. Esophageal dysphagia refers to difficulty with passage of a food bolus after successful passage from the pharynx to the esophagus. Intermittent mechanical obstruction to solid food, which suggests an esophageal ring or web, may be seen. Progressive dysphagia for solids and ultimately liquids suggests more intrinsic disease of the esophagus, which may originate from a peptic stricture or a malignancy. When a patient initially describes difficulty with swallowing of solids and liquids, it is often due to primary neuromuscular or motility disorders of the esophagus. Examples of these disorders are diffuse esophageal spasm, achalasia, and scleroderma. A complete discussion of these is beyond the scope of this chapter."
407
Oropharyngeal dysphagia is difficulty swallowing due to a lesion above or proximal to the esophagus. The patient complains of difficulty moving a food bolus into the pharynx and esophagus to initiate the involuntary swallowing reflex. Swallowing is a combination of integrated neural and muscular actions coordinated in the brain stem. Any process that alters the afferent and efferent limbs' nerves (fifth, seventh, ninth, and twelfth cranial nerves) or the brain stem swallowing center can cause oropharyngeal dysphagia. The patient may describe nasal regurgitation, dysarthria, nasal speech from muscular weakness, or coughing during swallowing. Liquids present more difficulty with this disorder than with esophageal dysphagia, in which liquids pass easily until the patient's esophagus is almost totally obstructed. This is due to the rapid movement of liquids from the oral cavity to the posterior pharynx, overwhelming an already disordered swallowing mechanism. Table 34-1 lists the diseases associated with oropharyngeal dysphagia, concentrating on neurologic mechanisms.
Dysphagia Evaluation Table 34-2 lists the tests that are useful in diagnosing the etiology of the dysphagia. If the diagnosis is obvious, as with a cerebrovascular accident (CVA), then the key issues are how severe is the swallowing deficit and whether there is associated pulmonary aspiration. In this instance, the most important test is the modified barium swallow using video fluoroscopy, which is often done by a radiologist and speech therapist." In this technique the initial swallowing mechanisms that lead to a liquid or solid bolus passing into the upper esophagus are closely examined and the risk of pulmonary aspiration is also evaluated. Aspiration is the entry of material below the true vocal cords. Identification of aspiration is important because many dysphagic patients may have silent episodes of aspiration without external signs of food or liquid entering the pulmonary tree. 10 If liquids present an aspiration risk, then foods with different consistencies are also examined to see if any consistency of food is safe. Some patients will be able to swallow more viscous or solid materials safely, and this will have further importance when one is trying to rehabilitate patients.'!" Aspiration risk reduction diets have been developed to help maximize patient intake while the aspiration risk is
minimized."
Gastrointestinal Dysfunction Gastrointestinal Motility Disorders of GI motility can involve primarily the stomach, such as gastroparesis, or be more pervasive and affect all areas of the GI tract. Patients with acute head injuries (HIs) often exhibit more difficulty with gastroparesis, which is usually short term. In addition, HI has
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34 • Enteral Nutrition and the Neurologic Diseases
• . . Conditions Causing Oropharyngeal . . Dysphagia
Neuromuscular Diseases Central nervous system (CNS) Cerebral vascular accldent (brain stem or pseudobulbar palsy) Cerebral palsy Parkinson disease Wilson disease Multiple sclerosis Amyotrophic lateral sclerosis Brain stem tumors Tabes dorsalis Miscellaneous congenital and degenerative disorders of the CNS Tardive dyskinesia (usually Irreversible and drug related-phenothiazine and metoclopramide) Dystonia (usually reversible and drug relatedantihistamines and nitrazepam) Peripheral nervous system Bulbar poliomyelitis Peripheral neuropathies (diphtheria, botulism, rabies, diabetes mellitus) Motor end plate Myasthenia gravis Muscle Muscular dystrophies Primary myositis Metabolic myopathy (thyrotoxicosis, myxedema, steroid myopathy) Dermatomyositis Amyloidosis Systemic lupus erythematosus
Abnormal Upper Esophageal Sphincter (UES) Relaxation Incomplete relaxation (crlcopharyngeal achalasia): CNS lymphoma, oculopharyngeal muscular dystrophy Decreased cricopharyngeal compliance Hypopharyngeal (Zenker diverticulum), cricopharyngeal bar Delayed UES relaxation; famlllal dysautonomia (Riley-Day syndrome)
Local Structural Lesions Inflammatory (pharyngitis, abscess, tuberculosis, syphllls) Neoplastic Congenital webs Plummer-Vinson syndrome Extrinsic compression (thyromegaly, cervical spine hyperostosis, lymphadenopathy) Primary head and neck tumors Surgical resection of the oropharynx XerostomIa (drugs, autoimmune diseases, radiation therapy) Adapted from Casteli DO, Donner MW: Evaluationof dysphagia: Acareful historyis crucial. Dysphagia 1987;2:65-71.
been associated with LES dysfunction. Helling and associates" evaluated the effect of HI on LES pressures. At 30 hours after injury, the LES pressure was 0.5 mm less than the gastric pressure, predisposing the patient to significant gastroesophageal reflux. The mean
• . . Diagnostic Tools In Dysphagia . . Evaluation
Careful history Physical examination (especially neurologic examination) Barium swallow Modified barium swallow (videofluoroscopy) Esophageal manometry Esophageal pH monitoring Endoscopic evaluation (hypopharynx or esophageal)
Johnson-DeMeester score, a rating of the degree of gastroesophageal reflux, was 327 (normal <14). Patients with chronic HIs may also have underlying diffuse GI motility disorders that affect them on a more global basis.
Gastroparesis Gastroparesis results from impaired contractile capacity of the stomach, which leads to defective gastric emptying. There are many causes of gastroparesis, which can be categorized as primary and secondary GI disorders." Primary disorders include idiopathic forms of gastroparesis, with which there is no evidence of systemic disease. These disorders comprise one third of cases and will not be discussed further. Diabetes remains the most common cause of gastroparesis. Patients with neurologic disorders may exhibit secondary disorders with which there is an underlying abnormality in either the smooth muscle or enteric nervous systems or both. The resulting disorder may manifest clinically as gastroparesis or with diffuse defects in GI motility. Kao and colleagues" evaluated 35 patients with moderate to severe HI who were matched to 16 control subjects. Delayed gastric emptying was more common in older patients and in patients with a lower Glasgow Coma Score." Weekes and co-workers'? reported on significant severe gastroparesis and regurgitation of tube feedings in gastric-fed patients with Hls.17 The ability to feed a patient with an HI into the stomach is hampered by the risk of GI regurgitation and aspiration. Acutely, gastric and duodenal contractions in rabbits are inhibited with increased intracranial pressure." In man, tolerance to gastric feeding is less than 50% in patients with acute Hls.19,2o,21-23 As has been reported with intracranial lesions, the etiology may be from a similar mechanism in which elevated intracranial pressure stimulates and compresses the emetic center of the floor of the fourth ventricle." In addition, patients with high spinal cord transections (above T5) may experience delayed gastric emptying.f The actual impact of delayed gastric function and gastroparesis in neurologic diseases is unknown, and
SECTION V • Disease Specific
these conditions may be underdiagnosed. Gastric hypomotility has been noted in Duchenne muscular dystrophy and appears to be a defect in the smooth muscle. These patients usually have bloating, acute gastric dilatation, or intestinal pseudo-obstruction, which can be fatal; therefore, any of these signs or symptoms may warrant an evaluation for gastroparesis.Pj? Table 34-3 lists neurologic diseases associated with 01 motility disorders.
Gastrointestinal Motility Evaluation and Treatment Evaluation of gastroparesis should first exclude an ulcerative, inflammatory, or neoplastic process of the stomach and duodenum. This can be accomplished by upper 01 tract endoscopy but may also require an upper 01 tract barium study, which examines the small bowel to exclude a partial obstruction. Also to be considered are medications and metabolic conditions, especially hypercalcemia. The gold standard for quantitative evaluation of gastric emptying is radioscintigraphic measurement. This method permits labeling of solid or liquid phases of gastric emptying and allows for measurement of transfer of the radiolabeled phases to different regions of the stomach. It is important to make sure that normal values for a given laboratory are available, because variability exists in the meals and individual protocols used. Currently available medications that can improve gastric emptying include metoclopramide, tegaserod, and erythromycin. Domperidone is not available in the United States. The use of these drugs in the patient with an acute HI has not been well studied. Altmayer and co-workers'" evaluated a group of patients with His in whom aspiration from tube feeding was documented. The addition of a pharmacologic promotility agent allowed gastric feedings to continue in these patients without subsequent difficulties. There are some concerns about the use of metoclopramide in patients with His, because it crosses the blood-brain barrier and is associated with many neurologic side effects. The other available promotility agents have rare central nervous system side effects and deserve further
' •
.
Neurologic Diseases Associated with Gastrointestinal Motility Disorders
Diabetic neuropathy and diabetic gastroparesis syndrome Idiopathic orthostatic hypotension Intracranial lesions Intrinsic myopathies and neuropathies Dystrophia myotonica Familial gut myopathies and neuropathies Progressive muscular dystrophy
409
investigation in this population. In the past few years, an implantable pacemaker for the stomach has been developed." Results have been varied. The primary patients receiving the gastric pacemaker are those with diabetes or idiopathic gastroparesis, not chronic neurologic disorders.
Enteral Feeding Considerations for Patients with Chronic Neurologic Disorders What follows is a series of questions to help determine the enteral nutrition issues of patients with more chronic neurologic diseases. 1. What is the patient's level of consciousness? 2. Can the patient protect the airway from episodes of gastroesophageal reflux? 3. What is the patient's ability to swallow liquids, thickened liquids, and soft and solid foods? 4. Is the patient at high risk for aspirating oropharyngeal secretions? 5. Will the need for enteral access be short term or long term? 6. Is there a difference between gastric and jejunal feeding in the population? 7. What are the patient's and family's desires for enteral feeding? 8. What are the nutrient dosing issues in patients with conditions such as Guillain-Barre syndrome or Duchenne muscular dystrophy?
Level of Consciousness Many patients with depressed levels of consciousness tolerate intragastric feedings well. However, if patients are fed by nasoenteric tubes, the protective barriers to gastroesophageal reflux, such as the LES and upper esophageal sphincter, may be compromised." Recent studies show that elevation of the head of the bed has been found to markedly decrease, but not eliminate, reflux episodes in patients receiving mechanical ventilation. 33,34 The use of a percutaneous gastrostomy tube preserves the natural anatomic barriers. Park and colleagues" compared nasoenteric tubes with PEO tubes in patients with persistent neurologic dysphagia and found no significant difference in episodes of aspiration. The patients with PEO tubes received more of their prescribed tube feeding because of frequent nasoenteric tube failure, such as occlusion or displacement. Monitoring of patients with depressed consciousness should include examining for abdominal distention, checking for high gastric residual volumes when they are fed intragastrically, and maintaining elevation of the head of the bed when clinically possible. The inappropriate use of gastric residual volume measurements should not preclude a patient's ability to safely receive gastric feedings. McClave and associates"
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34 • Enteral Nutrition and the Neurologic Diseases
demonstrated that gastric residual volumes less than 200 mLwere of no consequence to the patient. Residual volumes greater than 200 mL were placed back into the patient, and residual volumes were often normal when rechecked later.
Gastroesophageal Reflux Patients who exhibit multiple episodes of aspiration pneumonia should have gastroesophageal reflux investigated as a cause. Esophageal manometry, pH monitoring, and radionuclide tests may be helpful in this assessment. A recent study evaluated scintigraphic findings immediately before and 1 week after PEG tube placement." Evidence of reflux on either examination led to conversion to percutaneous gastrojejunostomy. The authors concluded that PEG tubes did not induce reflux and that scintigraphy was useful in selecting patients who can safely be fed by a PEG tube. Recently a North American Working Group published their consensus recommendations on tube feeding and aspiration." Jejunal feeding was recommended in those patients at risk for development of aspiration pneumonia (Table 34-4). Esophagogastroduodenoscopy (upper GI tract endoscopy) may show other signs of gastroesophageal reflux such as esophagitis, erosions, ulcers, strictures, Barrett's esophagus, and intrinsic masses. Options for patients with severe gastroesophageal reflux are medications to improve gastric emptying and increase lower esophageal pressure (e.g., metoclopramide and tegaserod), feeding into the small bowel rather than into the stomach, or surgical procedures to limit reflux. Albanese and co-workers" retrospectively compared Nissen fundoplication with fluoroscopically guided gastrojejunostomy tube placement in neurologically impaired children with gastroesophageal reflux. The nonoperative approach was found to have fewer major complications that required a second operation. Recent studies demonstrated the safety and efficacy of endoscopically placed jejunal feeding tubes (DPEJ). This provides another nonoperative approach for obtaining jejunal access.
Il!DDIII
M;qor Patient Risk Factors for _ _ Aspiration Previous episode of aspiration Decreased level of consciousness Neuromuscular diseases and structural abnormalities of the aerodlgestlve tract Endotracheal intubation Vomiting Persistently elevated gastric residual volumes Need for prolonged supine positioning of the patient
Swallowing Function After adequate evaluation of the patient's swallowing function, a treatment plan can be developed. 1o-I2,40,41 The prognosis of the underlying disease must also be considered. Some patients with CVAs may recover some or all of their swallowing function; thus, a nasoenteric tube or gastrostomy may provide a temporary bridge until recovery. Some patients may have difficulty only with liquids and may benefit from the use of thickening agents with or without additional enteral access to provide hydration or medications. Patients who have neurologic diseases in which the decline in swallowing function is progressive should be considered for more permanent enteral access options, such as PEG tube placement, as appropriate to their global treatment plan.
Aspiration Secretions
of Oropharyngeal
Aspiration is an important but often misunderstood complication of enteral feeding. Criteria for aspiration in much of the literature are poorly defined, leading to confusion between aspiration of oropharyngeal secretions and stomach contents including enteral alimentation.42-44 This confusion in the literature is part of the reason that the reported risk of aspiration pneumonia varies from 2% to 95%. Few data are available to judge the actual risk of oropharyngeal aspiration of secretions and subsequent aspiration pneumonia in neurologic diseases. Huxley and associates" demonstrated pharyngeal aspiration in humans using indium-Ill chloride in 10 patients with depressed consciousness and 20 control subjects. They showed that 70% of the patients and 45% of the control subjects aspirated pharyngeal secretions. Unfortunately, the relationship between this and the development of aspiration pneumonia is not fully understood, but it may occur when normal pulmonary defense mechanisms are either overwhelmed or impaired and the aspirated bacteria can multiply rapidly. In addition, one case report demonstrated by using a radionuclide salivagrarn that oral aspiration was the cause of recurrent pneumonias in an infant being fed through a PEG tube." Once documented, the only way to eliminate oropharyngeal aspiration totally as a cause of recurrent aspiration pneumonia is to perform a tracheostomy and to close the vocal cords surgically.
Short-Term versus Long-Term Enteral Access In choosing between enteral access options in patients with neurologic disorders, the clinician should estimate how long access will be needed, which is difficult for some conditions such as CVAs or acute His. For use less than 30 days, nasoenteric or oroenteric options
SECTION V • Disease Specific
are generally preferred unless contraindications or special circumstances obviate use of these routes." For longer periods, gastrostomies or jejunostomies are preferred and may reduce the risk of aspiration. Monitoring of these patients should include careful assessment of the actual amount of formula delivered compared with amounts prescribed so that underfeeding does not occur. 43,48 Local expertise will help determine whether radiologic, endoscopic, or surgical options are used.
Gastric versus Jejunal Feeding Gastric feeding is very common owing to its convenience and ease of use. Nasogastric tubes or gastrostomies are common and are preferred if there is good patient tolerance of intragastric feeding. In neurologic diseases, one of the main indications for a jejunostomy is significant gastroesophageal reflux disease, gastroparesis, or other gastric problems leading to aspiration of tube feedings, not oropharyngeal secretions, that in tum may lead to recurrent aspiration pneumonia." Jejunostomy feeding is very effective in patients with documented tube feeding aspiration; however, more data are needed to document the risks and benefits of long-term enteral access through a [ejunostomy.F'"
Ethics When we address the ethical use of enteral access and enteral nutrition in the neurologically impaired patient, multiple criteria need to be evaluated. These include predicted clinical outcome, quality of patient life, and attitudes and beliefs of patients and their families about artificial nutritional support. The use of PEG tubes in patients with CVAs has been investigated. Studies have shown a significant improvement in survival and improved rehabilitation potential.P'" Thirty-three percent of patients with CVAs who initially received PEG tubes, ultimately had a return of their swallowing function. In patients with amyotrophic lateral sclerosis who were experiencing weight loss and a reduction in global function, placement of a PEG tube and initiation of enteral feeding resulted in significant stabilization of their global function compared with patients who did not receive a PEG tube. 52 Weaver and colleagues's reported that quality of life was maintained or improved in patients with chronic neurologic diseases, including dementia, after PEG tube placement. However the use of enteral access in patients with dementia remains very controversial. Dementia is a progressive and ultimately fatal disease. A full discussion with family members and early identification of the goals of PEG tube placement will ensure intelligent, rational decisions regarding enteral access and the use of enteral nutrition.f
411
CONCLUSION The past three decades have seen a dramatic shift in the nutritional care of the patient with neurologic diseases. Initial fears of the safety of parenteral nutrition have been dispelled. A new sense of urgency for early enteral feeding has developed because of its positive impact on clinical outcomes. Nutritional support can now begin on the day of admission with parenteral nutrition, enteral nutrition, or a combination of both until the enteral route can be used to supply all the patient's needs. New enteral access devices have been created for this population and have been shown to allow enteral feeding soon after admission. These include percutaneous endoscopic gastrojejunostomy (PEG/J) and direct percutaneous endoscopic jejunostomy (DPEJ). Repeated trials of tolerance for gastric feeding can now be avoided with those newer devices so that effective enteral support can be started early. The goal of nutritional therapy in neurologically impaired patient is to minimize protein muscle mass loss, therefore improving clinical outcomes. For patients with more chronic neurologic diseases, many options for enteral access are now available and can be individualized to meet the patient's needs. Patients with recurrent episodes of aspiration pneumonia should be evaluated to determine whether it is caused by oropharyngeal secretions or intragastric contents. Therapy can then be focused on treating the underlying cause and not simply performing a jejunostomy when it may not benefit the patient. The clinical benefit of early PEG tube placement and enteral feeding in patients with CVAs and neuromuscular disorders has been proven. The goals of nutritional therapy in the patient with dementia need to be clearly defined. Access to the GI tract with a PEG, PEG/J, or DPEJ may serve as a means to provide calories in appropriate patients or fluids and medications in other instances. The diversity of neurologic diseases has hampered some of the research in this area; however, advancements made in the past two decades are likely to improve patient care and outcome. Aggressive, early nutritional support in the patient with an acute HI can make the rehabilitation process easier. Patients with more chronic neurologic diseases can have slow but progressive deterioration of their ability to eat independently and swallow safely. More options are available to the patient and physician, allowing more choices in the final months or years of life. More research is needed to help guide patients and clinicians in the optimal care of patients with these devastating neurologic diseases.
REFERENCES 1. Steffee WP: Malnutrition in hospitalized patients. lAMA 1980;
244:2630-2635.
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2. Drew JH, Koop CE, Grigger RP: A nutritional study of neurosurgical patients. J Neurosurg 1947;4:7-15. 3. Haider W, Lackner F, Schlick W, et al: Metabolic changes in the course of severe brain damage. Eur J Intensive Care Med 1975;1:19-26. 4. Rapp RP,Young AB,Twyman DL, et al: The favorable effect of early parenteral feeding on survival in head-injured patients. J Neurosurg 1983;58:906-912. 5. White RJ: Aspects and problems of total parenteral alimentation in the neurosurgery patient. In Manni C, Magalini SI,Scrascia E (eds): Total Parenteral Alimentation. Armsterdam, Excerpta Medica, 1976, pp 208--214. 6. Britton JER, Lipscomb G, Mohr PD, et al: The use of percutaneous endoscopic gastrostomy (PEG) feeding tubes in patients with neurological disease. J Neurol 1997;224; 431-434. 7. Lewis D, Khoshoo V, Pencharz PB, et al: Impact of nutritional rehabilitation on gastroesophageal reflux in neurologically impaired children. J Pediatr Surg 1994;29:167-170. 8. Castell DO, Donner MW: Evaluation of dysphagia: A careful history is crucial. Dysphagia 1987;2:65-71. 9. Logemann JA: Manual for the Videofluorographic Study to Swallowing, 2nd ed. Austin, Pro-Ed, 1993. 10. Horner J, Massey EW:Silent aspiration following stroke. Neurology 1988;38:317-319. II. Buchholz DW, Bosma JF, Donner MW: Adaptation, compensation and decompression of the pharyngeal swallow. Gastroinest Radiol 1985;10:235-239. 12. Logemann JA: Treatment for aspiration related to dysphagia: An overview. Dysphagia 1986;1:34-38. 13. Curran J, Groher ME: Development and dissemination of an aspiration risk reduction diet. Dysphagia 1990;5:6-12. 14. Helling TS, Evans LL, Fowler DL, et al: Infectious complications in patients with severe head injury. J Trauma 1988;28: 1575-1577. 15. Malagelada JR, Azpiroz F, Mearin F: Gastrointestinal motor function in health and disease. In Siesenger MH, Fordtran JS (eds): Gastrointestinal Disease: Pathophysiology/Diagnosis/ Management, 5th ed, vol I. Philadelphia, WB Saunders, 1993, pp 486-508. 16. Kao CH, ChangLai SP, Chieng PU, et al: Gastric emptying in headinjured patients. Am J Gastrol 1998;93:1108-1112. 17. Weekes E, Elia M: Observations on the pattems of 24-hour energy expenditure changes in body composition and gastric emptying in head-injured patients receiving nasogastric tube feedings. JPEN J Parenter Enteral Nutr 1996;20:31-37. 18. Garrick T, Mulvihill S, Busak S, et al: Intracerebroventicular pressure inhibits gastric antral and duodenal contractility but not acid secretion in conscious rabbits. Gastroenterology 1988; 96:26-31. 19. Clifton GL, Robertson CS, Constant CF: Enteral hyperalimentation in head injury. J Neurosurg 1985;62:186-193. 20. Norton JA, Ott LG, McClain C, et al: Intolerance to enteral feeding in the brain-injured patient. J Neurosurg 1988;68:62--66. 21. Hunt D, Rowlands D, Allen S: The inadequacy of enteral nutritional support in head injury patients during the early post-injured period [abstract]. J Parenter Enter Nutr 1985;9: 121. 22. Twyman D, Young B, Ott L, et al: High protein enteral feedings: A means of achieving positive nitrogen balance in head-injured patients. JPEN J Parenter Enteral Nutr 1985; 9:679--684. 23. Ott L, Young B, Phillips R, et al: Altered gastric emptying in the head-injured patient: Relationship to feeding tolerance. J Neurosurg 1991;94:738-742. 24. Wood JR, Camilleri M, Low PA, et al: Brainstem tumor presenting as an upper gut motility disorder. Gastroenterology 1985;89: 1411-1414. 25. Feasley RD, Szurszewski JH, Merritt JC, et al: Effects of traumatic spinal cord transection on human upper gastrointestinal motility and gastric emptying. Gastroenterology 1984;87: 69-75. 26. Barohn RJ, Levine EJ, Olson JO, et al: Gastric hypomotility in Duchenne's muscular dystrophy. N Engl J Med 1988;319: 5-18.
27. Crowe GG: Acute dilatation of stomach as a complication of muscular dystrophy. Br Med J 1961;1:1371. 28. Robin GC, de L Falewski G: Acute gastric dilatation in progressive muscular dystrophy. Lancer 1963;2: 171-172. 29. Leon SH, Schuffler MD, Kettler M, et al: Chronic intestinal pseudoobstruction as a complication of Duchenne's muscular dystrophy. Gastroenterology 1986;90:455-459. 30. Altmayer T, O'Dell MW,Jones M, et al: Cisapride for the treatment of gastroparesis in traumatic brain injury. Arch Phys Med Rehabil 1996;77:1093-1094. 31. McCallum RW, Chen JD, Lin Z, et al: Gastric pacing improves emptying and symptoms in patients with gastroparesis, Gastroenterology 1998;114:456-461. 32. Mittral RK, Stewart WR, Schirmer BD: Effect of a catheter in the pharynx on the frequency of transient lower esophageal sphincter relaxations. Gastroenterology 1992;103:1236-1240. 33. Torres A, Serra-Battles J, Ros E, et al: Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: The effect of body position. Ann Intern Med 1992;116: 540-543. 34. Ibanez J, Penafiel A, Raurich JM, et al: Gastroesophageal reflux in intubated patients receiving enteral nutrition: Effect of supine and semirecumbent positions. JPEN J Parenter Enteral Nutr 1992;16: 419-422. 35. Park RHR, Allison MC, Lang J, et al: Randomised comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding in patients with persisting neurological dysphagia. Br Med J 1992;304:1406-1409. 36. McClave SA, Snider HL, Lowen CC, et al: Use of residual volume as a marker for enteral feeding intolerance. Prospective blinded comparison with physical examination and radiologic findings. JPEN J Parenter Enteral Nutr 1992;16: 99-105. 37. Olson DL, Krubsack AJ, Stewart ET: Percutaneous enteral alimentation: Gastrostomy versus gastrojejunostomy. Radiology 1993; 187:105-108. 38. McClave SA, DeMeo MT, DeLegge MH, et al: North American summit on aspiration in the critically ill patient: Consensus statement. JPEN J Parenter Enteral Nutr 2002;26(suppl):S80-S85. 39. Albanese CT, Towbin RB, Ulman I, et al: Percutaneous gastrojejunostomy versus Nissen fundoplication for enteral feeding of the neurologically impaired child with gastroesophageal reflux. J Pediatr 1993;123:371-375. 40. Logemann JA, Kahrilas PJ: Relearning to swallow after strokeApplication of maneuvers and indirect biofeedback: A case study. Neurology 1990;40:1136-1138. 41. Horner J, Massey EW, Riski JE, et al: Aspiration following stroke: Clinical correlates and outcome. Neurology 1988;38: 1359-1362. 42. Cataldi-Betcher EL, Seltzer MH, Slocum BA, et al: Complications occurring during enteral nutrition support: A prospective study. JPEN J Parenter Enteral Nutr 1983;7:546-552. 43. Winterbauer RH, Durning RB, Barron E, et al: Aspirated nasogastric feeding solution detected by glucose strips. Ann Intern Med 1986;95:647--668. 44. Lazarus BA, Murphy JB. Culpepper L: Aspiration associated with long-term gastric versus jejunal feeding: A critical analysis of the literature. Arch Phys Med Rehabil 1990;71:46-53. 45. Huxley EJ, Viroslav J, Gray WR, et al: Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 1978;64:564-568. 46. Heyman S: The radionuclide salivagrarn for detecting the pulmonary aspiration in an infant. Pediatr Radiol 1989;19: 208--209. 47. Kirby DF, DeLegge MH, Fleming CR: AGA technical review on the use of enteral nutrition. Gastroenterology 1995;108: 1282-1301. 48. Kiel MK: Enteral tube feeding in a patient with traumatic brain injury. Arch Phys Med RehabilI994;75:116-117. 49. Welz CR, Morris JB, Mullen JL: Surgical jejunostomy in aspiration risk patients. Ann Surg 1992;215:140-145. 50. Wanklyn P, Cox N, Bellfield P: Outcome in patients who require a gastrostomy tube after stroke. Age Ageing 1995; 24:510-514.
SECTION V • Disease Specific 51. James A. Kapur K. Hawthorne AB: Long-term outcome of percutaneous endoscopic gastrostomy feeding in patients with dysphagic stroke. Age Ageing 1998;27:671-676. 52. Chio A. Finnochiaro E. Meineri P, et al: Safety and factors related to survival after percutaneous endoscopic gastrostomy in ALS. Am Acad Neurol 1999;53:1123-1125.
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53, Weaver JP, Odell P, Nelson C: Evaluation of the benefits of gastric tube feedings in an elderly population. Arch Fam Med 1993;2: 953-956. 54. Teno JM, Landrum K. Lyn J: Defining and measuring outcomes in end-stage dementia. Alzheimer Assoc Dis 1997;11:25-29.
Enteral Nutrition in Acute Pulmonary Disease David Ciccolella, MD
CHAPTER OUTLINE Introduction Epidemiology Clinical Presentation, Assessment of Severity, and Treatment Nutrition Assessment Assessment Typical Nutritional findings in Acute Respiratory Failure Indications for Enteral Nutrition Issues with Enteral Access Caloric, Protein, and Micronutrient Needs Nutrition Management Patient Monitoring Potential Complications Summary
INTRODUCTION Nutrition plays a significant role in the optimal care of patients with pulmonary disease because there is a significant interrelationship between nutritional status and respiratory disease. Malnutrition may cause impairment of the lung parenchyma, respiratory muscles, host defense, and central nervous system drive to breathe. These systems may be affected by an acute or acute-on-ehronic disease exacerbation resulting in acute respiratory failure, which also affects nutritional status. In the patient with chronic pulmonary disease, malnutrition may already be present, whereas in the patient without chronic pulmonary disease (e.g., a young healthy person with acute pneumonia causing acute respiratory distress syndrome [ARDS]), nutritional 414
status may have been adequate before onset of the acute process.
Epidemiology Acute respiratory failure may occur from a variety of diseases of the lung such as ARDS and exacerbation of chronic obstructive pulmonary disease (COPD). ARDS, described initially in 1967, is defined as an acute onset of respiratory impairment associated with bilateral infiltrates on a chest radiograph and severe hypoxemia without evidence for volume overload (pulmonary artery occlusion pressure ~18 mm Hg or left atrial hypertension).' The severity of hypoxemia is determined by the ratio of partial pressure of arterial oxygen to the fractional inspired oxygen concentration expressed as Pao2/Fio2. A value of 300 or less defines acute lung injury and a value of 200 or less defines ARDS. It has been difficult to determine the incidence of ARDS and estimates have varied widely, ranging from 5 to 75 per 100,000 persons or approximately 15,000 to 200,000 cases per year. Many of the chronic lung diseases are progressive and lead to acute respiratory distress or failure, which requires admission to the hospital, often to the intensive care unit (ICU). COPD is a common pulmonary disease, affecting approximately 9.3 and 7.3 men and women, respectively, per 1000 population worldwide in 19902 and often results in acute exacerbation and respiratory failure. The incidence of COPO in the United States was 16 million people in 1994. The relationship of COPD and respiratory failure to nutritional status has been studied more than that of any other disease of the lungs. Moreover, many of the principles of nutrition in acute exacerbation of COPD apply to other acute pulmonary diseases as well. Considering the foregoing, we will mainly discuss the nutritional aspects of acute respiratory failure from exacerbation of COPD and ARDS, focusing on the
SECTION V • Disease Specific
rationale, indications, and challenges in this group of patients.
Clinical Presentation, Assessment of Severity, and Treatment Acute pulmonary disease occurring in patients with or without chronic pulmonary disease may result from a wide spectrum of lung injury. The injury may be caused by a local infection such as acute tracheobronchitis or an exacerbation of COPD or a systemic process that leads to diffuse alveolar damage such as that seen with ARDS.
Chronic Obstructive Pulmonary Disease Acute exacerbations of COPD are commonly due to infection or air pollution, but for approximately 33% of exacerbations the etiology is unknown.' The clinical presentation can range from a brief illness requiring a few days of hospitalization to a severe illness with acute respiratory failure requiring mechanical ventilation in the ICU. An exacerbation of COPD is marked by increased dyspnea, especially at rest, wheezing, chest tightness, a productive cough with a change in the color and/or viscosity of sputum, and fever. Nonspecific symptoms may also occur and include malaise, fatigue, sleepiness or insomnia, confusion, decreased appetite, and sometimes depression. Physical examination shows evidence of respiratory distress, accessory muscle use, poor air movement, and wheezing. With severe presentations, more severe respiratory distress, cyanosis, paradoxical movements of the rib cage and abdomen, inability to speak in complete sentences, and alteration in consciousness may be seen. Arterial blood gas (ABG) measurements show hypoxemia with or without hypercapnia. The mortality of hospitalized patients with an exacerbation of COPD is approximately 10% and in those patients requiring ICU admission it can be as high as 25%.2 Each exacerbation of COPD can cause a significant deterioration in subsequent functional status and quality of life. The accurate assessment of severity of the acute exacerbation is important for determining the type of treatment and whether the patient is placed on the medical floor or is admitted to the ICU. The severity of acute exacerbation is assessed routinely by medical history, physical examination, pulmonary function tests, ABG measurements, and other laboratory tests. The medical history should include not only the acute symptoms but also the severity of the chronic disease and the frequency of prior exacerbations, especially those requiring intubation and mechanical ventilation. It is important to include the frequency, duration, and severity of new or worsening chronic symptoms of dyspnea, cough, sputum color and volume, and degree of impairment of daily activities. The change in frequency and dose of bronchodilators and in the amount of oxygen (oxygen concentration or flow rate) required and the need for mechanical ventilatory support are
415
helpful to assess severity of the current exacerbation. The ABG measurement is helpful in assessing the degree of hypoxemia and hypercarbia. In those with chronic lung disease, prior pulmonary function tests and ABG measurements made during a stable state are important to assess change and thus severity of the acute or chronic exacerbation. The treatment of acute pulmonary disease depends on the type and severity of disease and includes medication therapy, supplemental oxygen, a reduction of ventilatory workload, and nutritional support. Medication therapy for an acute exacerbation of pulmonary disease such as COPD includes nebulized bronchodilators (~2-agonists such as albuterol and anticholinergics such as ipratropium bromide), systemic corticosteroids, parenteral theophylline, and antibiotics. The nebulized bronchodilators albuterol and ipratropium bromide playa major role in the treatment of exacerbation of acute obstructive lung disease because of their effectiveness and safety. In contrast, theophylline, with its history of side effects and weaker bronchodilator effect, plays a minor role, and its use is generally reserved for patients with a suboptimal response to the nebulized bronchodilators. Systemic corticosteroids are often used in acute treatment and have been shown to improve airflow obstruction and reduce treatment failures and hospital stay.' Treatment of hypoxemia and impaired ventilation with hypercapnia depends on their severity. Hypoxemia can be treated with oxygen delivered via nasal cannula, plain or Venturi mask, or a high-flow, vapor-phased, humidified nasal cannula system (Vapotherrn, Annapolis, MD) from 20 to 40 Umin. For patients with acute respiratory failure who require a reduction in ventilatory workload, ventilatory support may be provided by mechanical ventilation either through invasive endotracheal intubation or noninvasive intermittent positivepressure ventilation (NIPPY) through a bilevel positive airway pressure mask. More commonly, conventional invasive mechanical ventilation using an endotracheal tube is used for ventilatory support. However, NIPPV can be used to avoid the complications of invasive mechanical ventilation with endotracheal intubation. NIPPV has been studied extensively in acute respiratory failure and success rates of 80%to 85% have been seen in the proper candidates. It improves blood gas values and reduces the length of hospital stay and mortality. Several reviews have delineated the indications and contraindications for use of NIPPV in respiratory tailure.r" NIPPV treatment may be used in patients with moderate to severe dyspnea associated with the use of accessory muscles and paradoxical abdominal motion, moderate to severe acidosis, and hypercapnia. Some contraindications include inability of patients to protect their airway" craniofacial injury, and recent facial or gastroesophageal
surgery.'
Acute Respiratory Distress Syndrome ADRS may result from a variety of illnesses, but the common illnesses associated with the development of ARDS
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35 • Enteral Nutrition in Acute Pulmonary Disease
include sepsis, pneumonia, gastric content aspiration, and severe trauma with shock and multiple transfusions. I Sepsis is the most common cause of ARDS,7 and pneumonia is the most common cause of ARDS developing outside of the hospital. During the development of ARDS, ongoing inflammation affecting the alveolar-capillary barrier is present. A number of inflammatory cells (e.g., neutrophils) and mediators (e.g., neutrophils, cytokines, prostaglandins, and leukotrienes) (are implicated in the resulting injury.I,B The coagulation and complement systems are also activated and are associated with increased coagulation and decreased fibrinolysis. Increased pulmonary vascular permeability and leakage occur from the endothelial damage, resulting in noncardiogenic pulmonary edema. The clinical presentation of a patient with ARDS includes rapidly progressive severe dyspnea, bilateral diffuse lung infiltrates, and hypoxemia. The severity of the hypoxemia is based on the ratio of the partial pressure of oxygen to the Fio2• A value less than 200 defines ARDS whereas a value less than 300 defines acute lung injury. Other abnormalities include worsened pulmonary mechanics showing increased lung stiffness and also increased dead space, which has been associated with increased mortality." In addition to the noncardiogenic pulmonary edema, the vascular injury may lead to pulmonary hypertension. Multiorgan system failure may occur during the course of the illness. The development of acute lung injury or ARDS may result in a mortality of 40% to 50%, more commonly from sepsis or multiorgan failure than from primary respiratory causes.l'" The treatment of ARDS is mainly supportive while the clinician attempts to identify and treat the underlying cause. This entails the maintenance of organ function, optimal fluid management, and provision of adequate oxygenation, for which most patients require conventional invasive mechanical ventilation. Although NIPPV has been used in ARDS, there are no controlled trials to evaluate morbidity or mortality rates, and therefore its use is rarely justified or advised." Careful fluid management is very important because increased lung fluid may increase lung stiffness and further worsen hypoxemia. I I Patients may require high concentrations of oxygen and also high airway pressures and volumes to ventilate the lung, which may result in further lung injury. The recognition of this ventilator-related morbidity, especially in this illness, has spurred investigation into better methods of using mechanical ventilation. Recently, the ARDS network trial showed that applying mechanical ventilation to the lungs with a lower tidal volume of 6 mUkg ideal body weight, and maintaining plateau pressures of less than 30 em H20 , rather than a much higher control tidal volume of 12 mUkg resulted in a 22% reduction in mortality." Although there is some controversy over the high control volume chosen, this lung-protective strategy results in lower airway pressures but at the risk of hypercapnia to avoid further lung damage or barotrauma. Nutritional support plays a vital role in treating the critically ill patient, and the type, amount, and mode of nutritional support depend on the nutrition assessment.
NUTRITION ASSESSMENT
Assessment An assessment of nutritional status should be systematically performed in patients with an acute exacerbation and/or respiratory failure" and is helpful to identify those with a higher risk of a poor outcome. The nutrition assessment is used to identify preexisting malnutrition, estimate the nutritional consequences of the current hospitalization, develop a nutrition care plan, and monitor the nutritional therapy. It is important for the physician to identify these patients and to understand the goals of nutritional intervention because these may be commonly overlooked or underestimated by physicians. The formal nutrition assessment is performed using information obtained from the history (medical, nutrition, and medication), physical examination, anthropometric measurements, and laboratory data. The nutrition history, including an evaluation of weight history and particularly recent involuntary weight loss, dietary intake, and medication usage (i.e., systemic corticosteroids or theophylline) are important to defining nutrition goals." Typically, patients who are severely ill or who are receiving mechanical ventilation are unable to provide any weight or diet history, but this may be obtained from family members or prior care providers. Physical examination may reveal nutritional and metabolic deficiencies. Easily recognized signs of proteincalorie deficiency include temporal muscle wasting, sunken supraclavicular fossa, and decreased adipose stores. A specific micronutrient deficiency may be indicated by a rash or glossitis. In addition to evaluation of the respiratory function, cardiovascular and gastrointestinal (e.g., gastric atony) system functions should be evaluated for evidence of dysfunction related to malnutrition and for the ability of the patient to tolerate nutritional support. An assessment of mental status is also important to evaluate the risk of aspiration related to mode of delivery. Anthropometric methods using measurements such as skinfold thickness and midarm muscle circumference can provide an estimation of protein reserves and subcutaneous fat stores, but in the critically ill patient these are not very accurate methods. The laboratory assessment includes measurement of serum albumin and prealbumin concentrations and other blood chemistry values including phosphate, magnesium, and calcium, as well as ABG values such as partial pressure of arterial carbon dioxide. Serum albumin and prealbumin concentrations have been used to evaluate visceral protein stores but are often affected by edema and other nonspecific changes such as infection and inflammation in the critically ill patient. Albumin is an independent risk factor for mortality but is not a good indicator of adequacy of nutritional support because of its relatively long half-life of 20 days. However, prealbumin has a short half-life of approximately 2 to 3 days and serial measurements are useful to evaluate the response
SECTION V • Disease Specific
to nutritional support. Phosphate is necessary for the synthesis of adenosine triphosphate and 2,3-diphosphoglycerol and is especially important for normal function of the heart and diaphragm. The Subjective Global Assessment (SGA) and the Harris-Benedict equation are two valid clinical instruments for assessing malnutrition and planning nutritional therapy. The SGA is a reproducible clinical method to evaluate nutrition status and illness severity that includes patient history and physical parameters. However, it has not been formally evaluated in critically ill patients, and some patients with mild degrees of malnutrition may be missed." In the patient with COPD and acute respiratory failure, a nutrition assessment on admission using a multiparameter index based on body weight, fat stores, lean body mass, and visceral protein status has been shown to be useful in identifying rnalnutrition.P However, a single prognostic nutritional index based on biochemical and anthropometric measurements is of limited value. Indirect calorimetry is helpful when it is difficult to evaluate nutritional needs but should not be done on a routine basis because of cost and technical difficulties."
Typical Nutritional Findings in Acute Respiratory Failure In patients with acute respiratory failure from either COPD or ARDS, malnutrition may exist on presentation or develop during the illness. On presentation to the hospital, approximately 60% of patients with exacerbation of COPD and acute respiratory failure were found to be malnourished based on a multiparameter nutritional index that included ideal body weight, triceps skinfold thickness, midarm muscle circumference, creatinine- height index, and albumin and prealbumin concentrations." Protein and fat stores were markedly depleted in almost 50% of patients. 12,15 Asevere decrease in prealbumin and albumin concentrations was found in 22% and 4% of patients, respectively. Approximately 40% of patients with a body weight of 90% or greater of ideal body weight were malnourished. The malnutrition was found to be more severe in patients requiring mechanical ventilation (74% vs. 43%).12 Moreover, weight loss has been found to be a risk factor for acute respiratory failure requiring mechanical ventilation." In elderly patients (older than 65 years of age) with acute communityacquired pneumonia, approximately 70% were found to have a kwashiorkor-like malnutrition." Approximately 33% had respiratory failure, and the most common underlying conditions were cardiac disease and COPD. In patients with ARDS, survivors had severe muscle wasting and a severe weight loss of 18% over 25 days.18,19 These patients also had a persistent functional disability 1 year after discharge. In patients with severe sepsis, 40% developed ARDS, and 92% of the patients with ARDS were found to have low or borderline serum total protein levels «6 g/dL).2o The initial serum protein level and its change were significantly correlated with weight gain (fluid retention), prolonged mechanical
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ventilation, ARDS development, and death in patients with sepsis. An acute exacerbation of COPD adversely affects nutritional status by causing decreased appetite and oral intake (i.e., caloric intake). Factors that may contribute to the decreased dietary intake are changes in breathing pattem and decreased oxygen uptake during chewing and swallowing," a reduction in the lung functional residual capacity and increased dyspnea due to gastric filling,22 and mouth breathing, causing an alteration in taste perception. 22,23 Leptin, the energy balance-regulating hormone that is produced by fat tissue, has been also associated with the decreased dietary intake in exacerbations of COPD.24 Patients with acute respiratory failure may have hypermetabolism because of the acute injury. The metabolic response to injury is characterized as ebb and flow phases followed by an anabolic phase. The ebb and flow phases involve activation of the sympathetic nervous system and the pituitary-adrenal release of hormones. The initial phase of the injury response, the ebb phase, may last for 1 to 2 days and is manifested by reduced oxygen consumption and energy expenditure. The flow phase follows and is characterized by increased metabolism or energy expenditure and an imbalance between catabolic and anabolic processes, causing a negative nitrogen balance. It is not until the recovery period of the illness that the anabolic phase can result in a reversal of this nitrogen imbalance. Many patients with stable COPD have hypermetaboIism,25,26 which is worsened by an acute exacerbation. The hypermetabolism results in utilization of adipose tissue and skeletal muscle by more metabolically active tissues such as the liver, bone, and other visceral organs, causing a redistribution of protein, fat, and glycogen, In an acute exacerbation of COPD an increase in resting energy expenditure is seen at hospital admission that significantly decreases at hospital discharge." Consequently, this is associated with an initial overall energy imbalance between the decreased dietary energy intake and increased energy expenditure that is gradually restored-? due to an increased appetite and dietary intake" and reduced energy expenditure.f Daily protein intake is also decreased, especially during the first part of an exacerbation of COPD,27 resulting in a protein imbalance. The severity of the decrease in protein synthesis and increase in protein catabolism during an acute exacerbation of COPDwith respiratory failure is not known. In patients with acute respiratory failure due to multiple trauma, sepsis, postoperative open-heart surgery, or ARDS, hypermetabolism was found to be highest in those with ARDS or sepsis." The patients with ARDS usually had hypermetabolism and the severity was approximately 30% greater than predicted energy expenditure. Hypophosphatemia is common in patients with acute respiratory failure before treatment. Further worsening of hypophosphatemia may occur in patients with acute respiratory failure with correction of acidosis by mechanical ventilation by causing a shift in phosphate from the extracellular to the intracellular space. Those who develop
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35 • Enteral Nutrition in Acute Pulmonary Disease
significant hypophosphatemia have a longer hospital stay and duration of mechanical ventilation." Other electrolyte abnormalities such as hypocalcemia and hypomagnesemia can reduce diaphragmatic function. 30.31 Chronic pulmonary disease has adverse effects on the nutritional status, but the resulting malnutrition also has adverse effects on the respiratory system. Malnutrition has been associated with a reduction in diaphragmatic muscle mass and an impairment of respiratory muscle strength,32,33 a reduction in ventilatory response to hypoxia," and an impairment in immune defense." Although these respiratory complications of malnutrition may further compromise the patient's condition, nutritional support has been associated with improvement in these functions.
Patients who are adequately nourished and for whom the anticipated time before initiation of oral intake is less than 5 to 7 days are not as likely to benefit from nutritional support. In contrast, patients most likely to benefit from nutritional support are those with preexisting malnutrition and for whom a prolonged period before the start of oral nutrition is anticipated. Patients with an acute prolonged exacerbation of COPOwho are malnourished and are unable to eat because of dyspnea despite maximal medication and oxygen therapy would benefit from enteral nutritional support. In general, enteral nutrition should be started in patients who have no evidence of clinical shock and who have an intact gastrointestinal tract.
Issues with Enteral Access Medications Medications such as theophylline and systemic corticosteroids may affect the nutritional status. Theophylline may have potential gastrointestinal side effects, especially by decreasing lower esophageal sphincter tone, which may cause more gastroesophageal reflux. Treatment of acute COPO with theophylline may result in more gastrointestinal side effects'" and potentially increase gastroesophageal reflux. Systemic glucocorticoid therapy for COPO may cause serious adverse effects, which include weight gain, glucose intolerance, myopathy, abdominal complaints, osteoporosis, and bone fractures, among others." Ouring an acute exacerbation of COPO, the prospective SCCOPE trial found that treatment with systemic corticosteroids for 2 and 8 weeks resulted in an increase in the frequency of hyperglycemia but not infections, hypertension, gastrointestinal bleeding, or psychiatric problems.' However, corticosteroid treatment may contribute to wasting syndromes by increasing protein catabolism and decreasing protein synthesis. In patients with an acute exacerbation of COPO who had prior prednisone burst therapy and were admitted to the hospital, it was found that the average daily prednisone dose contributed to both inspiratory and expiratory muscle weakness," In patients with nonrespiratory diseases, 8 weeks of corticosteroid therapy produced a decrease in both inspiratory muscle strength and endurance, which were markedly improved after tapering the dose of corticosteroids.P'"
Indications for Enteral Nutrition The indications for nutritional support are based on the patient's preexisting nutritional status, the duration of time before oral nutrition is started, and other comorbidities. It is generally agreed that enteral nutrition is superior to parenteral nutrition because it is associated with fewer complications and is more cost-ettectlve.v" Nutritional support should be initiated as early as possible in the course of critical illness. In a meta-analysis of 15 studies, early nutritional support, defined as being supplied within 36 hours of hospital admission or surgery, reduced the number of infections and length of hospital stay."
The oxygen demands and type of ventilatory support required by the patient affects the type of access for nutritional delivery. Patients hospitalized with an acute exacerbation of lung disease with severe hypoxemia may have high oxygen demands necessitating mask-delivered oxygen, which may prevent adequate nutrition because of the need to remove the mask while eating. In these patients, the use of conventional oxygen therapy via a nasal cannula (<6 Umin) while eating may decrease the hypoxemia and dyspnea, but the flow of oxygen is usually insufficient. Higher-flow oxygen with conventional humidification delivered via a nasal cannula typically is irritative and not usable. In the author's experience, the use of high-flow (20 to 40 Umin of an air-oxygen mixture), vapor-phased, humidified oxygen therapy via a nasal cannula has allowed patients with acute respiratory insufficiency to eat comfortably and adequately without oxygen desaturation. This may help to avoid the need for enteral tube feeding when the patient is too dyspneic to eat. The type of ventilatory support (noninvasive vs. invasive) affects access for nutritional delivery. Patients who require intubation and mechanical ventilation will require tube feeding. However, the use of NIPPY in selected patients may avoid the complications of endotracheal intubation and possibly the need for enteral tube feeding. Oepending on their ventilatory status and other factors, patients needing NIPPY may be able to eat while using the nasal mask." For patients using an oronasal mask, it may be removed, depending on the patient's status, for short periods of time to eat. Oronasal mask removal may be contraindicated in severe respiratory failure. The routine use of a gastric tube is not recommended for oronasal masks because of interference with a tight air seal.' However, if aerophagia and gastric distention occur, a nasogastric tube should be inserted. Majorcomplications such as hypotension, aspiration, and pneumothorax occur rarely.' Only one case report of esophageal perforation using NIPPY, which was temporally related, has been published." In those patients who require enteral tube feeding, there are two possible approaches: nasal or oral tube insertion (gastric or postpyloric) at the bedside, endoscopically, or fluoroscopically and tube enterostomy placed endoscopically, fluoroscopically, or surgically.
SECTION V • Disease Specific
The anticipated duration of enteral feeding, condition of the gastrointestinal tract (patency and motility), aspiration risk,and presence of intubation and mechanical ventilation will affect the type of approach. Primarily, the nasal or oral approach is considered for expected shortterm use whereas tube enterostomies are considered for expected long-term use (>4 weeks). In the ICU, placement of the feeding tube via the nasal route is preferred for nonintubated patients and the oral route is preferred for intubated patients receiving mechanical ventilation in either the gastric or, preferably, the postpyloric duodenal position. Although the postpyloric route has been preferred, the choice has been controversial because of the limited available evidence. Initially a large-bore nasogastric tube is usually inserted to start enteral feeding. This allows for regular aspiration of stomach contents, which is important to evaluate for adequate absorption of feedings and possibly for bleeding. However, this large-bore tube is usually replaced by a smaller-bore (8 to 12 F) polyurethane or silicone tube designed to enable transpyloric passage to deliver nutrients into the proximal duodenum, which theoretically should reduce the risk of aspiration. For nasal or oral enteric feeding tubes, multiple types of small caliber tubes are available. Some tube characteristics, such as lubrication, stylet type, and weighted tip, and the use of promotility agents may help with insertion and/or postpyloric tube placement because the main goal for placement of a small-ealiber tube is the small bowel. The choice of tube diameter and length depends on the use and placement of the orifice used to place the tube: gastric-30 to 36 inches, duodenal-43 inches, and jejunal-48 inches. Weighted tips may help with gastric insertion in the presence of cuffed endotracheal tubes but probably provide no advantage in attaining transpyloric passage. Fluoroscopic and endoscopic guidance methods have been used for postpyloric tube placement in the duodenum and jejunum. Confirmation of correct tube placement requires interpretation of radiographic plain films. Postpyloric tube feeding, especially distal to the ligament of Treitz, may be preferred theoretically over gastric feeding because it may reduce the risk of residual volumes and aspiration associated with gastric feeding, but spontaneous transpyloric passage of the feeding tube (usually within 8 to 24 hours) in critically ill patients with respiratory failure is usually unsuccessful because gastric atony is common. To promote the transpyloric placement of feeding tubes, promotility agents, stylets, and guided insertion have been used. The promotility agents used include metoclopramide 20 mg or erythromycin 200 to 400 mg intravenously, which are administered approximately 30 minutes before tube insertion. However, use of prokinetic agents alone is usually ineffective in critically ill patients and methods to guide insertion into the correct position are needed. Some literature reports suggest that use of inner stylets by an experienced and proficient operator may facilitate transpyloric placement of feeding tubes. If duodenal placement does not occur after several hours, fluoroscopic or endoscopic guidance may be used. Fluoroscopic guidance has been recommended
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for placement of small-bore feeding tubes transpylorically for the early initiation of feeding, especially in those requiring feeding for more than 3 weeks, unconscious patients or patients receiving mechanical ventilation, and those with significant gastric residual volumes despite the use of promotility agents. Alternatively, endoscopic placement of the feeding tube is usually successful and can be performed at the bedside, allowing immediate initiation of enteral feeding.
Caloric, Protein, and Micronutrient Needs The best method for determining energy expenditure and caloric needs has not been established in this patient population. There are several different methods for estimating energy expenditure and determining caloric needs. General guidelines for the critically ill patient with acute respiratory failure suggest 25 to 30 kcal/kg/day. Alternatively, total energy requirements may be estimated based on the Harris-Benedict equations, which use the parameters of sex, age, height, and weight to estimate basal energy needs multiplied by a stress factor. The gender specific formulas are Men: BEE =65 + [6.2 x W] + [12.7 x H] - [6.8 x A] Women: BEE =655 + [4.3 x W] + [4.6 x H] - [4.7 x A] where BEE is basal energy expenditure, W is weight (in pounds), H is height (in inches), and A is age (in years). Because these equations were determined using normal subjects at rest, a stress factor ranging from 1 to 1.5 is used to account for hypermetabolism. However, the use of a stress factor may result in oversupplementation, leading to hyperglycemia, electrolyte imbalances, and respiratory compromise and hypercapnia. Although estimation of energy needs using this formula may result in under- or oversupplementatlon.v-" the method is simple and commonly used. None of the disease-specific formulas has been validated. In the appropriate setting, energy requirements may also be determined by the Fick equation (oxygen uptake [\102] =cardiac output x (arterial oxygen concentration [Ca02] - venous oxygen concentration [Cv02D using a pulmonary artery catheter to calculate oxygen uptake which is then multiplied by 4.86 kcal/L" The determination of energy expenditure by indirect calorimetry using a metabolic cart is an accurate method, but it has limitations. An accurate measurement requires an expensive machine, a skilled technician, a stable Fi02, and a data collection period of 30 to 60 minutes. At Fi02 concentrations of 80% or more, the validity of the measurement is suspect. The determination of energy needs for the patient with acute respiratory failure is difficult because there is no proven optimal approach. Although there are difficulties in determining energy needs in critically ill patients with acute respiratory failure, patients should be supported at their estimated needs and not be given under- or oversupplementation. The caloric needs should be given as
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3S • Enteral Nutrition in Acute Pulmonary Disease
carbohydrate and lipid. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines suggest that patients with pulmonary disease with hypercapnia be given supplementation at or below estimated energy needs." A recent prospective cohort study of medical patients in the ICU, the majority of whom had respiratory failure and were receiving mechanical ventilation (94%), showed that the average caloric intake was 50% of the American College of Chest Physicians (ACCP) target recommendations." Moreover, this study suggested that moderate caloric intake (33% to 65% of ACCP targets or 9 to 18kcal/kg/day), after accounting for variables such as severity of illness, nutritional status, gastric aspirates, and route of feeding, was associated with a greater probability of achieving spontaneous ventilation before ICU discharge. Patients receiving more than 66% of the ACCP recommendations had a lower rate of being discharged from the hospital alive and a lower achievement of spontaneous ventilation. Although this conclusion requires rigorous study, the authors suggested that the ACCP caloric guidelines" may overestimate caloric needs because caloric intakes greater than 65% of ACCP targets were associated with excess morbidity and mortality.
Protein Needs In patients with acute respiratory failure, as in other patients, protein needs depend on the degree of metabolic stress. In general, these may vary from approximately 1.5to 2 g/kg of ideal body weight per day or more in the patient with moderate to high catabolism. The effectiveness of the protein dosing is assessed by monitoring nitrogen balance, which is calculated as follows when a steady state is reached: Nitrogen balance =(protein intake/6.25) - (UUN + 4) Protein intake and urinary urea nitrogen (UUN) are each expressed in grams per day. However, urine urea nitrogen measurements are not accurate when creatinine clearance is less than 20 mUmin. During the early phase of acute respiratory failure, nitrogen balance is typically negative, and the goal is to prevent protein loss by attempting to maintain a balance of zero.
Micron",trients Little information on requirements for minerals, trace elements, and vitamins during critical illness is available. Alternatively, there are established recommended daily allowances of micronutrients for healthy adults that can be used as a guide for dosing." Many of the commercial enteral formulas contain the proper micronutrients if given in an adequate volume.
NUTRITION MANAGEMENT Enteral nutrition can be initiated either intermittently or continuously; however, it is best tolerated as a continuous infusion into either the stomach or small bowel.
Before the enteral feeding is begun, the head of the bed should be elevated to 30 degrees or more. The continuous feeding should be delivered starting at full strength and at a constant rate of 10 to 20 mUhr throughout the day, titrating upward as tolerated. However, interruptions in feeding for either diagnostic or therapeutic procedures are not uncommon in critically ill patients receiving mechanical ventilation. 50•51 This commonly leads to a reduction in nutritional support. These problems may be anticipated and the use of higher rates of feeding or more nutrient dense formulations may be attempted to provide the necessary nutrition for the patient. A number of commercially prepared enteral formulas as well as disease-specific formulas that can be used to provide the necessary fluid, caloric, and protein requirements are available. In acute respiratory failure and ARDS, fluid management becomes especially important when the patient requires a large number of medications intravenously. This is exaggerated if the patient develops multi-organ dysfunction, particularly oliguric renal failure. In patients with volume overload or with ARDS, a fluidrestricted nutrient formulation may be of help. The formulas can be used to provide the appropriate admixtures of carbohydrate and fat. The total calories and admixture of carbohydrate and fat delivered may be of special importance to the patient with acute respiratory failure. The initiation of enteral nutrition is associated with an increase in metabolic rate manifested by increased oxygen consumption and carbon dioxide production, which require an increase in alveolar ventilation. 52.53 This may have adverse effects on weaning from mechanical ventilation especially when patients are overfed. 52. 54 However, the total calories delivered appears to have a greater impact than the actual carbohydrate-to-fat mix." Accordingly, total calories should match the requirements. Pulmonary-specific enteral formulas, which provide more calories from fat than from carbohydrates, have not been proven to be beneficial. It has been recommended that the percentage of total calories provided from fat should be between 20% and 40%.55 The addition of immune-modulating nutrients to enteral formulations has been used to alter the inflammatory response in ARDS. Fatty acids are incorporated into cellular membranes, but as a result of physiologic stress and sepsis, they are released and undergo cellular metabolism. 0)-3 fattyacids in the form of fishoil or canola oil produce different metabolic responses than vegetable oils, which are rich in 00-6 fatty acids. 0)-3 fatty acid metabolism results in formation of prostaglandins and leukotrienes of the 3 and 5 series, which are less immunosuppressive or proinflammatory than prostaglandins and leukotrienes derived from 0)-6 fatty acids." However, an excess of 0)-3 fatty acids themselves can cause immunosuppression. In patients with ARDS associated with pneumonia, trauma, sepsis, or aspiration injury, enteral nutrition with a diet rich in eicosapentaenoic and l' linolenic acids, and antioxidants improved lung neutrophil recruitment and gas exchange and decreased the incidence of organ failure, the need for mechanical ventilation, and the length of ICU stay.5&-58
SECTION V • Disease Specific
Other specific pharmaconutrients, such as growth hormone, have been used in an attempt to improve nutrition and outcome. In critically ill patients, part of the negative nitrogen balance has been ascribed to growth hormone resistance and reduction in insulin-like growth factor-l production and action. Prior studies of growth hormone treatment in various hospitalized patient groups have shown improvement in nitrogen balance. However, in a placebo-controlled study, treatment of critically ill patients receiving mechanical ventilation and prolonged intensive care with high doses of recombinant growth hormone resulted in increased morbidity and mortallty." Growth hormone improved nitrogen balance but did not improve grip strength or fatigue. Furthermore, the survivors in the growth hormone group had an increased duration of need for mechanical ventilation and ICU and hospital stay. The authors speculated that the immune system may have been modulated. In a smaller randomized, double-blind study in 20 patients receiving prolonged mechanical ventilation, growth hormone administration resulted in an increase in fat-free mass but did not reduce the weaning period."
PATIENT MONITORING
Potential Complications Complications may occur in any patient undergoing enteral nutrition support, but certain complications may have a greater impact in the patient with acute pulmonary disease. In general, the potential complications of enteral feeding are related to placement of the feeding tube and the feeding itself and include mechanical, gastrointestinal, infectious, and metabolic complications. Complications with the feeding tube may be divided into insertion- and postinsertion-related, according to the anatomical areas traversed. These can be further grouped into nasopharyngeal-otic-sinus, gastrointestinal, pulmonary, and metabolic compllcations.s'r'" Complications of enteral feeding tube insertion, especially with the use of small-bore tubes with stiff guidewires, are usually due to tube misplacement. These include perforation of the esophagus and of the lung into the pleural space. Pulmonary complications include pneumothorax, pneumomediastinum, subcutaneous emphysema, and death. Patients receiving mechanical ventilation with inflated endotracheal tube cuffs are at significant risk, probably owing to cuff compression of the esophagus posteriorly and the ability of the stiffened feeding catheter to slide past the cuff into the trachea. The stiff guidewires may cause significant problems and have been eliminated from use in some ICUs. Post-insertion tube complications include gastrointestinal tract erosion and ear and sinus infections. Prolonged use of nasal tubes may result in nasopharyngeal and laryngeal stenosis as well as pharyngeal and vocal cord paralysis. Some of the upper airway complications can be limited by using oroenteral tubes instead of nasoenteral tubes. Other complications are related to the amount and type of tube feedings.
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During the administration of feeding, several complications may occur. These include regurgitation, aspiration, diarrhea, contamination of feedings, and nutritionalmetabolic complications such as refeeding syndrome and drug-feeding interactions. Aspiration of feedings is a major problem especially for those with acute pulmonary disease who have decreased respiratory reserve. The mortality associated with severe aspiration may be high. Many factors affect the incidence of aspiration. These include the effect of the endotracheal tube, altered level of consciousness, supine posture, ileus, gastroparesis, gastroesophageal reflux disease, and feeding tube misplacement. Although the usefulness of postpyloric feeding tube placement to prevent aspiration is controversial, it is preferred in the critically ill patient with acute respiratory failure. Postpyloric tube feeding, especially distal to the ligament of Treitz, may reduce the risk of gastric feeding residual volumes and aspiration. Patients fed through endoscopically placed jejunal tubes had a significantly reduced incidence of aspiration, received a higher proportion of their caloric intake, and had greater improvement in prealbumin levels.64•65 The risk for aspiration may also be reduced by raising the head of the bed 30 to 45 degrees or more if possible. Use of a fine-bore feeding tube may help to minimize aspiration because these tubes may cause less gastroesophageal reflux than largebore tubes. 66 Metabolic complications may also occur in the critically ill patient with acute respiratory failure. These include hypophosphatemia, hypercapnia, and hyperglycemia. The development of hyperglycemia is common in the critically ill patient with acute respiratory failure and may be exacerbated by the initiation of enteral feeding and corticosteroid treatment. A recent large-scale study of surgical patients in the ICU who were receiving mechanical ventilation and were treated with intravenous insulin to maintain a blood glucose between 80 to 100 mgldL showed a significantly decreased mortality compared with standard treatment to maintain blood glucose between 180 to 200 mg/dl," Although further study is needed, maintenance of tighter glucose control, if possible, may improve outcome.
SUMMARY Nutrition plays an important role in the therapy of acute pulmonary disease. Many patients with an acute exacerbation of COPD and respiratory failure are significantly malnourished upon presentation to the hospital. Moreover, weight loss at presentation has been found to be a predictor for acute respiratory failure requiring mechanical ventilation. In the patient with COPDwhose condition is stable, hypermetabolism is common and is worsened during an acute exacerbation, which may result in further nutritional depletion. Because the prevalence of malnutrition is high, patients with acute exacerbations of COPD should have a nutrition assessment to identify those having a greater risk for complications. The goal of nutritional support is to prevent further loss of
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35 • Enteral Nutrition in Acute Pulmonary Disease
weight and muscle mass. The treatment of COPO and respiratory failure can affect nutritional status as well as the route of feeding. Medications such as corticosteroids commonly used to treat an exacerbation of COPO may contribute to muscle wasting and weakness. Patients requiring intubation and mechanical ventilation will need enteral tube feeding. However, patients able to receive ventilation with noninvasive methods may be able to eat orally and thus the need for enteral tube feeding is obviated. In patients who cannot eat orally because of high oxygen demands or dyspnea requiring continuous oxygen delivery through a face mask, treatment with high-flow, vapor-phased, humidified oxygen via a nasal cannula may allow them to eat orally without experiencing increased dyspnea and oxygen desaturation when the face mask is removed. This area needs further study, because little information on malnutrition and the role of nutritional intervention during an acute exacerbation of COPO and respiratory failure is available. AROS typically results in severe respiratory failure. It is associated with high morbidity and mortality, but recent studies have shown a reduced mortality, probably from better supportive care. Patients with AROS and especially those with sepsis commonly have hypermetabolism, which results in a negative nitrogen balance. Survivors of AROS are reported to have lost a significant amount of weight and to show extreme muscle wasting at hospital discharge and may have significant functional disability 1 year later. Assessment of nutrition is more difficult in these patients because of the severe illness and the use of mechanical ventilation and its impact on typical nutritional indices. The treatment of the disease has been basically supportive care. Enteral nutrition along with other supportive measures plays a significant role in the treatment of these patients. The early goals of enteral nutrition have been to decrease the negative nitrogen balance and thereby prevent loss of fat-free body mass. Immunonutrition is being explored for use as an active treatment for these patients. Overfeeding, hypercapnia, misplaced enteral tubes, diarrhea, and aspiration are some of the complications in this group of patients. REFERENCES I. Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-1349. 2. Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. NHLBIIWHO Workshop Report, Executive Summary, NIH Publication No. 2701A, March, 2001, pp. 1-30. 3. Niewoehner DE, Erbland ML, Deupree RH, et al: Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans AffairsCooperative Study Group. N Engl J Med 1999;340:1941-1947. 4. Liesching T, Kwok H, Hill N: Acute applications of noninvasive positive pressure ventilation. Chest 2003;124:699-713. 5. Mehta S, Hill NS: Noninvasive ventilation. Am J Respir Crit Care Med 2001;163:540-577. 6. Hillberg RE, Johnson DC: Current concepts: Noninvasive ventilation. N Engl J Med 1997;337:1746-1752. 7. Klein S, Kinney J, Jeejeebhoy K,et al: Nutritional support in clinical practice: Review of published data and recommendations for further research directions. JPEN J Parenter Enteral Nutr 1997;21: 133-156.
8. Artigas A, Bernard GR, Carlet J, et al: The American-European Consensus Conference on ARDS, Part 2: Ventilatory, supportive therapy, study design strategies, and issues related to recovery and remodeling. Am J Respir Crit Care Med 1998;157:1332-1347. 9. Nuckton TJ, Alonso JA, Kallet RH, et al: Pulmonary deadspace fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002;346:1281-1286. 10. The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308. 11. Factor P, Cicco lelia D, Sznajder JI: Fluid balance and renal function. In Haslett C, Evans T (eds): Adult Respiratory Distress Syndrome. London, Chapman and Hall, 1996, pp 481-493. 12. Laaban J.p, Kouchakji B, Marie-France D, et al: Nutritional status of patients with chronic obstructive pulmonary disease and acute respiratory failure. Chest 1993;103:1362-1368. 13. Donahoe M: Nutritional aspects of lung disease. Respir Care Clin North Am 1998;4:85-112. 14. American Society of Parenteral and Enteral Nutrition Board of Directors: Guidelines for the use of enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2001;26 (suppl 1):ISA-138SA. 15. Driver AG, McAlevy MT, Smith JL: Nutritional assessment of patients with chronic obstructive pulmonary disease and respiratory failure. Chest 1982;82:568--571. 16. Vitacca M, Clini E, Porta R, et al: Acute exacerbations in patients with COPD: Predictors of need for mechanical ventilation. Eur Respir J 1996;9:1487-1493. 17. Riquelme R, Torres A; EI-Ebiary M, et al: Community acquired pneumonia in the elderly: Clinical and nutritional aspects. Am J Respir Crit Care Med 1997;156:1908--1914. 18. Herridge MS, Cheung AM,Tansey CM, et al: One year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348:683-694. 19. Bihari DJ: Survivors of the acute respiratory distress syndrome [correspondence]. N Engl J Med 2003;348:2149. 20. Mangialiardi RJ, Martin GS, Bernard GR, et al: Hypoproteinemia predicts acute respiratory distress development, weight gain, and death in patients with sepsis. Crit Care Med 2000;28:3137-3145. 21. Schols AM: Nutrition in chronic obstructive pulmonary disease. Curr Opin Pulm Med 2000;6:110-115. 22. Chapman KM, Winter L: COPD: Using nutrition to prevent respiratory decline. Geriatrics 1996;51:37-42. 23. Chapman-Novakofski K, Brewer MS, Riskowski J, et al: Alterations in taste thresholds in men with chronic obstructive pulmonary disease. J Am Diet Assoc 1999;99:1536-1541. 24. Creutzberg EC, Wouters EFM, Vanderhoven-Augustin I, et al: Disturbances in leptin metabolism are related to energy imbalance during exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1239-1245. 25. Goldstein S, Askanazi J, Weissman C, et al: Energy expenditure in patients with chronic obstructive pulmonary disease. Chest 1987; 91:222-224. 26. Schols AMWJ, Fredix EWHM, Soeters PB, et al: Resting energy expenditure in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 1991;54:983-987. 27. Vermeeren MR, Schols M, Wouters EF: Effect of an acute exacerbation on nutritional and metabolic profile on patients with COPD. Eur Resp J 1997;10:2264-2269. 28. Kiiski R, Takala J: Hypermetabolism and efficiency of CO2 removal in acute respiratory failure. Chest 1994;105:1198--1203. 29. Marik PE, Bedigian MK: Refeeding hypophosphatemia in critically ill patients in an intensive care unit. Arch Surg 1996;131:1043-1047. 30. Aubier M, Viires N, Piquet J, et al: Effects of hypocalcemia on diaphragmatic strength generation. J Appl Physiol 1985;58: 2054-2061. 31. Dhingra S, Solven F, Wilson A, et al: Hypomagnesemia and respiratory muscle power. Am Rev Respir Dis 1984;129:497-498. 32. Kelly SM, Rosa A, Field S, et al: Inspiratory muscle strength and body composition in patients receiving total parenteral nutrition therapy. Am Rev Respir Dis 1984;130:33-37. 33. Arora NS, Rochester DF: Effect of body weight and muscularity on human diaphragm muscle mass, thickness and area. J Appl Physiol 1982;52:64-70.
SECTION V • Disease Specific 34. Doekel R. Zwillich C, Scoggin C, et al: Clinical semi-starvation: Depression of hypoxicventilatory response. NEngl J Med1976;295: 358-361. 35. Fuenzalida CE, PettyTL. Jones ML. et al: The immune response to short-term nutritional intervention in advanced chronic obstructive pulmonarydisease. Am RevRespir Dis 1990;142:49-56. 36. RiceKL, Leatherman JW, Duane PG, et al: Aminophylline foracute exacerbations of chronic obstructive pulmonary disease. Ann InternMed 1987;107:305-309. 37. Dujovne CA, Azarnoff DL: Clinical complicationsof glucocorticoid therapy: Aselected review. MedClinNorth Am 1973;57:1331-1342. 38. Decramer M, Lacquet LM. Fagard R, Rogiers P: Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir CritCare Med 1994;150:11-16. 39. Weiner P,Azgad Y. WeinerM: The effectof corticosteroids on inspiratory muscle performancein humans. Chest1993;104:1788-1791. 40. Gallagher CG: Respiratory steroid myopathy. AmJ Respir CritCare Med 1994;150:4-6. 41. Heyland DK: Nutritional support in the critically ill: A critical review of the evidence. CritCare Clin 1998;14:423-440. 42. Heyland DK, MacDonald S. Keefe L, et al:Totalparenteral nutrition in the critically ill.A meta-analysis. JAMA 1998;280:2013-2019. 43. Marik PE, Zaloga GP: Early enteral nutrition in acutely ill patients: Asystematic review. Crit Care Med2001;29:2264-2270. 44. Vande Louw A, BrocasE,Boiteau R, et al: Esophageal perforation associatedwith noninvasive ventilation. Chest2002;122:1857-1858. 45. Flancbaum L, Choban PS. Sambucco S. et al: Comparison of indirect calorimery, the Fick method, and prediction equations in estimating the energy requirements of critically ill patients. Am J Clin Nutr1999;69:461-466. 46. Pinard B, Geller E: Nutritional support during pulmonary failure. Crit Care Clin 1995;11:705-715. 47. Krishnan JA, Parce PB, Martinez A, et al: Caloricintake in medical ICU patients. Chest2003;124:297-305. 48. CerraFB, BenitezMR, Blackburn GL, et al: Applied nutrition in ICU patients. A ConsensusStatement of the American College of Chest Physicians (ACCP). Chest 1997;111:769-778. 49. Food and Nutrition Board, National Research Council: Recommended Dietary Allowances, 10th ed. Washington, DC, National AcademyPress, 1989. 50. McClave SA, Sexton LK, Spain DA, et al: Enteral tube feedingin the intensive care unit: Factors impeding adequate delivery. CritCare Med 1999;27:1252-1256. 51. De Jonghe B, Appere-De-Vechi C, Fournier M, et al: A prospective survey of nutritional supportpracticesin intensive care unit patients: Whatis prescribed? Whatis delivered? Crit CareMed2001;29:8-12. 52. Talpers S, Romberger D, Bunce S, et al: Nutritionally associated increasedcarbon dioxide production:Excesstotal caloriesvs.high proportion of carbohydrate calories. Chest 1992;102:551-555.
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53. Baker JP, Detsky AS, Stewart S, et al: Randomized trial in total parenteral nutrition in critically ill patients: Metabolic effects of varying glucose-lipid ratio as the energy source. Gastroenterology 1984;87:53-59. 54. AI-Saady NM, Blackmore CM, Bennet ED: High fat, low carbohydrate enteral feeding lowers PaC02 and reduces the period of ventilation in artificially ventilated patients. Intensive Care Med 1989;15:290-295. 55. Zaloga G, Ackerman M: A review of disease-specific formulas. MCN Clin IssuesCritCare Nurs 1994;5:421-435. 56. McCowen KC, Bistrian BR: Immunonutrition: Problematicor problem solving? AmJ Clin Nutr2003;77:764-770. 57. Gadek J, DeMichele S, Karlstad M, et al: Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distresssyndrome.CritCare Med 1999;27:1409-1420. 58. Pacht ER, DeMichele S, Nelson JL, et al: Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants reduces alveolar inflammatory mediators and protein influx in patients with acute respiratory distress syndrome. Crit Care Med 2003;31:491-500. 59. TakalaJ, Ruokonen E,Webster NR, et al: Increased mortality associated withgrowthhormone treatment in criticallyill adults. NEngl J Med 1999;341:785-792. 60. Pichard C, Kyle U, ChevroletJ-C, et al: Lack of effectsof recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: A prospective, randomized, controlled study. CritCare Med 1996;24:403-413. 61. Boyes RJ, Kruse JA: Nasogastric and nasoenteral intubation. Crit Care Clin 1992;4:865-878. 62. Valentine RJ, Turner WW: Pleural complications of nasoenteric feedingtubes. JPEN J Parenter Enter Nutr 1985;9:605-607. 63. Olbrantz KR, Gelfand D, Choplin R, et al: Pneumothorax complicating enteral feeding tube placement. JPEN J Parenter Enter Nutr 1985;9:210-211. 64. Montecalvo MA, Steger KA, Farber HW, et al: Nutritional outcome and pneumonia in critical care patients randomized to gastricversus jejunaltube feedings. The critical care research team. Crit Care Med 1992;20:1377-1387. 65. Davies AR, FroomesPR, French CJ, et al: Randomizedcomparison of nasojejunaland nasogastric feeding in criticallyill patients. Crit Care Med 2002;30:586-590. 66. Ibanez J, PenafielA, Marse P, et al: Incidence of gastroesophageal reflux and aspiration in mechanically ventilated patients using small-bore nasogastric tubes. JPEN J Parenter Entr Nutr 2000;24: 103-106. 67. van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345: 1359-1367.
Nutrition in Stable Chronic Obstructive Pulmonary Disease Ivone Martins Ferreira, MD, MSc, PhD
CHAPTER OUTLINE Introduction Dimension of the Problem Consequences of Chronic Obstructive Pulmonary Disease-Associated Weight Loss Nutritional Assessment Energy Requirement Causes of Weight Loss and Muscle Wasting Nutritional Management in Chronic Obstructive Pulmonary Disease Immediate and Short-Term (Equal to or Less Than Two Weeks) Effects of Nutritional Supplements Effects of Longer-Term Nutritional Supplements (Longer Than Two Weeks) Studies on Enteral Nutritional Support Difficulties in Studying Nutritional Support Anabolic Substances: Anabolic Steroids Anabolic Substances: Growth Hormone Appetite Stimulants Patient Monitoring Factors Associated with Nonresponse to Nutritional Support Specific Considerations Summary and Future Directions
INTRODUCTION Chronic obstructive pulmonary disease (CaPO) is a disease state characterized by airflow limitation that is, at least in part, irreversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.' The pathogenesis and the clinical manifestations of capo are not restricted to pulmonary inflammation and structural remodeling. Indeed, this disorder is associated
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with clinically significant systemic alterations in biochemistry and organ function. The systemic aspect of capo includes oxidative stress and altered circulating levels of inflammatory mediators and acute-phase proteins. As in other chronic inflammatory conditions, weight loss, muscle wasting, and tissue depletion are commonly seen in patients with COPD.2
Dimension of the Problem Internationally, capo is a major cause of chronic morbidity and mortality. It is currently the fourth leading cause of death throughout the world,' and further increases in the prevalence and mortality can be predicted in the coming decades. In the United States, the age-adjusted death rate rose between 1965 and 1998 for COPD, whereas it fell for coronary heart disease, stroke, and other cardiovascular diseases.' capo affects more than 17 million people and is responsible for 2.2 million disability-adjusted life years and one-half million potential years of life lost." Direct costs are estimated to be over $18 billion annually.' Because of its progressive and debilitating nature, capo has the potential to interfere with a person's ability to work, leading to lost wages for workers and lost productivity for their employers. On the basis of data from the third U.S. National Health and Nutrition Examination Survey (NHANES 111), in a recent report it was estimated that in 1994 COPD was responsible for approximately $9.9 billion worth of lost work, after adjustments for severity and its effect on labor market participation.' Malnutrition has a negative impact on the clinical course of patients with capo, because nutrition and ventilation are intimately related. Both oxygen and nutrients participate together in the process of respiration to supply the required energy for activities of daily living. In the absence of capo, malnutrition alone is associated with a significant impairment of respiratory strength and endurance': its presence with capo may
SECTION V • Disease Specific
aggravate the already existing respiratory muscle dysfunction that is caused by chronic airflow limitation and hyperinflation. A number of individuals with capo experience involuntary weight loss as their condition progresses. Malnutrition occurs in 20% to 30% of patients with clinically stable moderate to severe capo. However, in the United States, more than 50% of patients with respiratory failure are affected," whereas in some other countries, rates of up to 70% have been reported." In advanced capo, the presence of severe weight loss, referred to as pulmonary cachexia, occurs in 24% to 27% of patients."
Consequences of Chronic Obstructive Pulmonary Disease-Associated Weight Loss Several studies have shown an association between malnutrition and impaired pulmonary status among patients with COPD.8-to Individuals with low body weight have more gas trapping," more dyspnea." lower diffusion capacity, and lower exercise capacity than those with similar pulmonary mechanics but normal weight. Several factors contribute to the impaired respiratory status in malnourished patients with COPD. As with healthy individuals, malnutrition impairs skeletal muscle function. to It also results in a reduced diaphragmatic mass, associated with a decrease in both strength and endurance of the respiratory muscles. to In livingpatients with capo, the thickness of the sternocleidomastoid muscle, determined anthropometrically, was reduced in underweight (75% ideal body weight [IBW]) patients compared with 52% of the control subjects and 77% of well-nourished patients with capo. to Hyperinflation, particularly dynamic hyperinflation, may cause a serious mechanical disadvantage for the diaphragm of patients with capo and impair forcegenerating capacity. With hyperinflation, diaphragm muscle fibers are shortened, appositional and insertional actions may be impaired, and the radius of the curvature increases, resulting in a decrease in transdiaphragmatic pressure (Pdi) for any given tangential tension produced by the diaphragm (Laplace's law). There may also be uncoupling between the costal and crural portions of the diaphragm. Loss of respiratory muscle bulk that occurs with severe malnutrition thus compounds the impaired force-generating capacity of the diaphragm." As muscle mass and function decrease, muscles become overloaded during ventilation. Progressively, muscles become less efficient due to fatigue. Respiratory failure is a common finding as disease and weight loss progress. However, muscular changes are not confined only to the respiratory muscles; peripheral muscles are also affected, resulting in decreased mobility and a greater risk of falls. The skeletal muscle atrophy that occurs in capo is specific to fibers IIA/IIX and IIA and is associated with disturbed metabolic capacity.P In addition, patients with capo plus a low body mass index (BMI)
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have low bone mineral density.14.15 A 8MI that was less than or equal to 22 kglm 2 (of height) was the only independent factor that correlated with osteoporosis as an outcome." Malnutrition decreases respiratory drive, damages lung parenchyma, and impairs lung and airway defense mechanisms." Malnutrition in patients with capo has been associated with an increased susceptibility to infection, partially due to impaired cell immunity, reduced secretory immunoglobulin A, decreased pulmonary alveolar macrophage function, and increased colonization and adherence of bacteria in the upper and lower airways. 18 Malnourished subjects have worse scores on a qualityof-life questionnaire," increased hospitalizations for pulmonary system-related problems, and higher mortality than adequately nourished patients. A low BMI and the use of supplemental oxygen in the home are both independent predictors of reduced survival among hypoxic patients with COPD.20
NUTRITIONAL ASSESSMENT The goals of nutritional screening and intervention for people with capo are both preventive and therapeutic in nature. A thorough medical history and physical examination are essential in assessing patients for nutritional depletion and weight loss. A comprehensive nutrition assessment includes a detailed history of present and past illnesses, a dietary history, and a description of the current problem. A change in body weight is the best indicator of nutritional impairment. Anthropometric measurements, a variety of simple, noninvasive techniques that provide information about the body and its compartments, are most widely used in the assessment of nutritional status. The BMI is an index of average nutritional status and is useful in helping to diagnose and classify malnutrition, although it does not differentiate lean mass from fat mass. More specific measurements include midarm muscle circumference, which reflects lean body mass; arm muscle circumference, which partially depends upon the width of the humeral bone; and the triceps skinfold, which is an index of fat mass. The sum of all skinfold measurements gives a more precise estimate of body fat. Simple screening can be based on the measurement of the BMI and course of weight change, as shown in Table 36-1. Based on BMI, patients older than 50 years of age are considered to be underweight when their BMI is less than 21 kg/m 2. Significant weight loss is commonly defined as more than 10% weight loss in the last 6 months or more than 5% in the last month. However, it should be noted that every period of involuntary loss that cannot be attributed to daily fluctuations should be taken into consideration." Estimates of body fat, together with the rate of change in body fat content over time, are useful in assessing the presence and severity of protein-energy malnutrition that is so common in patients with capo. A large and rapid loss of body fat is indicative of severe negative energy balance.
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_ _ Characterization of Malnutrition Weight
Underweight (8MI <21, age >50)
Loss % IBW %UBW Change (%) I week I month 3 months 6 months
Nonnai Weight (21< 8MI < 25)
Overweight (25 < 8MI < 30)
Mild
Moderate
Severe
80-90 80...95
70-80 75-84
<75 <75
Moderate 1...2 5
Severe 2 >5 >7.5 >10
7.5 10
BMl, body mass index; IBW, ideal body weight; UBW. usual body weight.
Energy Requirement Several methods are available for estimating the caloric requirements of patients with respiratory diseases. Energy levels can be estimated, calculated with formulas or nomograms, or determined by using measurements of energy expenditure. Estimates of resting energy requirements can be obtained from the Harris-Benedict equation, which takes into account sex, weight, height, and age (Table 36-2). Based on the severity of the patient's illness, a stress factor or percentage increase in energy requirements is then added to the calculation. Stress factors are based on estimated metabolic needs that are over and above resting needs and vary with body temperature, degree of physical activity, or extent of injury. However, the use of the Harris-Benedict in clinical practice is controversial.P and it is not specific for capo. An equation specifically for patients with COPD23 has been suggested that is also shown in Table 36-2. Because weight and height in isolation do not differentiate fat and lean body mass, it is extremely important to evaluate body composition through other methods, such as bioimpedance-i-" or dual energy X-ray absorptiometry (DEXA).26,27 Studies have shown that a reduction in fat-free mass can be present even among patients whose body weight is normal." Body composition has an interesting relationship with lung diseases. The relationship of lung disease with an abnormal BMI has been most extensively studied in asthma. In contrast to patients with capo, patients with asthma had higher BMI levels and a higher proportion of obesity than control subjects. 29,3o A recent study suggested that abnormal BMI levels among asthmatic patients are present before the diagnosis and before the onset of respiratory symptoms." There were a significantly higher number of obese and preobese individuals who later
developed asthma than in the control group. This suggests that, rather than being a consequence of this obstructive disease, higher BMI levels may play more of a causative role. For several decades, the belief that weight loss was an inevitable consequence of capo was widely held. More recently, the hypothesis that a low BMI may in reality be a risk factor for the disease has been given some consideration. Recent findings from the Baltimore Study of Aging suggested that low BMI itself could be a risk factor for COPD.32 This study showed that the risk of men developing capo was inversely related to BMI, even after correction for other factors such as smoking, age, forced expiratory capacity in the firstsecond (FEV!), central obesity, and education." However, this study had two significant limitations: it was retrospective and it did not include a sufficient number of women to draw conclusions for both sexes. In animals, malnutrition has been linked to emphysematous changes of the lungs, probably related to antiprotease deficiency. The findings of Cook and assoelates" of emphysema, bronchiectasis, and bullae in young women with anorexia nervosa further raised the suspicion of "nutritional emphysema." However, Pieters and colleagues" disagreed with this hypothesis, because they studied 24women with anorexia who all had normal lung function. Interestingly, respiratory muscle strength for these women was compromised, with inspiratory muscle strength (PlmaJ measuring 59% of predicted and expiratory muscle strength measuring 35% of the predicted value, along with the residual volume being increased to 160% of the predicted value. In the past, anthropometric measures were used to differentiate patients with emphysema from those with chronic bronchitis. Evidence that malnutrition is more common in patients with emphysema than in those with chronic bronchitis'[ was confirmed in recent studies
_ _ Equations for Prediction of Resting Energy Expenditure (kca1/24 hr) Men Normal COPD
66.47 + 13.75 (W) + 5.0 (H) - 6.76 (A) 11.5 W + 952
A, age in years; H, height in centimeters; W, weight in kilograms. Data from references 22 and 23.
Women 655.1 + 9.56 (W) + 4.85 (H) - 4.68 (A) 14.1 W + 515
SECTION V • Disease Specific
that included the measurement of body composition. Engelen and associates" studied body composition in a large group of patients with capo, who had been classified as having either emphysema or chronic bronchitis using high-resolution computed tomographic criteria measured by DEXA. Lean body mass depletion was found in 37% of the patients with emphysema and 12% of those with chronic bronchitis, whereas only 4% of healthy control subjects showed depletion. Although body weight was normal, lean body mass depletion was found in 16% of the patients with emphysema and in 8% of those with chronic bronchitis. Body weight and composition were significantly different between the group with chronic bronchitis and the group with emphysema. The patients with emphysema had lower values for BMl, fat-free mass (FFM) index, and fat mass index than the group with chronic bronchitis." Later, this same group looked into the presence and contribution of FFM depletion in the extremities in relation to muscle weakness in capo. Whole body composition and extremity FFM were lower in patients with both emphysema and chronic bronchitis than in the control subjects, but trunk FFM was lower only in patients with emphysema. Extremity FFM was comparable between the two subtypes of capo, although skeletal muscle function was lower than in healthy individuals. Therefore, extremity FFM wasting is associated with skeletal muscle weakness, independent of capo subtype, but marked differences in body composition can be demonstrated between patients with emphysema and those suffering from chronic bronchitis." This finding has significant clinical implications, because lean body mass is directly related to exercise capacity in patients with COPD.37 It is now known that fat mass is not just an energy reservoir but plays an important role in energy homeostasis by producing leptin, among other proteins." This adipocyte-derived hormone represents an afferent hormonal signal to the brain in a feedback mechanism that regulates fat mass, has a regulating role in lipid metabolism and glucose homeostasis, and increases thermogenesis." Takabatake and co-workers" reported that serum leptin levels were significantly lower in patients with capo than in healthy control subjects. Schols and colleagues" reported lower levels of leptin in both subtypes of capo and also found that patients with emphysema who also had lower BMI had lower levels of leptin than patients with bronchitis. Both studies suggested a physiologic regulation of leptin, independent of tumor necrosis factor (TNF). In summary, data from the literature appear to support the importance of evaluating body composition in patients with capo.
Causes of Weight Loss and Muscle Wasting The weight loss in capo probably results from both a failure of an adaptive response to undernutrition and an inadequate intake for total energy expenditure. Weight
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loss and particularly loss of fat mass may occur if an increased energy requirement is not balanced by dietary intake. Metabolic and mechanical inefficiency contribute to the elevated energy expenditure in capo. Other explanations for weight loss include hypermetabolism," tissue hypoxia," diet-induced thermogenesis," and use of corticosteroids. It can also be related to an imbalance in the continuously ongoing process of protein synthesis and breakdown.' Hormonal changes are closely related to overall protein turnover. Insulin, growth hormone (GH), insulin-like growth factors (IGFs), and anabolic hormones favor protein synthesis, whereas glucocorticoids stimulate proteolysis, especially in muscle tissue. In the absence of fasting, insulin normally suppresses the breakdown of protein. GH also increases FFM and generates a positive nitrogen balance, as well as depletion of fat mass," Evidence exists for GH resistance under conditions of catabolism, which occurs in inflammation. Fasting and catabolic states are associated with reduced GH receptor binding, reduced IGF-1 gene expression, and low levels of IGF-1-binding proteins." The infusion of interleukin (IL)-l and TNF-a in animals is associated with low plasma levels of IGF-1 and reduced protein synthesis. When the myoblasts are exposed to TNF-a,the ability of IGF-1 to stimulate protein synthesis is inhibited in a dose-dependent fashion.' Given the relationship between weight loss and TNF-a, several reports have postulated a contributory role of systemic inflammation to this catabolic response, similar to the cachexia syndromes associated with heart failure and cystic fibrosis.45,46 These studies have demonstrated elevated levels of TNF-a in patients with COPD.27,45,46 Circulating levels of TNF-a, IL-6, and soluble receptors were significantly higher in patients with capo with a BMI less than 20 kg/rn" or a low creatinine-height index (less than 80%) than in patients with normal BMI and creatinine-height index." Li and associate" studied the underlying mechanisms of TNF-a effects in differentiated skeletal muscle mass and demonstrated a reduction in total protein content and a loss of myosin heavy chain content. These changes were present at TNF-a concentrations similar to those found in patients with capo. Chronic hypoxia can potentiate weight loss by increasing the production of cytokines. In vitro, hypoxia increases the release of IL-1 and TNF-a in human alveolar macrophage. This suggests that the inflammatory process can be stimulated or aggravated by the tissue hypoxia present in severe capo. The findings of Pitsiou and colleagues'? agreed with this hypothesis. They compared levels of TNF-a in patients with emphysema and chronic bronchitis and found it to be twice as high in the first group. Patients with emphysema had hypermetabolism, lower oxygen delivery, lower diffusion capacity, and lower BMI than did patients with chronic bronchitis. TNF-a and TNF-a plus interferon are likely to affect skeletal muscle regulation by inhibiting the formation of new myofibers, degenerating newly formed myotubes, and inhibiting the body's ability to repair damaged
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36 • Nutrition in Stable Chronic Obstructive Pulmonary Disease
skeletal muscle. Inflammatory cytokines, such as TNF-a and IL-1~, can also contribute to muscle wasting through the activation of nuclear factor KB (NF-KB), promoting the inhibition of myogenic differentiation." One important consideration when the causes of weight loss in patients with COPD are examined is the potential effect of systemic corticosteroid therapy. The chronic use of corticosteroids, as often occurs in patients with COPD, is associated with muscle weakness and protein breakdown. Glucocorticoids stimulate proteolysis and inhibit protein synthesis and amino acid transport into cells. Another pathway that may contribute to muscle wasting is apoptosis, because chronic inflammation can trigger programmed cell death. A recent study showed that the numbers of apoptotic cells increased progressively in biopsy samples of healthy active subjects, healthy inactive subjects, subjects with COPO and a normal BMI, and subjects with COPO and a low BM!. There was an inverse correlation between BMI and the number of apoptotic cells." This is a fascinating subject; however, these results should be interpreted with caution, because this study only used BMI, without a direct measure of body composition, and the control subjects were younger than the subjects under study.52 However, this is a new direction and certainly deserves further study.
NUTRITIONAL MANAGEMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE When indicated, nutritional support should initially start by assessing and adapting the patient's dietary habits, food choice, meal pattern, etc. Desired goals of nutrition and screening are shown in Table 36-3. Because these patients have normal gastrointestinal tracts, oral, and in some patients, enteral supplements are recommended first. Nutritional support should be administered as energy-elensesupplements in divided doses to avoid loss
. . . Goals of Nutrition SCreening and _ _ Intervention In COPD Measurement of body weight in each visit; calculation of BMI Maintenance of reasonable body weight (BMI 22-27 kg/m 2) Serum albumin level >3.5 g/dl, Immunocompetence maintained (delayed cutaneous hypersensitivity to common recall antigens, normal T-cell function and/or complement activity) Maximize treatment Respiratory rate <30 breaths/min Prevention or improvement in comorbid conditions associated with COPD Periodic spirometry testing to maintain: Absolute FEV) >40% of predicted value FVC (forced vital capacity) normal FEVdFVC ratio >70% of predict normal Evaluation of ability to carry out ADLs/IADLs Evaluation of ability to walk specific: distances (6-minute walking test) ADLs, activities of daily living; lADLs, instrumental activities of daily living.
of appetite and adverse metabolic and ventilatory effects resulting from a high caloric load." Although most patients tolerate carbohydrate loads, diet content and volume per meal may have to be modified for patients with severe dyspnea or hypercapnia." Daily protein intake should be at least 1.5 g/kg of body weight to allow optimal protein synthesis." When feasible, patients should participate in an exercise program to stimulate an anabolic response and increase lean body mass instead of fat storage. Exercise improves the effectiveness of nutritional therapy and stimulates the appetite. If weight gain and functional improvement occur, therapy should be continued or moved to a maintenance regimen, depending on results. If the desired response is not noted, the patient's compliance should be assessed; ifthis is not an issue, more calories may be needed by oral supplements or by enteral routes. For the next step, the addition of anabolic agents should be considered. However, despite these interventions, some patients will not reach the intended goal, because the mechanism of weight loss may not be reversible by caloric supplementation." Given the association between COPO and weight loss, a number of clinical trials have examined the influence of nutritional supplements, either alone or with anabolic substances such as steroids or growth hormone, on patients with COPD. Results of a systematic review of the literature's and meta-analysis on this subject have recently been published.54,55 For the review, publications of randomized, controlled trials in all languages were electronically retrieved from the Cochrane Airways Group Specialized Trials Registry, the Cochrane Library, MEDUNE, EMBASE, and CINAHL, from the beginning of the databases until 1998. An update of the literature search in 2001 revealed no new studies, and a further literature search in 2002 identified the article by Vermeeren and associates.v discussed later. Abstracts presented at relevant international scientific meetings of, for example, the American Thoracic Society and the European Respiratory Society, were hand-searched, and experts and authors of all papers included in the synthesis were contacted for information on any other relevant studies either published in the last 10 years, completed but unpublished, or in progress. Randomized, controlled trials of nutritional support grouped by type and duration of intervention are shown in Table 36-4. A summary of the literature findings follows.
Immediate and Short-Term (Equal to or Less Than Two Weeks) Effects of Nutritional Supplements Four publications studied the immediate effect of meals with different carbohydrate and fat composition, using a crossover design.57~o Immediately after a meal high in carbohydrate, carbon dioxide production (VC02) and respiratory quotient increased and exercise capacity decreased. The increased VC02 and ventilatory requirement were more marked after the ingestion of a high-carbohydrate load compared with a high-fat load;
..
SECTION V • Disease Specific
429
Randomized, Controlled Trials of Nutritional Support In COPD Grouped by Type and Duration of Intervention
Different ')(, of CHO and fat
Immediate Effects
Short-Term «2 Weeks)
Brown et al, 198557 Efthimiou et al, 199258 Akrabawi et al, 199659 Frankfort et ai, 199160 Vermeeren et ai, 200156
Goldstein et al, 198861 Angelillo et al, 198562 Goldstein et al, 198963
Supplementation (increased calories)
Anabolic steroids Growth hormone
Long-Term (>2 Weeks)
Efthimiou et ai, 198871 Whittaker et al, 198967; Ryan et al, 199392 Lewis et ai, 198764 Knowles et al, 198873 DeLetter et al, 199 J72 Fuenzalida et al, 199069 Otte et ai, 198970 Rogers et al, 199265 Vargas et al, 199568 Schols et al, 199566 Schols et ai, 199566 Ferreira et al, 199826 Burdet et al, 199782 Casaburi et ai, 199783
Modified from Ferreira I, Brooks 0, Lacasse Y, et al: Nutritional intervention in COPD: A systematic overview. Chest 2001;119:353-363.
however, high-fat meals were associated with delayed gastric emptying." The three studies on short-term nutritional supplements (<2 weeks) had similar results.61--Q3 Although the increase in Vco, might cause aggravation in patients in respiratory failure, in patients with stable conditions its effect was small and had little clinical significance. 59 Interestingly, in a study published after the Cochrane Review, no difference in exercise capacity was found and although the high content of carbohydrate increased the respiratory quotient, dyspnea was significantly greater after a high-fat content meal."
Effects of Longer-Term Nutritional Supplements (Longer Than Two Weeks) Of greater significance are the studies of nutritional supplements given for longer than 2 weeks. A total of 10 reports on the effects of nutritional supplements in COPD,64-73 defined as caloric supplementation lasting for at least 2 weeks, have been published. A summary of these studies is shown in Table 36-5. Only eight studies were included in the meta-analysis because important data were not obtained from the authors of the other twO. 65•68 Results from one of the studies included were analyzed as two contrasts, giving a total of nine contrasts." No significant randomized study was published after this meta-analysis. In this meta-analysis, the effects of nutritional supplements on weight, arm muscle circumference, triceps skinfold, 6-minute walking test, FEV Io and respiratory muscle strength were evaluated. The effect size was small in all nine contrasts. The 95% confidence intervals for all of the outcomes included zero. Their actual values
were small and were unlikely to be clinically important (see Table 36-5).55 The two outcomes (6-minute walking test and FEVD for which the minimal clinically important difference is known'" did not exceed this value. All the effect sizes for the outcome measures were homogeneous (P > .05), such that the effect of the nutritional intervention was consistent across the studies, irrespective of the duration or the amount of the nutritional support. In the studies included, weight was the outcome reported most often. Because changes in weight can be due to changes in fat73 and given that many patients with capo have reduced FFM, nutritional support would be more accurately assessed against body mass. Lean body mass, the preferred outcome measure of a positive energy balance, was reported in only two trials, and for one of them the raw data could not be obtained from the primary author. Too few studies reported on dyspnea or a sense of well-being to be able to say that these important health-related quality-of-life measures were included as outcomes. During the 3 months of oral nutritional supplementation, Efthimiou and colleagues" showed an improvement in breathlessness and general well-being that gradually decreased over the subsequent 3 months. In contrast, Otte and co-workers.P using a different scale, did not identify any changes in well-being associated with nutritional supplements. The implications of this meta-analysis are troubling for clinicians who note the harmful effects of weight loss in capo, the associated reduction in scores for healthrelated quality of life, the higher risk of infection, and the higher mortality. Another recent meta-analysis of dietary advice for illness-related malnutrition in adults included some studies with patients with capo. This review included 1185 randomized participants from a variety of clinical backgrounds. The results were similarly disappointing. The authors concluded that there was a lack of evidence for
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36 • Nutrition in Stable Chronic Obstructive Pulmonary Disease
_ _ Summary of Trials with Supplementation Longer than 2 Weeks Supplementation Amount/Route/Length
Trials
Patient Status/Setting
Lewis et ai, 198764
Undernourished/outpatients
500-1000 cal/day/oral/ 8 weeks
Knowles et al, 198873
Nourished/undernourlshed/ outpatients
Increased calories 18%26%/oral/ 8 weeks
Efthimiou et ai, 198871
Undernourished/outpatients
640-1280 kcal/day/oral/ 12 weeks
Whittaker et al, 198867 ; Ryan et aI, 199392
Undernourished/inpatients
1000 kcal/day/nasoenteral tube/If days
Otte et ai, 198970
Undernourished/outpatients
400 keel/day/oral/ 13 weeks
Fuenzalida et ai, 199069
Undemourlshed/inpatlents/ followed as outpatients
1080 kcal/oral/21 days Inpatlent/21 days outpatient
DeLetter et ai, 199172
Undernourished/outpatients
1 can (355 kcal)/day/oral/ 9 weeks
Rogers et al, 199265
Undernourished/inpatients
1.7 REE kcal/day/oral/ 4 weeks
Vargas et ai, 199568
Undernourished/outpatients
Schols et ai, 199566
Undernourished/outpatients
1000 keel/day/oral/ 3 months + Inspiratory muscle training 420 keel/day/oral/ 8 weeks
Results No significant difference in W, AMC, PIT, respiratory muscle strength No changes in AC or TSF; weight gain, but returned to baseline after supplementation stopped Increase In W, TSF, AMC, Plmax and well-being; weight loss when supplementation stopped Increase in PEmax, no change In Plmax and adductor polllcls Ryan: Increase in weight Increase In weight, sum sklnfold, no changes In PIT, dyspnea score, or well-being Increase In lymphocytes, cutaneous reactivity, TSF and AMC; weight gain In both groups Increase in W, TSF, and fat mass; no changes in PIT or 6-mlnute walking test Increase in weight, PEmax, handgrlp, and 6-minute walking test No changes In anthropometry or respiratory muscle strength Increase in weight, fat-free mass and respiratory muscle strength; no changes in 6-minute walking test
Quality Score
2
4 4
2 2
2
AC, arm circumference; AMC, arm muscle circumference; PEmax' expiratory muscle strength; Plmax, inspiratory muscle strength; PIT, pulmonary function test; REE, resting energy expenditure; TSF, triceps skinfold; W, weight. Modified from Ferreira I, Brooks 0, Lacasse Y,et al: Nutritional intervention in capo: A systematic overview. Chest 2001;119:353-363.
the provision of dietary advice. Specifically, there were almost no usable data from which to draw conclusions about the effect of dietary advice alone or dietary advice with oral supplements compared with no advice and limited data for advice alone or advice plus supplements compared with supplements alone. It is therefore unclear whether the provision of dietary advice provides any clinical benefits for patients with illness-related malnutrition. The results of this review suggested that oral nutritional supplements may have a greater role than dietary advice in increasing body weight and energy intake, but there were insufficient data on functional outcomes and survival to draw any firm conclusion. The data further suggested that nutritional supplements may enhance weight gain in the short term, but whether this gain could be sustained or whether survival and mortality would also be improved remains uncertain."
Studies on Enteral Nutritional Support Of the randomized, controlled trials included in the meta-analysis, only one study used tube feeding in
COPD.67 In patients with stable COPD, the oral route is preferred. Tube feeding is clearly indicated for patients who are severely ill or receiving mechanical ventilation or in situations in which the oral route cannot be used. Although of concern for all patients requiring enteral nutrition, patients with respiratory disease are particularly susceptible to adverse sequelae of pulmonary aspiration and the metabolic complication of nutrition-related hypercapnia. Complications of tube feeding can be classified as mechanical (tracheal intubation, clogging or obstruction of tube, or aspiration of enteral tube feeding), infectious, gastrointestinal (vomiting, abdominal distension, or diarrhea), or metabolic (hyperglycemia. hyperphosphatemia, or hypercapnia)." Weight loss in COPO is such a concern that in one abstract of a study presented in 1994, patients were subjected to an aggressive regimen of nutritional support. The intervention group was randomly assigned to receive nocturnal enteral support for 4 months via a percutaneous gastrostomy tube, whereas the control group received oral nutritional support. There was a significant weight gain in the intervention group, but it was due to an expansion of fat compartments, with no significant increase in lean body mass."
SECTION V • Disease Specific
Difficulties in Studying Nutritional Support Studies of nutritional support in which the observer is blinded and impartial to the group allocation present challenges in both design and execution. Controlling for nutritional support in an outpatient setting is difficult, because only partial supervision is possible. [fthe supplements are associated with side effects such as bloating, fullness, or dyspnea, subjects are tempted to reduce the amount of the supplement or, alternatively, to reduce their usual nutritional intake so that their net caloric intake falls. 73 In the meta-analysis by Ferreira and associates/" only six of the studies reviewed 65-67,7o,72.73 were considered to be of high quality as reflected by their achieving a score of more than two of a possible five in the study design assessment scale of Jadad and colleagues" and only two studies were double-blind. In the meta-analysis of Baldwin and co-workers" of illness-related malnutrition, the methodologic quality of the studies was poor, and in only one were the investigators measuring the outcomes blinded to the treatment group.
Anabolic Substances: Anabolic Steroids The use of anabolic steroids for weight gain stemmed from observations that the differences in muscle mass between men and women was attributable to the difference in testosterone levels between the sexes and that hypogonadal patients responded to androgen therapy with an increase in muscle mass. Over the past 20 years, a variety of reports have claimed that anabolic steroids improved the performance of high-level athletes because of an increase in skeletal muscle mass and strength." In normal men, supraphysiologic doses of testosterone have been shown to increase muscle size and strength." Anabolic substances have been investigated as a treatment alternative to promote anabolism in a variety of wasting diseases such as human immunodeficiency virus (H[V) infection and capo. Of note, 25% to 60% of patients with H[V infection have testosterone levels in the hypogonadal range, and this hypogonadism is associated with weight loss in H[V infecticn" Similarly, hypogonadism has been reported in patients with COPD.8o Anabolic steroids can act simultaneously to (1) induce an anabolic effect on protein via androgenic receptors and (2) inhibit protein catabolism through the action of glucocorticosteroid receptors." Some authors suggested that testosterone stimulates muscle growth by its effects on somatomedin and that there is also the possibility of action on the neuromuscular junction." Stanozolol, a synthetic drug derived from testosterone, was used in a randomized, controlled trial to evaluate the potential benefits of anabolic steroids in rnalnourished male individuals with capo, whose BM[ was less than 20 kg/m" and whose P[max was less than 60% of the predicted value.P The study group received 250 mg of testosterone intramuscularly to start, plus 12 mg of oral
431
stanozolol each day for 27 weeks, during which time the control group received a placebo. Both groups participated in inspiratory muscle exercise training during weeks 9 to 27 and cycle ergometer exercises during weeks 18to 27. At the end of 6 months, the control and treatment group differed, with subjects who received anabolic steroids weighing an average of 2 kg more than control subjects. This increase in body weight was associated with significant increases in arm muscle and thigh circumference and in lean body mass as measured by DEXA. There was no significant increase in maximal or functional exercise capacity (6-minute walking test) and no difference in peripheral muscle strength (unpublished data). Both groups experienced improvements in respiratory muscle strength, with a 20% increase in P[max in the control group and a 41% increase in the study group." Stanozolol was used in this study because of its predominantly anabolic effect. The dose was double the recommended dose (6 mg) in an attempt to reproduce the high dosage used by athletes. Patients were closely followed and checked for side effects during the 6 months of use of this medication. There was no evidence of clinical or biochemical side effects and no differences in biochemical measures (electrolytes, glucose, calcium, phosphorus magnesium, total protein albumin, blood cell count, prostatic acid phosphatase, or prostate size) between groups or over time. The results of all screening tests for side effects of anabolic steroids did not change. Levels of luteinizing hormone and testosterone were similar in both groups at baseline, but showed significant decreases in those receiving anabolic steroids, because they were receiving hormone replacement and no longer had hypogonadism. Another randomized, controlled trial, also involving patients in rehabilitation programs, began with 217 male and female patients who, according to body weight (<90% IBW) or FFM «67% in men and <63% in women) were stratified into depleted (malnourished) and nondepleted groups at baseline. Those in the depleted group had [ower inspiratory pressures and [ower 12-minute walking distances than those in the nondepleted group. The weight gains of those who received nutrition alone or those who received nutrition plus anabolic steroids were similar, although those who were malnourished gained more weight than those who were not (2.9 ± 2.9 kg for nutrition alone vs. 2.4 ± 2.2 kg for nutrition plus anabolic steroids). Moreover, patients who received combined therapy (nutrition plus anabolic steroids) showed a greater increase in FFM compared with those who received only nutritional supplements and in whom the weight gain was predominantly due to the expansion of fat mass. There was an improvement in Plmax; however, values were not significantly different from those of the group who received nutrition alone. In both groups 12-minute distance improved, although more than one third of the patients were too disabled to participate in a walking test. No side effects were reported, even in female patients who received one half the dose given to male patients/" These two trials showed an improvement in weight gain and an increase in lean muscle mass, but there were no improvements in exercise capacity or respiratory muscle
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36 • Nutrition in Stable Chronic Obstructive Pulmonary Disease
strength, which were the ultimate goals. Unfortunately, quality of life was not evaluated in these studies.
Anabolic Substances: Growth Hormone GH has intense effects on body composition. Itsdeficiency in adults is associated with an increase in body fat deposits and a decrease in body lean mass, with an overall increase in body weight. Human growth hormone comprises 5% to 10% of the dry weight of the human pituitary gland, weighing approximately 10 mg. It is secreted in cyclical impulses matching an individual's circadian rhythm." GH acts mainly through IGFs, a family of peptides with amino acid structures similar to those of proinsulin. IGFs are produced in the liver and are stimulated by GH, other substances such as insulin, and nutritional factors." In a 3-week-long, randomized, double-blind trial, Burdet and colleagues'S administered recombinant human GH (rhGH) or placebo to 16 subjects (14 male and two female) with COPD, who were participating in a pulmonary rehabilitation program. Their baseline weight was less than 90% of IBW. After 21 days, lean body mass increased 2.3 ± 1.6 kg in the rhGH group and 1.1 ± 0.9 in the control group. These gains persisted for 2 months after cessation of rhGH administration. However, there was no effect on respiratory muscle strength, peripheral muscle strength, or maximal power during exercise or sensation of dyspnea.P Similarly, Casaburi and colleaguesf reported a similar protocol in abstract form. In this study, 29 patients with moderate to severe COPD trained for 6 weeks and were randomly assigned to receive GH plus training (12 subjects), GH plus placebo (12 subjects), or placebo (5 subjects). Levels of IGFs were low at baseline and increased markedly in the GH group only. There was an increase in lean body mass of 6.4 ± 5.6% in the GH group, with no change in the placebo group. Once more, there was no change in exercise capacity, measured by incremental test or endurance test, although the cross section of the muscle increased 6.1 ± 2.5% in the study group and 2.0 ± 2.5% in the control group. Common side effects associated with GH use, such as fluid retention, increases in fasting blood glucose values, symptoms of carpal tunnel syndrome, and gynecomastia" were not reported in these two studies. At this point, randomized, controlled trials with GH have shown significant improvements in weight gain and lean body mass; however, it did not change exercise capacity or quality of life in patients with COPD, major goals of researchers and clinicians.
Appetite Stimulants In a recent study, megestrol acetate, a progestational appetite stimulant, stimulated weight gain (3.2 kg vs. 0.7 kg in the placebo group). Once again, this gain was due mainly to an increase in fat mass." In addition, there were no changes in respiratory muscle strength and the 6-minute walking test between groups, with a significant
improvement in the placebo group at week 8 (P =0.12). Although cortisol and testosterone levels decreased in the study group, this may be an additional option worth considering for some patients.
PATIENT MONITORING Factors Associated with Nonresponse to Nutritional Support Understanding factors that determine the response to nutritional support is essential, because response to treatment is a critical indicator. Patients who have a positive response to treatment also have a lower mortality rate." Schols and colleagues" studied the prognostic implications of body weight changes in COPD and constructed two survival curves. The first reflected a retrospective review of 400 patients with COPD undergoing rehabilitation, none of whom had been given nutritional supplements. They noted that a low BMI, older age, and low arterial oxygen saturation were independent predictors of mortality. When subjects were classified into quintiles based on BMI, a threshold value of 25 kg/m'' was identified, below which mortality was increased. Weight change, entered as a time-dependent covariate, remained an independent predictor of mortality in addition to all variables that were entered. The second curve was based on a post hoc analysis of the study mentioned earlier" of patients who received nutritional support or nutritional support plus anabolic steroids. Among these subjects, weight gain of more than 2 kg in 8 weeks, in both malnourished and nourished subjects, as well as an increase in Plmax , were significant predictors of survival. These two studies support the hypothesis that body weight has an independent effect on survival of patients with COPD.85 Despite positive effects of nutritional support in some patients with COPD, other patients do not show an adequate response to therapy. Noncompliance with therapy, elevated energy requirements, side effects of the supplement, bloating, and the inability of patients to consume extra calories may all be potential causes. In addition, the relative preservation of fat mass in some normal to underweight patients indicates inadequate metabolic handling." This was confirmed prospectively by Creutzberg and colleagues." who investigated predictors of weight response to a standardized nutritional support regimen as an integrated part of a pulmonary rehabilitation program. Nonresponse was associated with an elevated systemic inflammatory response, as reflected by higher levels of soluble TNF receptors, circulating leptin and acute-phase proteins, hyperglycemia, and disturbed body water compartments.
Specific Considerations In patients with COPD, electrolyte abnormalities, an imbalance of arterial blood gases, and hyperinflation of the lungs may complicate or confound the effects of
SECTION V • Disease Specific
malnutrition on respiratory muscle performance. It is necessary to evaluate these patients and make appropriate corrections to improve their outcome. Hypophosphatemia may be prevalent in hospitalized patients as well as in critically ill patients. 87,88 Significant improvement of respiratory muscle weakness, measured by Pdi measurements, has been well documented in patients receiving mechanical ventilation after correction of hypophosphatemia.P Fiaccadori and colleagues'" found hypophosphatemia in 21.5% of 158 patients with an exacerbation of COPD. Hypomagnesemia may also cause respiratory muscle weakness that is reversible after magnesium replacement. Hypomagnesemia was present in only 9.4% whereas low muscle levels of magnesium were evident in 47% of patients with COPD admitted to the intensive care unit." Hypocalcemia and hypokalemia may also cause respiratory muscle weakness. The population with COPO is generally older, with comorbidities and receiving multiple therapies, rendering them more susceptible to problems with abnormal values. The arterial blood gas imbalance, found in both hypoxia and hypercapnic acidosis has been shown to decrease respiratory muscle contractility and endurance in humans." Patients should receive the maximum dose of medication, should have the saturation of their oxygen evaluated, and should receive continuous oxygen when indicated. I
SUMMARY AND FUTURE DIRECTIONS Nutritional depletion in patients with COPO is common and has a negative impact on respiratory as well as skeletal muscle function, contributing to the morbidity and mortality of this condition. It is therefore valuable to include management strategies that improve the energy balance to help the patient gain weight and increase their FFM. Even though some reports showed positive results, nutritional support for more than 2 weeks did not produce a significant effect for any of the main outcomes. The use of anabolic agents does result in weight gain and an increase in FFM. Selected patients, especially those with associated hypogonadism, may benefit from a combination of nutritional support plus anabolic steroids. Large randomized trials that examine qualityof-life and survival outcomes should be encouraged. Research has shown that COPO is characterized by a complex response of a variety of metabolic pathways. Further research is needed to clarify the complexity of metabolic alteration related to inflammation, hypoxia, hypercapnia, and energetic deprivations. Different factors can be contributing to the changes seen in muscles in patients with COPD. The relative contribution of each factor could be as different in each patient as it is in different types of muscle. Systemic corticosteroids should be used with caution in patients with COPD, taking into account the side effects. Because of the importance of muscle function, morbidity, mortality, and quality of life, treatment should be based on the individual needs of each patient. The assessment should include, at a
433
minimum, BMI, body composition, and skeletal and respiratory muscle function. Evaluation of functional exercise capacity (such as the 6-minute walking test) and the ability to carry on activities of daily living should also be included. It is possible that nutritional therapy should be more individualized and directed at the causal factors. In the future, cytokines or cytokine inhibitors may prove to be more advantageous than corticosteroids in the treatment of COPD. New therapies may include antiTNF-a agents, similar to treatments for inflammatory bowel disease and rheumatoid arthritis that significantly reduce inflammation and improve symptoms and quality of life, even in patients who were unresponsive to corticosteroids." Another possibility might be the use of anti-inflammatory cytokines, such as IL-IO, that are inhibitors of TNF-a and chemokines. Because inflammatory cytokines may contribute to muscle wasting through the inhibition of myogenic differentiation via NF-KB, we can hypothesize that novel therapies for direct inhibition of NF-KB may prove beneficial in reducing the muscle wasting associated with cachexia- Studies with IGF-I are also under way and seem to be promising. Acknowledgment The author thanks Ms Victoria Pennick, RN, Bsc,MHSc, for manuscript revision.
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39. Takabatake N, Nakamura H, Abe S, et al: Circulating leptin in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159(4 part 1):1215-1219. 40. Schols AM, Creutzberg EC, Buurman WA, et al: Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1220-1226. 41. Schols AM: TNF-alpha and hypermetabolism in chronic obstructive pulmonary disease. Clin Nutr 1999;18:255-257. 42. Donahoe M, Rogers RM, Cottrell JJ: Is loss of body weight in chronic obstructive pulmonary disease patients with emphysema secondary to low tissue oxygenation? Respiration 1992;59(suppI2): 33-39. 43. Donahoe M, Rogers RM: Mechanisms of weight loss in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1993;48: 522-529. 44. Jenkins RC, Ross RJ: Growth hormone therapy for protein catabolism. Q J Med 1996;89:813-819. 45. Di Francia M, Barbier 0, Mege JL, et al: Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994;150(5 part 1):1453-1455. 46. de Godoy I, Donahoe M, Calhoun WJ, et al: Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med 1996;153:633-637. 47. Eid AA, lonescu AA, Nixon LS, et al: Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164(8 part 1):1414-1418. 48. Li YP, Reid MB: Effect of tumor necrosis factor-alpha on skeletal muscle metabolism. Curr Opin RheumatoI2001;13:483-487. 49. Pitsiou G, Kyriazis G, Hatzizisi 0, et al: Tumor necrosis factor-alpha serum levels, weight loss and tissue oxygenation in chronic obstructive pulmonary disease. Respir Med 2002;96:594--598. 50. Langen RC, Schols AM, Kelders MC, et al: Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear Iactor-xls. FASEB J 2001;15:1169-1180. 51. Agusti AG, Sauleda J, Miralles C, et al: Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:485-489. 52. Lewis MI: Apoptosis as a potential mechanism of muscle cachexia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:434-436. 53. Ferreira I, Brooks 0, Lacasse Y, et al: Nutritional intervention in COPD: A systematic overview. Chest 2001;119:353-363. 54. Ferreira 1M, Brooks 0, Lacasse Y,et al: Nutritional supplementation in stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2000;(3):CD000998. 55. Ferreira 1M, Brooks 0, Lacasse Y, et al: Nutritional support for individuals with capo: A meta-analysis. Chest 2000;117:672-678. 56. Vermeeren MA, Wouters EF, Nelissen LH, et al: Acute effects of different nutritional supplements on symptoms and functional capacity in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 2001;73:295-301. 57. Brown SE, Nagendran RC, McHugh JW, et al: Effects of a large carbohydrate load on walking performance in chronic air-flow obstruction. Am Rev Respir Dis 1985;132:960-962. 58. Efthimiou J, Mounsey PJ, Benson ON, et al: Effect of carbohydrate rich versus fat rich loads on gas exchange and walking performance in patients with chronic obstructive lung disease. Thorax 1992;47:451-456. 59. Akrabawi SS, Mobarhan S, Stoltz RR, et al: Gastric emptying, pulmonary function, gas exchange, and respiratory quotient after feeding a moderate versus high fat enteral formula meal in chronic obstructive pulmonary disease patients. Nutrition 1996;12: 260-265. 60. Frankfort JD, Fischer CE, Stansbury OW, et al: Effects of high and low carbohydrate meals on maximum exercise performance in chronic airflow obstruction. Chest 1991;100:792-795. 61. Goldstein SA,Thomashow BM,Kvetan V, et al: Nitrogen and energy relationships in malnourished patients with emphysema. Am Rev Respir Dis 1988;138:636-644. 62. Angelillo VA, Bedi S, Durfee 0, et al: Effects of low and high carbohydrate feeding in ambulatory patients with chronic obstructive pulmonary disease and hypercapnia. Ann Intern Med 1985; 103:883-885.
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63. Goldstein SA, AskanaziJ, Elwyn DH, et al: Submaximal exercise in emphysema and malnutritionat two levelsof carbohydrate and fat intake. J Appl Physiol 1989;67:1048-1055. 64. Lewis MI, Belman MJ, Dorr-Uyemura L: Nutritional supplementation in ambulatory patients with chronic obstructive pulmonary disease. Am Rev RespirDis 1987;135:1062-1068. 65. Rogers RM, Donahoe M, Costantino J: Physiologic effects of oral supplemental feeding in malnourished patients with chronic obstructive pulmonary disease. A randomized control study. Am Rev RespirDis 1992;146:1511-1517. 66. Schols AM, Soeters PB, Mostert R, et al: Physiologic effectsof nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial. AmJ RespirCritCare Med 1995;152(4 part 1):1268-1274. 67. WhittakerJS, Ryan CF, Buckley PA, et al: The effects of refeeding on peripheral and respiratory muscle function in malnourished chronic obstructive pulmonary disease patients. Am RevRespirDis 1990;142:283-288. 68. Vargas MD, Puig A, Pia de La Mazza C: Pacientes con limitation cronica al flujoaereo: efectos del entrenamiento muscular respiratorio con valvulade carga umral construida con tecnologia apropiada. asociada a apoyo nutritional. Rev Med Chile 1995;123: 1225-1234. 69. Fuenzalida CE, PettyTL, Jones ML, et al: The immune response to short-term nutritional intervention in advanced chronic obstructive pulmonary disease. Am Rev Respir Dis 1990;142:49-56. 70. Otte KE, Ahlburg P, D'Amore F, et al: Nutritional repletion in malnourished patients with emphysema. JPEN J Parenter Enteral Nutr 1989;13:152-156. 71. Efthimiou J, FlemingJ, GomesC, et al: The effect of supplementary oral nutrition in poorly nourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1988;137:1075-1082. 72. DeLetter MC: A Nutritional Intervention for Persons with Chronic Airflow Obstruction, University of Kentucky, 1991. 73. Knowles JB, Fairbam MS, Wiggs BJ, et al: Dietarysupplementation and respiratory muscle performance in patients with COPD. Chest 1988;93:977-983. 74. Baldwin C, Parsons T, Logan S: Dietary advice for illness-related malnutrition in adults. Cochrane Database Syst Rev 2001;(2): CD002008. 75. Donahoe M, Mancino J, Constantino J: The effects of an aggressive nutritional support regimen on body composition in patients with severe COPD and weight loss [abstract]. AmJ RespirCritCare Med 1994;149:313A. 76. Jadad AR, Moore RA, Carroll D, et al: Assessing the quality of reports of randomized clinical trials: Isblinding necessary?Control ClinTrials1996;17:1-12. 77. Wadler GI: Druguse update. Med Clin North Am 1994;78:439-455.
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78. Bhasin S, Storer TW, Berman N, et al: The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N EnglJ Med 1996;335:1-7. 79. BhasinS,StorerTW,Javanbakht M, et al: Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels.JAMA 2000;283:763-770. 80. Kamischke A, Kemper DE, Castel MA, et al: Testosterone levels in men with chronic obstructive pulmonary disease with or without glucocorticoid therapy. Eur RespirJ 1998;11 :41-45. 81. Shetty KSGKL, Rudman D: New uses for human growth hormone. Endocrinologist 1993;3:205-211. 82. Burdet L, de MuraIt B,Schutz Y, et al: Administrationof growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study. Am J Respir CritCare Med 1997;156:1800-1806. 83. Casaburi R, Carlone S, Tosoline R, et al: Randomized controlled trial of growth hormone in severe COPD patients undergoing endurance training [abstract]. AmJ RespirCritCare Med 1997;155: A498. 84. Weisberg J, Wanger J, Olson J, et al: Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients. Chest 2002;121:1070-1078. 85. Schols AM, Slangen J, Volovics L, et al: Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. AmJ Respir CritCare Med 1998;157(6 part 1):1791-1797. 86. Creutzberg EC, Schols AM, Weling-Scheepers CA, et al: Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease. Am J Respir CritCare Med 2000;161(3 part 1):745-752. 87. Fiaccadori E, Coffrini E, Fracchia C, et al: Hypophosphatemia and phosphorus depletion in respiratory and peripheral muscles of patients with respiratory failure due to CGPD. Chest 1994;105: 1392-1398. 88. Fiaccadori E, Coffrini E, Ronda N, et al: Hypophosphatemia in course of chronic obstructive pulmonary disease. Prevalence, mechanisms, and relationships with skeletal muscle phosphorus content. Chest 1990;97:857-868. 89. Aubier M, Murciano D, Lecocguic Y, et al: Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N EnglJ Med 1985;313:420-424. 90. Jardim JR, Farkas G, Prefaud C: The failing inspiratory muscles under normoxic and hypoxic conditions. Am Rev Respir Dis 1981;124:376-381. 91. Barnes PJ: Cytokine modulators as novel therapies for airway disease. Eur RespirJ 2001;18(suppl34):67s-77s. 92. Ryan CF, Road JD, Buckley PA, et al: Energy balance in stable malnourished patients with chronic obstructive pulmonary disease. Chest 1993;103:1038-1044.
Acute Pancreatitis C. H. C. Dejong, MD, PhD J. W. M. Greve, MD, PhD P. B. Soeters, MD, PhD
CHAPTER OUTLINE Introduction Pathophysiology of Acute Pancreatitis Nutrition Assessment Who Should Be Fed?
Nutrition: Patient Management and Monitoring Specific Nutrients
Conclusions
INTRODUCTION In the past decades, there has been a steady increase in the incidence of acute pancreatitis. 1Acute pancreatitis is an unpredictable disease of varyingseverity and differing etiologies that currently accounts for about 3% of all admissions for acute abdominal pain. In general, the disease takes a relatively benign course and spontaneous recovery with conservative treatment is to be expected in the majority of patients.' However, in 20% to 30% of patients, severe acute pancreatitis develops, and the prognosis in this subgroup of patients is much worse.' Thus, whereas mortality in the whole group of patients with pancreatitis has been reported to be between 2% and 10%,4 it iswell below 1%in patients with mild disease," and death rates increase steeply to between 10% and 23% in patients with severe disease.' Consequently, the latter group accounts for more than 80% of the mortality due to this disease. On the basis of this fact, the 1992 Atlanta International Symposium on Acute Pancreatitis proposed that patients be classified into groups with either mild, acute, or severe acute pancreatitis" (reviewedin references 4 and 7). Although this classification is far from perfect,it does provide a stratification criterion for both research and clinical management. Realizing that it is important to foresee which patients will develop severe acute pancreatitis and which patients will only suffer from mild disease, many respected
436
clinicians have attempted to develop a system to predict disease severity and hence the course of the disease. Recognition and definition of severe pancreatitis solely by clinical examination is notoriously unreliable. Classically, patients present with sudden-onset epigastric pain, which is continuous and not colicky in nature and which may radiate to the back. The typical patient is a middle-aged female with gallstones or a male with a history of recent alcohol abuse. On physical examination, the usual finding is diffuse severe epigastric pain in a patient without frank peritonitis. Unfortunately, these findings are neither specific for pancreatitis, nor do they help to discriminate between mild and severe disease. Shock, respiratory distress, and peritonitis are consistently seen with a severe attack, but they are also nonspecific and usually late phenomena. Cullen sign (ecchymosis of the umbilicus) (Fig. 37-1) and Grey-Turnersign (flank ecchymosis) are more typical of severe acute pancreatitis, but they are late signs. Against the background of this perceived inaccuracy in predicting disease severity and outcome, various scoring systems have been designed on the basis of clinical and laboratory findings with the purpose of predicting more accurately disease severity and outcome. The most commonly used of these numeric scoring systems is still the Ranson score (Table 37-1).8 Alternative scoring systems, such as the Imrie (Glasgow) criteria and the Acute Physiology and Chronic Health Evaluation (APACHE II) score,3,9--12 have been introduced more recently. What these scoring systems have in common is that higher scores should predict more severe disease. Although they are all fairly accurate at the two extremes of the disease spectrum, their usefulness in the grey area in between is limited. Hence, they are valuable for comparison of patient groups, but their value in everyday clinical practice in individual patients is limited. Balthazar and colleagues introduced in the mid-1980s a computed tomography (CT) scan-based scoring system (reviewed in reference 4). Initially, this system was based on nonenhanced CT images (no intravenous or oral contrast material). The disadvantage of this scoring system initially was that it did not give information
437
SECTION V • Disease Specific
•
Revised Balthazar Score: Assessment of severity Using Contrast-Enhanced CT Scanning Necrosis
cr
Grade
Points
Percentage
Additional Points
Severity Index
A B C D
0 1 2 3 4
0 0 <30% 30-50% >50%
0 0 2 4 6
0 1 4 7 10
E
Note: the cr severity index is calculated by adding the cr grade assigned points to those attributed based on the percentage necrosis. cr grades: A, normal pancreas; B, enlarged pancreas; C, (peri-)pancreatic inflammation; D,single peri pancreatic fluid collection; E, two or more collections and/or retroperitoneal air. Modified from Balthazar EJ: Acute pancreatitis: Assessment of severity with clinical and cr evaluation. Radiology 2002; 223:603-613.
FIGURE 37-1. Periumbilical ecchymosis (Cullen sign) in acute, severe, necrotizing pancreatitis.
about the extent of pancreatic necrosis. In the past decade, it has become clear that pancreatic necrosis, especially if it becomes infected is a crucial determinant of outcome.' Hence, the Balthazar CT score was revised to include the extent of necrosis of the gland as assessed by intravenous contrast-enhanced CT (Table 37-2 and
..
Fig. 37-2). Good correlation has been shown between this CT severity index and the development of local complications and death rates.' In the past decade, the management of acute pancreatitis has changed drarnatically.P This has been due to improvements in our understanding of the role of pancreatic necrosis and infection, the increased availability of modem CT scanning, improved intensive care facilities, and advances in surgical treatment (Fig. 37-3). In the past, attempts have been made to influence the outcome of (severe) acute pancreatits, by focusing on factors of supposed etiologic or pathophysiologic importance. In this context, the issue of nutrition issubject to ongoing debate. In this chapter, we will discuss the role of nutrition in acute pancreatitis, as well as potential problems, in the context of the etiology and pathophysiology of acute pancreatitis.
Ranson Score: Assessment of Severity of Acute Pancreatitis
On admission Age White blood cell count Serum glucose level AST level Serum LDH/ALT ratio During initial 48 hours Hematocrit Serum urea Calcium Pa02 Base deficit Positive fluid balance
>55 years x 109/L >11 mrnol/L >350IU/L >250IU/L
> 16
Decrease >0.10 Increase> 1.8 rnrnol/L <2 mrnol/L <8 kPa >4 mrnol/L >6 L
ALT, alanine aminotransferase; AST,aspartate aminotransferase; LDH, lactate dehydrogenase; Pa02' partial pressure of arterial oxygen. Data from Ranson JH, Rifkind KM, Roses DF, et al: Objective early identification of severe acute pancreatitis. Am J Gastroenterol 1974;61:443-451.
FIGURE 37-2. Contrast-enhanced computed tomography (CT) scan guided fine needle aspiration for bacteriology of necrotizing pancreatitis with gas in the retroperitoneum (Balthazar E).
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37 • Acute Pancreatitis
C
D
FIGURE 37-3. Surgical approach of patient with severe, acute necrotizing pancreatitis. (A) A bilateral sub-costal curvilinear incision is used to gain access to the abdomen. (B) The gastrocolic ligament is divided between clamps or using ultracision, exposing the lesser sac and the ventral aspect of the inflamed pancreas. (e) By blunt dissection, abscesses are opened and necrosis is removed, taking care not to damage the colonic vasculature, superior mesenteric vein, or the splenic vein. (D) Silicone inlet and sump-type outlet drains facilitate postoperative closed suction drainage. If possible, a jejunostomy or a nasojejunal feeding tube is inserted in the first jejunal loops.
PATHOPHYSIOLOGY OF ACUTE PANCREATITIS The two main etiologic factors in acute pancreatitis are alcohol and gallstone disease, although a variety of rarer causes, such as viruses, hypercalcemia, hyperlipidemia, trauma, and drugs (angiotensin-converting enzyme [ACE] inhibitors or immune suppressants), have been reported as well." Irrespective of etiology, the disease is characterized by autodigestion of the gland." This is due to inappropriate release of proteolytic enzyme, with a resulting local and systemic activation of the inflammatory cascade," which appears to be unstoppable. The latter is known to contribute to the occurrence of the systemic inflammatory response syndrome (SIRS), accompanied by acute-phase protein secretion." Progressive autodigestion contributes to an initially sterile pancreatic
necrosis, which is likely to become infected. IS Infected necrosis in turn can result in septicemia, leading to unrestrained SIRS, which often progresses to multiple organ dysfunction and failure. Mortality due to pancreatitis has a biphasic distribution," with early deaths occurring during the first days of admission and delayed mortality occurring after 2 to 3 weeks. It is well known that the majority of late deaths are related to secondary infection of pancreatic necrosis. Secondary infection occurs in about 30% to 70% of patients with necrosis-" and is the main determinant of the development of multiple system organ failure. Multiple organ failure, in tum, results in deficient renal clearance of toxic substances and cytokines, reduced hepatic clearance of endotoxin, 17 and increased gut permeability." The latter facilitates translocation of microorganisms from the gut lumen into blood, increasing the risk of secondary
SECTION V • Disease Specific
infection of pancreatic necrosis. The resulting vicious circle ends in severe sepsis and multiple organ failure with a mortality rate of 20% to 50%.5 This pathophysiologic background has formed the basis for three major targeted treatment categories. In the past, the concept of "resting the pancreas?" to reduce pancreatic secretion and to avoid further activation of pancreatic enzyme secretion has been considered to be of prime importance. This concept has formed the basis for withholding food and providing gastric drainage and more recently for administration of pharmacologic agents, such as somatostatin or its analog octreotide to reduce pancreatic secretion. Over the years, however, this concept has proved to be untenable, and somatostatin has not been shown to be beneficial in the treatment of acute pancreatitis'P':" and hence is not mentioned in the recent International Association of Pancreatology (lAP) Guidelines for the Surgical Management of Acute Pancreatitis (fable 37-3).5 More recently, it has been thought that it should be possible to lessen S[RS in patients with severe acute pancreatitis by giving specific anti-inflammatory components, such as platelet-activating factor antagonists,22,23 Preliminary results with lexipafant, a platelet-activating factor antagonist, were promising. However, results of a large multicenter trial did not confirm any effect on morbidity or mortality in these patients.P' Therefore, there appears to be no place for lexipafant in the treatment of acute pancreatitis. Currently, secondary infection of pancreatic necrosis constitutes one of the crucial factors in the progression of SIRS to sepsis in patients with severe acute pancreatitis, Because many of the microorganisms encountered in infected necrosis originate in the intestine, combating these microbes by selective decontamination
_
• .
439
of the gut as well as by administration of systemic antibiotics has been explored.P Available evidence suggests that it is beneficial to administer broad-spectrum antibiotics in an early stage to prevent pancreatic infection, even though this may not reduce mortality,1,3,26,27 as has also been explicitly stated in the [AP guidelinesf In this context, it is worth mentioning that in a randomized, controlled trial comparing selective gut decontamination to standard treatment in patients with predicted severe acute pancreatitis, a reduction in morbidity and mortality was found." This has, however, not led to widespread implementation of the selective decontamination concept in severe acute pancreatitis. It is somewhat surprising that the lAP guidelines.! like the United Kingdom guidelines for the management of acute pancreatitis'? do not specifically mention nutrition in their recommendations. The guidelines of the American College of Gastroenterologists recommend administration of parenteral nutrition to patients with severe disease who will not receive oral nutrition for 7 to 10 days." However, there is growing evidence that enteral nutrition should not merely be looked upon as a means of providing calories and nitrogen. Instead, enteral nutrition may provide a way to modulate the acute-phase response and improve immune function by protecting gut barrier function." In the following, we will discuss the potential role of nutrition in the management of acute pancreatitis' in greater detail.
NUTRITION ASSESSMENT It has been estimated that approximately 30% of patients with an attack of acute pancreatitis are already malnourished at the onset of disease." The main causes
International Association of Pancreatologv Guidelines for the Surgical Management of Acute Pancreatltls 5
Recommendation I. Mild acute pancreatitis is not an indication for pancreatic surgery. 2. The use of prophylactic broad-spectrum antibiotics reduces infection rates In CT-proven necrotizing pancreatitis, but may not improve survival. 3. Fine needle aspiration for bacteriology (FNAB) should be performed to differentiate between sterile and infected pancreatic necrosis in patients with sepsis syndrome. 4. Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention including surgery and radiologic drainage. 5. Patients with sterile pancreatic necrosis (negative FNAB results) should be managed conservatively and only selected patients should undergo intervention. 6. Early surgery within 14 days after onset of the disease is not recommended in patients with necrotizing pancreatitis unless there are specific indications. 7. Surgical and other forms of interventional management should favor an organ-preserving approach, which involves debridement or necrosectomy combined with a postoperative management concept that maximizes postoperative evacuation of retroperitoneal debris and exudates. 8. Cholecystectomy should be performed to avoid recurrence of gallstone-associated acute pancreatitis. 9. In mild gallstone-associated acute pancreatitis, cholecystectomy should be performed as soon as the patient has recovered and ideally during the same hospital admission. 10. In severe gallstone-associated pancreatitis, cholecystectomy should be delayed until there is sufficient resolution of the inflammatory response and clinical recovery. II. Endoscopic sphincterotomy is an alternative to cholecystectomy in those who are not fit to undergo surgery to lower the risk of recurrence of gallstone-associated pancreatitis. There is, however, a theoretical risk of introducing infection into patients with sterile pancreatic necrosis.
Strength"
B A B B
B
B B B B
B
B
"Strength of recommendation: A, strong evidence requiring a meta-analysis of randomized, controlled trials or at least one randomized, controlled trial; B, intermediate evidence, requiring nonrandomized clinical studies (for details, see reference 5).
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37. Acute Pancreatitis
of the disease are gallstones and alcohol abuse. Particularly in the group of patients with the latter problem, specific nutritional deficiencies may already be present at the time of the initial attack. Patients with gallstone disease may develop obstructive jaundice, potentially resulting in hepatic dysfunction or cholangitis. Activation of the proinflammatory cytokine cascade initiates the systemic inflammatory response, leading to an increase in capillary leak, diminished tissue perfusion, and augmentation of energy and nitrogen expenditure," If sepsis complicates acute pancreatitis, about 80% of patients have profound hypermetabolism, with increased nutrient requirements because of a rise in resting energy expenditure and enhanced protein breakdown." Nitrogen losses may amount to 20 to 40 g/day in patients with acute pancreatitis. Hyperlipidemia is often encountered in patients with acute pancreatitis, but this may be either cause or consequence. Obviously, the classical "nothing by mouth" approach may deprive an already catabolic host of crucial nutrients, thus aggravating the nutritional status. Also, this classic treatment results in intestinal rest, and this may have serious adverse effects for the patient with acute pancreatitis. The absence of enteral nutrition induces intestinal villus atrophy and adversely affects intestinal barrier function.i-" which may facilitate bacterial translocation. It therefore makes sense to feed patients with acute pancreatitis, both from the point of view of preventing protein-ealorie malnutrition and of protecting intestinal barrier function. In recent years, a vast body of research has provided sufficient data to support a consensus view on the role of nutrition in the management of acute pancreatitis."
Who Should Be Fed? That it is necessary to provide a patient with acute pancreatitis with the necessary nutrients to meet the needs of increased energy and nitrogen and to allow repair processes to go on seems self-evident. The majority of patients with acute pancreatitis have mild disease that can be managed by standard supportive measures. Spontaneous recovery with resumption of oral intake generally occurs within 3 to 7 days, and, therefore, there is no need for special nutritional treatment unless such patients are malnourished before the initial attack.P' On the other hand, patients with severe acute pancreatitis should receive nutritional support? because of the severity and protracted nature of the disease and their prolonged inability to eat. In the concept of the role of nutrition as a therapeutic intervention or merely a supportive measure, the route of administration and the use of specific nutrients have received considerable attention in the past two decades. In this concept, it is assumed that any form of nutrition is better than no nutrition at all. However, although this concept sounds attractive theoretically, there is not much evidence to support it. Clearly, nutrition in patients with severe acute pancreatitis may be beneficial
because it may combat ongoing catabolism and associated malnutrition.! On the other hand, Powell and colleagues" showed that early enteral nutrition compared with no nutrition in patients with predicted severe pancreatitis (but one half of whom ultimately were determined to have mild disease) did not affect overall outcome, had no effect on markers of SIRS, and presumably had an adverse effect on intestinal barrier function." In general, interpretation of studies of nutrition in acute pancreatitis is rendered difficult by a multitude of confounding variables. Patients with severe pancreatitis, determined on admission based on Ranson or Imrie criteria, often develop only mild pancreatitis. 29,32 Impaired gastric emptying, ileus, and abdominal compartment syndrome" often make oral feeding difficult. Enteral feeding tubes are sometimes difficult to position, and dislodgement is a common occurrence. Clearly, the appropriate administration of calories and nitrogen by the oral route is not feasible if one adheres to a nothing by mouth regimen. Even if one does not adhere to this regimen, it may be exceedingly difficult to achieve nutritional goals by the oral route. Therefore, the first choice for nutritional support in patients with acute severe pancreatitis has long been parenteral nutrition ePN). Many studies have explored the feasibility and benefits of total PN in pancreatitis. It has been shown in most institutions that PN is feasible and safe. PN does not significantly stimulate pancreatic secretion in humans," and there is no adverse effect of PN on pancreatic function.P'" The advantage of PN is that it is possible to administer the required amount of nutrition, irrespective of bowel function." However, in the only randomized, controlled trial of PN versus no nutrition at all, PN did not improve outcome in patients with mild to moderate pancreatitis." To our knowledge, such a trial has not been conducted in patients with severe pancreatitis. Administration of PN requires insertion of an intravenous line. This introduces the risk of line sepsis, which may lead to secondary infection of pancreatic necrosis. Sitges-Serra and associates" suggested that parenteral feeding leads to expansion of the extracellular fluid compartment, to rapid weight gain, and to a decrease in plasma albumin levels and hemoglobin. These are associated with an increase in postoperative complications in nutritionally depleted surgical patients." However, it may well be that these effects of PN on extracellular fluid merely represent the effect of rehydrating in a moderately dehydrated patient group. Obviously, the effects on serum albumin levels described above are counteracted by the beneficial effects of administering nutrition." Furthermore, one risk of PN is overfeeding of patients, which may adversely affect outcome," a problem that has been addressed by many authors. Hyperlipidemia and hepatic dysfunction may lead to discontinuation of PN. Administration of carbohydrates in this situation is usually not appropriate because this may aggravate hepatic steatosis in patients who already have some degree of insulin resistance.i Finally,deprivation of luminal nutrients during PN is associated with mucosal atrophy in animals and
SECTION V • Disease Specific
man,30AO leading to increased intestinal perrneability'? and translocation of microorganisms and endotoxin. Evidence is accumulating that enteral nutrition, even if administered in small quantities, prevents intestinal mucosal atrophy, thereby improving intestinal barrier function." It remains unclear whether this is related to the route or to a different nutrient composition by that route. Clearly, improvement of intestinal barrier function is beneficial, because it prevents bacteria and their products from gaining access to the circulation," either by the portal or lymphatic route. This may reduce the risk of secondary infection of pancreatic necrosis, thus interrupting the vicious circle that is so important in the pathophysiology of acute pancreatitis. Also, enteral nutrition makes intravenous access unnecessary, which reduces the risk of systemic bacteremia due to line colonization and infection. In addition, enteral nutrition has been shown to reduce septic complications compared with PN in both rats and humans with severe acute pancreatitis. 43,44 However, in the only randomized, controlled trial of enteral nutrition versus no nutrition in patients with moderate to severe acute pancreatitis, no significant beneficial effect was observed." The optimal timing of the start of nutrition and the appropriate quantities are still subject to debate. As stated above, the belief that the pancreas and hence the bowel should be rested has been held for years. Needless to say, this was a major impediment to the introduction of (early) enteral nutrition. However, enteral nutrition beyond Treitz's ligament induces hardly any activation of pancreatic enzyme secretion, is relatively simple to achieve, and has a limited risk of complications.42,43,45 In addition, Eatock and colleagues" showed that early nasogastric feeding (within 48 hours of admission) was feasible and safe in patients with acute severe pancreatitis. Furthermore, enteral nutrition is considerably cheaper than PN,2,43,47 although ensuring proper infusion of enteral nutrition requires more time for the nursing staff. To our knowledge, three randomized, controlled trials comparing (early) enteral nutrition with PN have been conducted. 43,47,48 In patients with acute severe pancreatitis, Kalfarentzos and co-workers" demonstrated a significant reduction in septic complications in the enteral nutrition group. In patients with mild to moderate pancreatitis, Windsor and colleagues" failed to show a significant reduction in SIRS, sepsis, organ failure, or intensive care unit stay in the enteral nutrition group, although a tendency toward improved outcome in this group was observed. In a third study during mild acute pancreatitis, only a significant cost benefit of enteral nutrition was demonstrated." Two of these trials43,47 were included in a recent Cochrane Review." The authors concluded that there is a trend toward a reduction in adverse outcomes of severe acute pancreatitis after administration of enteral nutrition compared with PN, but the data are insufficient to draw firm conclusions. It is well known that oral nutrition stimulates pancreatic secretion. Thus, as stated earlier, for a long time, it was argued that the pancreas should be rested." However, several authors have disputed this dogma, and
441
there is now convincing evidence that this rigid concept is not tenable, because fasting and nasogastric suction are not beneficial." Oral, intragastric, intraduodenal, or even colonic infusion of nutrients does significantly stimulate pancreatic secretion. 2.51,52 On the other hand, enteral nutrition into the proximal jejunum by a nasojejunal tube does not have significant effects on enzyme secretion by the pancreas. 2,45,53 Also, enteral nutrition by a jejunostomy feeding tube during acute pancreatitis prevents bacterial translocation in rats." Clearly, delayed gastric emptying, abdominal compartment syndrorne." diarrhea, aspiration of gut contents, inability to place a jejunal feeding tube, tube dislodgement, and ileus due to pancreatitis may affect the feasibility of full enteral nutrition. The implementation of early enteral nutrition therefore makes adequate clinical monitoring of intestinal function compulsory. Against this background, it is hardly surprising that several authors'!" were only able to achieve administration of 20% to 70% of targeted caloric requirements by the enteral route. However, this is not an argument against enteral nutrition. An ever-increasing number of studies have shown that early enteral nutrition is safe 54 in patients with acute severe pancreatitis." In view of the obvious logic of using the natural route of nutrition and the proven health and cost benefits, it would seem safe to say that enteral nutrition by a nasojejunal or jejunostomy feeding tube should be the goal whenever possible.7,47 Enteral nutrition supplemented with pre- and/or probiotics may prove to be a promising way for enteral feeding of patients with pancreatitis in the future."
NUTRITION: PATIENT MANAGEMENT AND MONITORING A recent consensus statement on the role of nutrition in acute pancreatitis provides a useful guide for nutritional goals in every day clinical practice (fables 37-4 and 37-5). We commonly start enteral nutrition using standard enteral nutrition formulas at a rate of 25 mUhr using a continuous feeding regimen. This rate is then increased by 25 mUhr/day until full enteral nutrition is • . •
,
European Society of Parenteral and Enteral Nutrition Guidelines on Nutrition In severe Acute Pancreatitis
Recommendation
1. Patients with severe disease, complications, or a need for surgery require early nutritional support to prevent the adverse effects of nutrient deprivation. If this is not feasible by the enteral route, parenteral nutrition should be combined with enteral feeding. 2. A combined enteral and parenteral nutrition approach allows the nutritional goal to be reached most of the time. 3. The use of intravenous lipids as part of parenteral nutrition is safe when hypertrlglyceridemia (>12 mmol/L) is avoided. Data from Meier R, Beglinger C, Layer P, et al: ESPEN Guidelines on Nutrition in Acute Pancreatitis. Clin Nutr 2002;21: 173-183.
442
37 • Acute Pancreatitis
_ _ Nutritional Goals In Acute Pancreatitis Energy Carbohydrates Lipids Protein Micronutrients
25-35 kcal/kg BWjday
3-6 g/kg BW/day Aim for blood glucose < 10 rnrnol/L <2 g/kg BW/day Aim for plasma triglycerides <12mmol/l, 1.2-1.5 g/kg BW/day Guided by laboratory findings
Note: ~im for full enteral nutrition; if this cannot be achieved, give
additional parenteral nutrition. BW, body weight. Data from Meier R, BeglingerC, Layer P, et al: ESPEN Guidelines on Nutrition in Acute Pancreatitis. Clin Nutr 2002;21:173-183.
a problem, consideration of a transgastric jejunal tube is worthwhile (Fig. 37-4). The condition of the patient should be closely monitored..A return of normal stool passage indicates improvement In bowel function. Likewise, disappearance of edema isa ~i~n of reduced disease activityand improvement in the nutntIona~ status of the patient. This can usually also be ?bserved In labo~atory investigations,in which an increase In serum albumin level and a return of the number of thrombocytes and white blood cells toward normal numbers confirm that the patient's condition is improving.
Specific Nutrients attained (500 to 2500 mUday depending on nutritional composition and the patient's body size), until the level of tolerance of the patient is reached. Diarrhea can be treated by switching to cyclic feeding or by administering loperamide. Loperamide should always be administered wi~h extreme caution, because diarrhea may be paradoxical, and this drug may precipitate complete paralytic ileus. Occasionally, domperidone, erythromycin (as a prokinetic macrolide), or cisapride can be used in patients who seem to have problems with proximal peristalsis. If the nutritional goals cannot be attained solely by the enteral route, the addition of parenteral nutrition is strongly advised. Feeding tubes can be placed endoscopically or radiologically. The initial success rates of radiologically placed tubes is higher than that of endoscopically placed tubes, but the late complication rate is also higher. 55 Enteral feeding tube blockage and tube dislodgement are common problems. Tube blockage often may be solved by flushing the tube with a small syringe using saline or warm tap water. Guidewires can also be used to unclog feeding tubes. In patients in whom prolonged paralytic ileus precludes complete enteral nutrition or high gastric residual volume remains
FIGURE 37-4. Triple lumen tube, with proximal lumen for gastric decompression and flexible distal feeding end. If the distal end is positioned immediately beyond Treitz's ligament, the proximal opening is in the stomach.
Several nutrients have recently been suggested to have b~neficial. e~fects in critically ill patients. Of these, glutarmne, argirune, and the so-called immune-enhancing formulas enriched with specific substrates are of particular interest. Glutamine is the most abundant free amino acid in body pools.56 Most of it is produced and stored in skeletal muscle, from which it is released under many (patho) physiologic conditions. Glutamine is a fuel for the gut and immune system" and is important in nitrogen and acid-base horneostasts.w" It is currently considered t~ be .a c~nditionally essential amino acid." This paradigm implies that under physiologic circum-stances the body can produce sufficient amounts of glutamine (meaning that it is dispensable), but that this is not the case during critical illness and nutritional depletion when glutamine requirements are increased. 58 Depletion in itself has been suggested to lead to decreased plasma glutamine concentrations.f but these may also be an effect of the inflammatory state associated with chronic disease or malignancy (K. W. Hulsewe, unpublished results). Because glutamine uptake by the intestines is known to be concentration dependent in the range of oto 600 umol/L, it is hardly surprising that these reduced plasma glutamine concentrations are reflected in diminished gut glutamine uptake and mucosal glutamine content.59 The functional significance of these alterations is ~nderpinned by t~e observation of gut mucosal atrophy In patIents and animals receiving glutamine-free PN and its reversal by glutamine-enriched formulas." Glutamineenriched PN thus prevents mucosal atrophy and improves intestinal barrier function. 4o.58 Enteral administration of. glutamine-enriched nutrition to multiple tr~uma patients reduces septic complications compared with the use of glutamine-free enteral nutrition." Studies on glutamine supplementation during pancreatitis are scarce, despite the fact that glutamine levels in plasma and ~.uscle are known to decrease in acute severe pancreatitis (and therefore, there would be a rationale to supply glutamine).61,62 In the only study comparing standard and glutamine-enriched PN in patients with acute pancreatitis, the glutamine-fed group had diminished release of the cytokine interleukin-8 from peripheral blood mononuclear cells and improved lymphocyte proliferation.P This is in line with observations by others
SECTION V • Disease Specific
that glutamine-enriched enteral nutrition lowers the systemic inflammatory response in multiple trauma patients.P Arginine has immunotrophic effects,64 and these may play a role in the beneficial effects of arginine supplementation in critically ill patients. Arginine plays a role in intestinal mucosal regeneration in severely injured animals/" Some of the benefits of glutamine supplementation have even been attributed to arginine." Thus, the enterocytes convert glutamine to citrulline, which is released in the portal vein and passes through the liver without uptake. Citrulline is then converted by the kidneys to arginine; this could explain increased arginine levels during glutamine supplementation.P''" To our knowledge, no trials have been conducted on supplementation of arginine alone to the nutritional regimen of patients with acute pancreatitis. This may be a fruitful area for future research. Similarly, immuneenhancing formulas containing arginine, nucleotides, and (0-3 fatty acids may improve outcome in surgical patients," but their benefit in critically ill patients is dubious. Currently, no reports are available on their use in patients with acute pancreatitis.!
CONCLUSIONS The interpretation of available data from studies on nutrition in pancreatitis is difficult because this patient group is heterogeneous. Patients with mild acute pancreatitis do not need nutritional support because normal oral intake is usually resumed within 4 to 7 days.' There are no data to suggest that nutritional support affects the underlying disease process.' It would appear that nutritional support is of benefit in patients with severe acute pancreatitis, because it may prevent underlying malnutrition and starvation. Thus, nutritional support should be considered for any patient with severe acute pancreatitis.2 There is no convincing evidence that either enteral or parenteral nutrition is superior, although there are more and more data to suggest that early enteral nutrition is beneficial. 43.49 Obviously, from a theoretical standpoint enteral nutrition would seem preferable. The route of nutrition should therefore be decided by clinical monitoring of intestinal tolerance and the need to achieve adequate nutritional intake." For this purpose, a combination of early parenteral and enteral nutrition as soon as tolerated is the most realistic option. If a patient with severe acute pancreatitis undergoes surgery for treatment of intra-abdominal complications, it is wise to insert a nasojejunal or jejunostomy feeding tube." The potential benefits of specific nutrients in acute severe pancreatitis require further studies. Finally, it should be emphasized that in recent years, several excellent guidelines for the management of acute pancreatitis have appeared. 5.7,10,12 Such guidelines provide a powerful tool for improving the quality of patient care and research. Future strategies in the management of acute pancreatitis should include measures to improve compliance with these guidelines."
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27. Powell JJ, Miles R, Siriwardena AK: Antibiotic prophylaxis in the initial management of severe acute pancreatitis. Br J Surg 1998;85:582-587. 28. Luiten E./, Hop WC, Lange JF, Brulning HA:Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 1995;222:57-65. 29. Olah A, Belagyi T, Issekutz A, et al: Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis. Br J Surg 2002;89:1103-1107. 30. Groos S, Hunefeld G, Luciano L:Parenteral versus enteral nutrition: Morphological changes in human adult intestinal mucosa. J Submicrosc Cytol PathoI1996;28:61-74. 31. Powell JJ, Murchison IT, Fearon KC, et al: Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg 2000;87: 1375-1381. 32. Olah A, Pardavi G, Belagyi T, et al: Early nasojejunal feeding in acute pancreatitis is associated with a lower complication rate. Nutrition 2002;18:259-262. 33. Saggi BH, Sugerman HJ, Ivatury RR, Bloomfield GL: Abdominal compartment syndrome. J Trauma 1998;45:597--609. 34. Niederau C, Sonnenberg A, Erckenbrecht J: Effects of intravenous infusion of amino acids, fat or glucose on unstimulated pancreatic secretion in healthy humans. Dig Dis Sci 1985;30:445-455. 35. Fan BG, Salehi A, Stemby B, et al: Total parenteral nutrition influences both endocrine and exocrine function of rat pancreas. Pancreas 1997;15:147-153. 36. Sax HC,Warner BW,Talamini MA, et al: Early total parenteral nutrition in acute pancreatitis: Lack of beneficial effects. Am J Surg 1987;153:117-124. 37. Sitges-Serra A, Areas G, Guirao X, et al: Extracellular fluid expansion during parenteral refeeding. Clin Nutr 1992;11:63-68. 38. Margarson MP, Soni N: Serum albumin: Touchstone or totem? Anaesthesia 1998;53:789-803. 39. MacFie J: Enteral versus parenteral nutrition: The significance of bacterial translocation and gut-barrier function. Nutrition 2000;16:606--611. 40. van der Hulst RRWJ, van Kreel BK, von Meyenfeldt MF, et al: Glutamine and the preservation of gut integrity. Lancet 1993;341:1363-1365. 41. Braga M, Gianotti L, Costantini E, et al: Impact of enteral nutrition on intestinal bacterial translocation and mortality in burned mice. Clin Nutr 1994;13:256-261. 42. Nakad A, Piessevaux H, Marot JC, et al: Is early enteral nutrition in acute pancreatitis dangerous? About 20 patients fed by an endoscopically placed nasogastrojejunal tube. Pancreas 1998;17: 187-193. 43. Kalfarentzos F, Kehagias J, Mead N, et al: Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: Results of a randomized prospective trial. Br J Surg 1997;84:1665-1669. 44. Kotani J, Usami M, Nomura H, et al: Enteral nutrition prevents bacterial translocation but does not improve survival during acute pancreatitis. Arch Surg 1999;134:287-292. 45. Vu MK, van der Veek PP, Frolich M, et al: Does jejunal feeding activate exocrine pancreatic secretion? Eur J Clin Invest 1999;29: 1053-1059. 46. Eatock FC, Brombacher GO,Steven A, et al: Nasogastric feeding in severe acute pancreatitis may be practical and safe. Int J Pancreatol 2000;28:23-29. 47. McClave SA, Greene LM, Snider HL,et al: Comparison of the safety of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN J Parenter Enteral Nutr 1997;21:14-20.
48. Windsor AC,Kanwar S, Li AG,et al: Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998;42:431-435. 49. Al-Ornran M, Groof A, Wilke 0: Enteral versus parenteral nutrition for acute pancreatitis [Cochrane Review). Cochrane Database Syst Rev 2003:CD002837. 50. Naeije R, Salingret E, Clumeck N, et al: Is nasogastric suction necessary in acute pancreatitis? Br Med J 1978;2:659-660. 51. Riepl RL, Fiedler F, Ernstberger M, et al: Effect of intraduodenal taurodeoxycholate and L-phenylalanine on pancreatic secretion and on gastroenteropancreatic peptide release in man. Eur J Med Res 1996;1:499-505. 52. Compan AF, Medrano J, Calpena R, et al: Canine pancreatic responses to intracolonic perfused nutrients. Pancreas 1998;17: 194-200. 53. Pfeiffer A, Vidon N, Feurle GE, et al: Effect of jejunal infusion of different caloric loads on pancreatic enzyme secretion and gastrointestinal hormone response in man. Eur J Clin Invest 1993; 23:57--62. 54. Braga M, Gianotti L, Gentilini 0, et al: Feeding the gut early after digestive surgery: Results of a nine-year experience. Clin Nutr 2002;21:59-65. 55. Lim APIF, van Overhagen H, Nicolai JJ: Gastrostomy tubes inserted with radiologic techniques. Ned Tijdschr Geneeskd 2003;147: 373-377. 56. van Acker BA, von Meyenfeldt MF, van der Hulst RR, et al: Glutamine: The pivot of our nitrogen economy? JPEN J Parenter Enteral Nutr 1999;23:S45-S48. 57. Lacey JM, Wilmore OW: Is glutamine a conditionally essential amino acid? Nutr Rev 1990;48:297-309. 58. Wilmore OW: Glutamine and the gut. Gastroenterology 1994; 107:1885-1901. 59. van der Hulst RRWJ, Deutz NEP, von Meyenfeldt MF, et al: Decrease of mucosal glutamine concentration in the nutritionally depleted patient. Clin Nutr 1994;13:228-233. 60. Houdijk APJ, Rijnsburger ER, Jansen J, et al: Randomized trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772-776. 61. Roth E, Zoch G, Mauritz W, et al: Metabolic changes of patients with acute necrotizing pancreatitis. Infusionsther Klin Ernahr 1986;13:172-174,177-179. 62. O'Riordain MG, De Beaux A, Fearon KC: Effect of glutamine on immune function in the surgical patient. Nutrition 1996;12(11-12 suppl):S82-sB4. 63. de Beaux AC, O'Riordain MG, Ross JA, et al: Glutamine-supplemented total parenteral nutrition reduces blood mononuclear cell interleukin-8 release in severe acute pancreatitis. Nutrition 1998;14:261-265. 64. Barbul A: Arginine and immune function. Nutrition 1990;6:53-58. 65. Welters CFM, Dejong CHC, Deutz NEP, Heineman E: Effects of parenteral arginine supplementation on the intestinal adaptive response after massive small bowel resection in the rat. J Surg Res 1999;85:259-266. 66. Houdijk APJ, van Leeuwen PAM, Teerlink T, et al: Glutamineenriched enteral diet increases renal arginine production. JPEN J Parenter Enteral Nutr 1994;18:422-426. 67. AlyEA, Milne R, Johnson CD: Non-eompliance with national guidelines in the management of acute pancreatitis in the United Kingdom. Dig Surg 2002;19:192-198.
Chronic Pancreatitis James S. Scolapio, MD Massimo Raimondo, MD Michele Bishop, MD
CHAPTER OUTLINE Introduction Etiology and Epidemiology Pathophysiology Clinical Presentation Diagnostic Methods Nutrition Assessment Nutrition Management Caloric Needs Pancreatic Enzyme Replacement Pain Management Pancreatic Pseudocyst Cystic Fibrosis Patient Monitoring
INTRODUCTION
Etiology and Epidemiology The etiology of chronic pancreatitis includes alcohol in 70% of cases in Western societies and is idiopathic in approximately 20% of cases. Since the mid-1990s, much has been learned about the role of genetic mutations in chronic pancreatitis. Up to 37% of patients with idiopathic chronic pancreatitis have mutations in the cystic fibrosis gene (CFTR).1.2 Mutations in the cationic trypsinogen gene (PRSS I) were identified as a cause of hereditary pancreatitis in 1996 by Whitcomb and colleagues.' Hereditary pancreatitis is an autosomal dominant disorder characterized by recurrent attacks of acute pancreatitis starting in childhood or adolescence, with frequent progression to chronic pancreatitis. Recently, Witt and colleagues" reported an association of mutations in the serine protease inhibitor, SPINK I (PSTI), in 23% of patients with idiopathic chronic pancreatitis. Other causes of chronic pancreatitis include malnutrition (tropical), hyperparathyroidism with associated hypercalcemia, hypertriglyceridemia, and obstruction of
the pancreatic duct. For tropical or nutritional pancreatitis, the etiology is not clearly understood. Malnutrition and deficiency of certain micronutrients such as zinc, copper, and selenium may result in antioxidant deficiency and unopposed free radical injury, resulting in chronic pancreatitis.! Tropical pancreatitis is seen in geographical areas within 30 degrees latitude of the equator. Populations with tropical pancreatitis have been studied for genetic mutations; no association with CFTR or PRSSI has been found. However, 44% have been found to carry SPINK I mutations, suggesting a genetic predisposition." Patients with chronic pancreatitis may develop significant malnutrition resulting from the fear of eating (sitophobia) because of the consequence of abdominal pain and gastrointestinal malabsorption. Of the various causes of chronic pancreatitis, use of alcohol is associated with the poorest dietary intake and the worst nutritional deficits. Both experimental and epidemiologic studies indicate that the risk for alcohol-induced pancreatitis is higher in people consuming a high-fat, highprotein diet," The effects of alcohol combined with a high-fat, high-protein diet appear to be additive. Genetic as well as environmental factors may explain this observation, because many alcoholics will develop chronic pancreatitis without evidence of consumption of a highfat diet. Also, because only a small percentage of people who drink alcohol actually develop pancreatic disease, other genetic and environmental influences are suggested in the development of chronic pancreatitis. The prevalence of chronic pancreatitis in autopsy studies ranges between 0.04% and 5%.8 Clinical studies suggest large differences in prevalence in different parts of the world. A study from Copenhagen in 1978 reported an incidence of 8.2 cases/lOO,OOO individuals." Prospective studies with uniform diagnostic criteria in the United States are underway.
Pathophysiology Chronic pancreatitis is a progressive inflammatory disease in which irreversible morphologic damage and loss of organ function are accompanied by organ 445
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38. Chronic Pancreatitis
fibrosis. The mechanism that causes fibrosis is not known. Fibrosis may result from a deregulation of the normal repair process after tissue injury.'? A mediator of fibrotic reactions during regeneration in many tissues is transforming growth factor-S. 11 Transforming growth factor-~ stimulates the deposition of extracellular matrix, which most likely results in pancreatic gland damage. With progressive damage, a decrease in digestive enzyme release from the exocrine pancreatic gland results in the malabsorption of food. The acinar cells of the pancreas secrete digestiveenzymes. Bicarbonate issecreted from the ductal epithelial cells, and the islet cells secrete insulin. Approximately 80% of the pancreas consists of acinar cells. The proteolytic enzymes, which include trypsinogen, chymotrypsinogen, procarboxypeptidase, and proaminopeptidase, are secreted in the proenzyme form. Enterokinase, an enzyme produced by the duodenal mucosa, converts trypsinogen to trypsin, which then activates the other proteolytic enzymes. The other enzymes, lipase (for fat digestion), amylase (for carbohydrate digestion), and ribonuclease, are secreted in their active form and therefore do not require activation by trypsin. The exocrine pancreas also produces bicarbonate. Bicarbonate originates from the intralobular and small interlobular ducts of the pancreas. The most potent stimulant of pancreatic enzyme and bicarbonate secretion is secretin. The duodenal pH and duodenal products of fat in our diet influence secretin release. Cholecystokinin (CCK) is the other major gut hormone that controls pancreatic secretion. The hydrolytic products of digestion (including protein and fat) release CCK. CCK release occurs within 10 to 30 minutes of eating a protein or fat meal. By stimulation of vagal cholinergic afferent nerves originating in the duodenal mucosa, the pancreatic acinar cells are then stimulated to release the digestive enzymes mentioned earlier. Given that the receptors for secretin and CCK are located in the duodenum, patients with acute pancreatitis should be fed into the jejunum. Activated pancreatic enzymes then inhibit the release of CCK and exocrine pancreas secretion. This negative feedback mechanism may have clinical significance in chronic pancreatitis because large doses of exogenous pancreatic enzymes reduce pancreatic stimulation and may lessen a patient's abdominal pain. Malabsorption does not occur until pancreatic enzyme secretion is reduced to less than 10% of normal. 12 Therefore, steatorrhea occurs late in the course of chronic pancreatitis. Lipase secretion decreases more than the secretion of proteolytic enzymes; therefore, fat malabsorption is greater than that of protein. Besides a reduction in pancreatic enzyme secretion, bicarbonate secretion is also reduced, resulting in low duodenal pH (<4). Low duodenal pH will inactivate pancreatic enzymes and precipitate bile acids. As a result of intestinal malabsorption, weight loss is one of the primary presenting features of chronic pancreatitis.
Clinical Presentation The most common presenting symptom of chronic pancreatitis is abdominal pain. The pain is usually described
as a dull epigastric pain with radiation to the midback. This pain is usually intermittent and is aggravated by food intake. The mechanism of pain in chronic pancreatitis is unclear. Proposed theories have included inflammation of peripancreatic tissue, increased intraductal pressure, and neural inflammation. The differentiation of pain from chronic pancreatitis from pain from other causes of abdominal pain may be difficult. For example, chronic mesenteric ischemia and peptic ulcer disease can present with similar symptoms including postprandial pain and weight loss. Postprandial abdominal pain and bloating with or without nausea and vomiting may suggest gastric outlet obstruction or mechanical bowel obstruction as the cause. Although a history of alcohol intake should point one in the direction of pancreatitis, other causes of abdominal pain should be excluded. Many patients with presumed chronic pancreatitis have drug-dependent personalities, and it may be very difficult to determine the true cause of a patient's pain. Weight loss is also a common feature of chronic pancreatitis. Weight loss occurs because of malabsorption and a patient's fear of eating; hence the daily caloric intake is significantly reduced. The weight loss is usually gradual. Rapid weight loss would suggest another diagnosis such as pancreatic cancer. Diarrhea and steatorrhea occur when exocrine secretion of pancreatic enzymes is insufficient to maintain normal absorption of dietary fat. The patient may note a change in stool characteristics, including the presence of oil droplets and stools that float and have a bad odor. These findings suggest pancreatic steatorrhea. Deficiency of fat-soluble vitamins (vitamins A, D, E, and K) may occur with associated signs and symptoms. Other clinical features of chronic pancreatitis may include symptoms of diabetes mellitus, i.e., polyuria and polydipsia. Jaundice may also occur because of common bile duct compression by the inflamed pancreas. Occasionally a ruptured pancreatic duct may present with ascites and pleural effusions. Regardless of the clinical presentation, it is important to establish the correct diagnosis. Early satiety may occur due to extrinsic compression of the stomach or duodenum by a pancreatic pseudocyst.
Diagnostic Methods The diagnosis of chronic pancreatitis begins with a detailed history followed by radiographic and specific testing. Blood chemistry values alone are not sufficient to make the diagnosis. The finding of pancreatic calcification on a plain radiograph of the abdomen is diagnostic of chronic pancreatitis; however, patients may have chronic pancreatitis without radiographic evidence of calcification. Computed tomography (CT) may be diagnostic if duct dilation, calcification, and cystic lesions are seen. CT scanning is also useful to exclude a solid pancreatic tumor. Intraductal papillary mucinous tumors of the pancreas may produce findings similar to those of chronic pancreatitis on CT scans. Endoscopic retrograde cholangiopancreatography (ERCP) would be necessary to differentiate the two. ERCP is considered to be the most sensitive and specific test for the diagnosis
SECTION V. Disease Specific
of chronic pancreatitis and is currently considered the gold standard against which all other tests are compared." An irregular dilated pancreatic duct and side branches are consistent with chronic pancreatitis. Because ERCP is an invasive test with potential complications, it is usually not the first line of testing to make a diagnosis of chronic pancreatitis. Direct tests for pancreatic exocrine secretion include CCK and secretin stimulation. The finding of subnormal secretion of pancreatic enzymes and bicarbonate in aspirated duodenal juice after intravenous administration of either CCK or secretin is considered by some to be a sensitive and specific test for the diagnosis of chronic pancreatitis. A laboratory with technicians specifically trained in and knowledgeable about these stimulation tests is very important and is often the limiting factor in accurate testing. Although an elevated 72-hour fecal fat collection, while the patient is consuming a 100 g fat diet for 3 days, is diagnostic of malabsorption; other disease processes such as sprue, bacterial overgrowth, and small bowel mucosal disease can produce similar results. Compliance with the 100 g of fat diet over 3 days is also difficult to achieve.) Therefore, a 72-hour fecal fat collection alone is not diagnostic of chronic pancreatitis.
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square meter (height). Signs of peripheral edema and ascites should be noted because these will artificially increase a patient's weight. Poor dentition, loss of subcutaneous fat, and loss of temporal muscle mass are other signs of weight loss and inadequate nutrition. Laboratory tests including serum electrolyte concentrations, albumin level, prothrombin time (vitamin K-dependent), and a 72-hour fecal fat collection are also important in the nutrition assessment of a patient. In addition, serum levels of vitamin Bl2 and fat-soluble vitamins should be checked. To evaluate the nutritional status of the patient, the authors use the Subjective Global Assessment score. IS Minimal reduction of food intake with less than 5% loss in body weight is scored "A." Evidence of reduced food intake with 5% to 10% weight loss and little evidence of body wasting is scored "B." Reduced food intake with greater than 10% weight loss and loss of subcutaneous fat and muscle is scored "C." A patient with a Subjective Global Assessment score of C is considered to be severely malnourished, and nutritional support, i.e., oral supplements, tube feeding, or parenteral nutrition should be considered.
NUTRITION MANAGEMENT NUTRITION ASSESSMENT
Caloric Needs Nutrition assessment begins with taking a history specifically related to the pattern of weight loss and quantity and quality of a patient's diet. Questions related to bowel function including diarrhea and signs to suggest malabsorption such as oil droplets and visualization of undigested food particles in the stool should be asked. Also patients should be asked if they have postprandial abdominal pain that is limiting the amount and type of food they consume. If postprandial pain is not limiting their caloric intake, patients should be specifically asked why they think their food intake has been reduced. Usuallypatients are very insightful as to the cause of their reduced food intake. Referralto a dietitian for appropriate estimation of the type and amount of daily food intake is appropriate. Often a written food diary is helpful. Given that alcohol abuse is the leading cause of chronic pancreatitis, an estimation of the amount of alcohol intake is important. Alcohol is known as an "empty calorie," i.e., 7 kcal/g without protein or vitamins, and the relative risk of chronic pancreatitis increases linearly as a function of the amount of alcohol consumed. There appears to be no threshold on the amount of alcohol required to cause pancreatitis. Asking for signs and symptoms of chronic liver disease is also important because the liver is the principle organ of nutrient assembly. In most studies the time between heavy alcohol consumption and onset of chronic pancreatitis is 18years. 14 The duration of alcohol consumption required to produce chronic pancreatitis is shorter than that required to produce cirrhosis of the liver. Interestingly, patients rarely have both alcoholinduced liver disease and pancreatitis. The physical examination should begin with accurate height and weight measurements. The body mass index of a patient is calculated as kilograms (weight) per
Nutrition management begins with an estimation of the caloric requirements of the patient. Caloric needs can be calculated using the Harris-Benedict equation or indirect calorimetry. Energy requirements using the HarrisBenedict equation can be calculated as follows: REE =66.5 + (13.75 x W) + (5.0 x H) - 6.75 x A (for men) REE =665.1 + (9.56 x W) + (1.85 x H) - (4.676 x A) (for women) where REE is resting energy expenditure, W is weight (kilograms), H is height (centimeters), and A is age (years). Although energy requirements may be increased by 15% to 30% of what is expected based on the HarrisBenedict equation, overfeeding should be avoided." Ideally the patient should be maintained in positive nitrogen balance by feeding total calories based on the Harris-Benedict equation plus 20%, which is approximately 25 to 30 kcal/kg/day. Dietary management begins with total abstinence from alcohol. Prognosis after abstinence is controversial. Trapnell" reported that 75% of his patients with chronic alcoholic pancreatitis experienced pain relief when they stopped drinking. Marks and associates" found that symptoms did not progress as rapidly after a patient discontinued alcohol use. Others have found progression of symptoms even after abstinence. Despite the controversy, total abstinence should be recommended. Protein should supply approximately 1.0 to 1.5 g/kg/day and lipids approximately 30% of the total calories with 40% to 60% of the nutrient mixture as carbohydrate. Hyperglycemia may occur, with insulin being required to maintain serum glucose
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levels less than 200 mg/dL. Serum glucose levels greater than 200 mg/dL result in a greater risk of infection.'? A low-fat diet, with fat making up less than 30% of total calories, should be given to select patients to minimize steatorrhea. Semielemental diets containing fat in the form of medium-ehain triglycerides are reported to cause less stimulation of pancreatic exocrine secretion and diarrhea compared with standard formulas of longchain triglycerides.2o-22 Serum triglyceride levels should be maintained at less than 400 mg/dL. Replacement of combined antioxidants (selenium, methionine, and vitamins A, C, and E) has been shown to reduce pancreatic inflammation and pain in patients with both acute and chronic pancreatltis.Pf" Small studies have suggested that daily antioxidant intake should include 600 Ilg of organic selenium, 9000 LV. of vitamin A, 500 mg of vitamin C, 270 LV. of vitamin E, and 2 g of methionine. Antioxidants can be administered in parenteral nutrition as well. In patients fed enterally, a multivitamin immediate-release tablet or liquid can be given orally or via a feeding tube.
Pancreatic Enzyme Replacement Treatment of exocrine insufficiency is focused on pancreatic enzyme replacernent.P Ingestion of exogenous pancreatic enzymes in sufficient quantities can correct protein malabsorption and correct steatorrhea. The amount of porcine lipase in exogenous preparations varies, ranging from 0 to 8000 units per tablet. The minimal required dose of lipase is 28,000 units per meal. The use of commercially available preparations containing 3500 units of lipase would require a dose of approximately eight tablets with each meal. Pancreatic lipase is more fragile in an acid environment than is trypsin. Low gastric and duodenal pH (pH <4) can inactivate lipase. Therefore, commercial products of porcine lipase rarely abolish steatorrhea because the ingested lipase is inactivated within the intestinal lumen by acid and proteases. Weight maintenance, symptomatic improvement of diarrhea, and a decrease in 72-hour fecal fat excretion are the goals of therapy. If steatorrhea persists, the addition of a histamine (H2) antagonist or proton pump inhibitor may be of benefit. If correction with an H2 antagonist or proton pump inhibitor fails, enteric-eoated preparations may be effective. Enteric coating is effective only if pancreatic enzymes are delivered to the upper small intestine with ingested food, which allows adequate mixing of the lipolytic activity with each meal. Reduction of steatorrhea using an enteric-eoated preparation does not appear to be superior to use of nonenteric-eoated preparations." Microencapsulated preparations containing large amounts of lipase (75,000 to 225,000 units/day) have been withdrawn from the market because of reports of colonic strictures in children with cystic fibrosis." Suzuki and co-workers'v" published results showing correction of steatorrhea in dogs using bacterial lipase and a high-fat, high-ealorie diet. Raimondo and colleague" reported that in vitro lipolytic activity of bacterial lipase (isolated from the bacteria Burkholderia plantariij
survives better than porcine lipase in human gastric and duodenal juice in the presence of physiologic postprandial concentrations of bile acids. Clinical studies are needed to confirm the in vitro activity of the bacterial lipase for the correction of steatorrhea in patients with chronic pancreatitis.
Pain Management Appropriate management of a patient's postprandial abdominal pain is also important in the nutrition management of patients with chronic pancreatitis. Abdominal pain is the primary reason why patients require hospitalization. The presumed causes of pain are increased pancreatic duct pressure, entrapment of nerves, and pancreatic ischemia. Several studies in patients with pain from chronic pancreatitis have reported increased intraductal pressure compared with that in normal subjects." Patients with a dilated pancreatic duct have been reported to have improved pain scores after surgical decompression. Pain also appears to decrease spontaneously in the advanced phases of chronic pancreatitis as the duct decreases in size. Exogenous administration of pancreatic enzymes may also reduce pain associated with chronic pancreatitis. Three controlled studies reported pain relief in 73% of patients treated with nonenteric-coated pancreatic enzyme preparations.Y" Two other studies showed that oral administration of pancreatic enzymes did not significantly relieve abdominal pain compared with a placebo.P:" A meta-analysis of pancreatic enzyme supplementation to reduce pain in patients with chronic pancreatitis failed to show a beneficial effect." Oral analgesics are often needed to treat a patient's pain. Nonsteroidal anti-inflammatory medications may be helpful in some patients. If these medications are not helpful, narcotics may be added. Referral to a specialized pain clinic is very important in the authors' opinion, given the high potential for narcotic dependency in this patient population. Dosing 30 to 60 minutes before mealtime may also be helpful in reducing a patient's postprandial abdominal pain. For patients in whom medications fail, celiac plexus block using steroids may be helpful. However, the effect is usually short-lived, lasting approximately 6 months or less, and repeat treatment is usually required.f For patients with pain despite analgesia and celiac plexus block, an endoscopic or surgical approach should be considered. Appropriate candidates for each method will depend on the characteristics of the pancreatic duct seen on imaging studies.
Pancreatic Pseudocyst During the course of chronic pancreatitis, pseudocysts will occur in approximately 15% to 35% of patients. An increase in the pressure of the pseudocyst and enlarging size are the factors responsible for pain. Large pseudocysts can also obstruct the duodenum, resulting in gastric outlet obstruction and subsequent weight loss.
SECTION V • Disease Specific
Patients without pain or gastric outlet obstruction can be followed without intervention.P In those patients with postprandial abdominal pain or symptoms of obstruction, intervention, i.e., drainage or a period of bowel rest, is necessary. Usually bowel rest will reduce a patient's abdominal pain and result in a reduction in the size of the pseudocyst. During this period, which may take up to 6 weeks, nutritional support is necessary. Placement of a nasojejunal feeding tube and feeding of a semielemental diet can be successful, but most patients will refuse to have a tube placed in their nostril for this length of time." Parenteral nutrition can also be used successfully; however, it is associated with the risk of catheter sepsis." Insurance companies and Medicare need to approve payment before this form of treatment is considered at home. The administration of subcutaneous octreotide may also be used successfully in the treatment of a symptomatic pseudocyst." If patients are still symptomatic after 6 weeks of bowel rest and a retrial of oral feeding, endoscopic or surgical drainage is required. In some patients, endoscopic or surgical drainage should be the first line of treatment, thus avoiding the need for the patient to go without an oral diet for a prolonged period of time.
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patients with CF should receive dietary counseling, pancreatic enzyme replacement, and vitamin supplementation. In older children, enzyme dosage should not exceed 3000 units of lipase/kg of body weight per meal. Enzyme levels are adjusted until adequate growth and stool excretion are achieved. Evaluation of a 72-hour fecal fat collection is also useful to guide therapy. Patients with a weight-to-height index of 85% to 90% of ideal weight should receive oral supplements, patients with a weight-to-height index less than 85% of ideal body weight should receive enteral feeding with a gastrostomy tube, and children with weight-to-height index less than 75% should receive continuous nocturnal enteral or parenteral nutrition." Nocturnal feeding allows the patient to eat during the day. With continuous tube feeding, pancreatic enzymes are necessary and can be administered in a powdered form through the gastrostomy tube. Enzymes should be given at the beginning of the feeding and again 4 to 6 hours later. There is no evidence that specialized formulas are better tolerated than standard polymeric formulas. Patients with CF also require increased sodium in their diets. Patients with CF should receive a water-miscible vitamin designed specifically for patients with CF and fat-soluble vitamin status should be monitored annually.
Cystic Fibrosis Cystic fibrosis (CF) needs special mention because it is a cause of chronic pancreatitis that is often overlooked. Furthermore, the nutrition management of these patients is somewhat different from that of adults with chronic pancreatitis. CF is an autosomal recessive genetic syndrome that affects children. Therefore, nutrition for growth is important unlike in the adult patient. Factors that adversely affect nutritional status include pancreatic insufficiency, malabsorption of fat and fat-soluble vitamins, and short bowel from intestinal resection due to meconium ileus. Also chronic lung infection, diabetes, and cholestatic liver disease can contribute to poor nutrition in CF. Approximately 85% of patients with CF have pancreatic insufficiency at birth or in early childhood. The remaining 15% retain enough functional acinar cell reserve of the exocrine pancreas and do not have steatorrhea and malabsorption. However, the patients with a sufficient pancreas are at risk of recurrent and chronic pancreatitis. These patients have deficient secretion of bicarbonate and chloride and high macromolecule concentration of ductal secretions." Overall patients with CF and a sufficient pancreas have a milder phenotype and longer survival than their counterparts with pancreatic insufficiency. Nutrition assessment is first done by determining energy requirements of the patient. Caloric intake, activity level, and estimated degree of intestinal malabsorption are then determined. Monitoring of growth (height, weight, and head circumference) is important. Children with CFhave increased energy needs during growth. The recommended diet for patients with CF is a high-calorie (120% to 150% of basal), high-protein, and moderate-fat diet with an emphasis on nutrient-dense foods." All
PATIENT MONITORING The goals of nutrition therapy in patients with chronic pancreatitis are to maintain weight, minimize fat loss in the stool, and maintain adequate control of the patient's abdominal pain. Patients should weigh themselves weekly and report any significant weight loss to their health care provider. Patients should also work closely with a dietitian to monitor caloric intake. If a patient has inadequate caloric intake, oral supplements or enteral feeding may be necessary. To monitor the effect of pancreatic enzyme replacement, the amount of stooling and 72-hour fecal fat collection should be documented. Monitoring the patient's abdominal pain is also necessary because an increase in postprandial abdominal pain will decrease the patient's oral intake, resulting in weight loss. Serum levels of fat-soluble vitamins and vitamin 8 12 should be evaluated biannually. In children with cystic fibrosis, close monitoring of the growth chart is also very important. REFERENCES 1. Sharer N, Schwarz M, Malone G, et al: Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med
1998;339:64!Hi52. 2. Cohn JA, Friedman KJ, Noone PG, et al: Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339:653-658. 3. Whitcomb DC, Gorry MC, Preston RA, et al: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14:141-145. 4. Witt H, Luck W, Hennies HC, et al: Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25:213-216. 5. Pitchumoni CS: Special problems of tropical pancreatitis. Clin Gastroenterol 1984;13:941-959.
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6. Durno C, Corey M, Zielenski J, et al: Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 2002;123:1857-1864. 7. Levy P, Mathurin P, Roqueplo A, et al: A multidimensional casecontrol study of dietary, alcohol, and tobacco habits in alcoholic men with chronic pancreatitis. Pancreas 1995;10:231-238. 8. Skyhoj Olsen T: The incidence and clinical relevance of chronic inflammation in the pancreas autopsy material. Acta Pathol Microbiol Scand [A] 1978;86:361-365. 9. Copenhagen Pancreatitis Study: An interim report from a prospective epidemiological multicenter study. Scand J Gastroenterol 1981;16:305-312. 10. Rodemann HP, Binder A, Burger A, et al: The underlying cellular mechanism of fibrosis. Kidney Int Suppl 1996;54:S32-S36. I I. Roberts AB, Heine UI, Flanders KC, et al: Transforming growth factors. Major role in regulation of extracellular matrix. Ann NYAcad Sci 1990;580:225-232. 12. DiMagno EP, Go VLM, Summerskill WJH: Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973;288:813-815. 13. Caletti G, Brocchi E, Agostini D, et al: Sensitivity of endoscopic retrograde pancreatography in chronic pancreatitis. Br J Surg 1982;69: 507-509. 14. Almela P, Aparisi L,Grau F, et al: Influence of alcohol consumption on the initial development of chronic pancreatitis. Rev Esp Enferm Dig 1997;89:741-746. 15. Detsky A, Mclaughlin J, Baker J: What is subjective global assessment of nutritional status? JPEN J Parenter Enteral Nutr 1987;11: 8-13. 16. Dickerson RN, Vehe KL, Mullen JL, et al: Resting energy expenditure in patients with pancreatitis. Crit Care Med 1991;19:4~90. 17. Trapnell JE: Chronic relapsing pancreatitis: A review of 64 cases. Br J Surg 1979;66:471-475. 18. Marks IN, Girdwood AH, Banks S, et al: The prognosis of alcoholinduced calcific pancreatitis. S Afr Med 11980;57:640-643. 19. Alexiewicz JM, Kumar D, Smorgorzewski M, et al: Polymorphonuclear leukocytes in noninsulin dependent diabetes mellitus: Abnormalities in metabolism and function. Ann Intern Med 1995; 123:919--924. 20. Keith RG: Effect of a low fat elemental diet on pancreatic secretion during pancreatitis. Surg Gynecol Obstet 1980;151:337-343. 21. Vidon N, Hecketsweiler P, Butel J, et al: Effect of continuous jejunal perfusion of elemental and complex nutritional solutions on pancreatic enzyme secretion in human subjects. Gut 1978;19: 194-198. 22. Shea JC, Bishop MD, Parker EM, et al: An enteral therapy containing medium chain triglycerides and hydrolyzed peptides reduces postprandial pain associated with chronic pancreatitis. Pancreatology 2003;3:36-40. 23. Braganza JM, Jeffrey IJM, Foster J, et al: Recalcitrant pancreatitis: Eventual control by antioxidants. Pancreas 1987;2:489-494. 24. Braganza JM,Thomas A, Robinson A:Antioxidants to treat chronic pancreatitis in childhood? Case report and possible implications for pathogenesis. Int J PancreatoI1988;3:209--216. 25. Uden S, Bilton D, Nathan L, et al: Antioxidant therapy for recurrent pancreatitis: Placebo-controlled trial. Aliment Pharmacol Ther 1990;4:357-371. 26. DeWaele B, Vierendeels T, Willems G: Vitamin status in patients with acute pancreatitis. Clin Nutr 1992;11:83-85.
27. Mathew P, Wyllie R, Van Lente F, et al: Antioxidants in hereditary pancreatitis. Am J GastroenteroI1996;91:1558-1562. 28. VanGossum A, Closset P, Noel E, et al: Deficiency in antioxidant factors in patients with alcohol-related chronic pancreatitis. Dig Dis Sci 1996;41:1225-1231. 29. Layer, P, Keller J: Lipase supplementation therapy standards, alternatives and perspectives. Pancreas 2003;26:1-7. 30. Layer P, Go VL, DiMagno EP: Fate of pancreatic enzymes during small intestinal aboral transit in humans. Am J Physiol 1986;251: G475-G480. 31. Taylor CJ: Colonic strictures in cystic fibrosis. Lancet 1994;343: 615-616. 32. Suzuki A, Mizumoto A, Rerknimitr R, et al: Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption in pancreatic-insufficient dogs. Gastroenterology 1999;116:431-437. 33. Suzuki A, Mizumoto A, Sarr MG, et al: Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: A new therapy of steatorrhea? Gastroenterology 1997;112:2048-2055. 34. Raimondo M, DiMagno EP: Lipolytic activity of bacterial lipase survives better than that of porcine lipase in human gastric and duodenal content. Gastroenterology 1994;107:231-235. 35. Ebbehoj N, Borly L, Bulow J, et al: Pancreatic tissue pressure in chronic pancreatitis. Relation to pain, morphology and function. Scand J Gastroenterol 1990;25:1046-1051. 36. Isaksson G, Ishe I: Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Dig Dis Sci 1983;28:97-102. 37. Ramo DJ, Puolakkainen PA, Seppala K, et al: Self administration of enzyme substitution in the treatment of exocrine pancreatic insufficiency. Scand J Gastroenterol 1989;24:668-692. 38. SiaffJ, Jacobson D, Tillman CR, et al: Protease-specific suppression of pancreatic exocrine secretion. Gastroenterology 1984;87:44-52. 39. Halgreen H, Pedersen NT, Worning H: Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol 1986;21:104-108. 40. Mossner J, Secknus R, Meyer J, et al: Treatment of pain with pancreatic extracts in chronic pancreatitis: Results of a prospectivecontrolled multicenter trial. Digestion 1992;53:54-66. 41. Brown A, Hughes M,Tenner S, Banks PA: Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis. A meta-analysis. Am J Gastroenterol 1997;92:2032-2035. 42. Pap A, Nauss LA,DiMagno EP: Is percutaneous celiac plexus block associated with pain relief in chronic pancreatitis? A comparison among analgesic, alcohol and steroid PCPB. Pancreas 1990;5: 725-729. 43. Vitas GJ, Sarr MG: Selected management of pancreatic pseudocysts: Operative versus expectant management. Surgery 1992;111: 123-130. 44. Scolapio JS, Picco M,Tarrosa V: Enteral versus parenteral nutrition: The patient's perspective. JPEN J Parenter Enteral Nutr 2002;26: 248-250. 45. Scolapio JS, Fleming CR, Kelly D:Survival of home parenteral nutrition patients: Twenty-years experience at the Mayo Clinic. Mayo Clinic Proc 1999;74:217-222. 46. GulloL, Pezzilli R, De Giorgio R: Effect of octreotide on pain in patients with chronic pancreatitis. Dig Surg 1996;13:465-468. 47. A.S.P.E.N. Board of Directors and Clinical Guidelines Task Force: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002;26 (l suppl):68SA-70SA.
Short Bowel Syndrome Clarivet Torres, MD Jon A. Vanderhoof, MD
CHAPTER OUTLINE Introduction Anatomic Development of the Normal Bowel Etiology Nutrient Effects and Intestinal Adaptation Role of Parenteral Nutrition Role of Enteral Nutrition Morphologic Changes and Pathophysiologic Abnormal ities Factors Responsible for Morphologic and Functional Changes Clinical Management Initial Phase Later Phases Complications Surgical Management Conclusion
INTRODUCTION Short bowel syndrome is a clinical condition characterized by a lossof intestinal length or competence, resulting in a malabsorptionof nutrients, fluids, and/or electrolytes. Regardless of many attempts to describe thissyndrome on the basis of the intestinal length, there appears to be no minimum small bowel length to define short bowel syndrome. The essential defect is the lack of adequate mucosal surface to achieve enteral nutrition autonomy.v" Wilmore in 19724 reviewed the clinical experience with extensive intestinal resection in the neonatal period. He concluded that survival with enteral nutrition is possible in newbom infants with a minimumsmall bowel length of 40 cm and no ileocecal valveor 15ern of small bowel and an intactvalve." Otherstudiessuggestedthat ifinfants have at least 10to 20 ern of small bowel (even without an ileocecal valve), they can be weaned from parenteral nutritional support.v" The spectrum of short bowel syndrome variesand can be limited to an ileal/colon resection (most
common) versusextensivesmall bowel and colonic resections leading to high jejunostomyor jejunocolonic anastomosis. The resected small bowel begins to adapt almost immediately. The length of the bowel and other factors such as innervation, hormonal effects, and bacteria present in the bowel will affect adaptation.
ANATOMIC DEVELOPMENT OF THE NORMAL BOWEL The small intestine is derived from the embryonic midgut, which begins rapid growth in length after the fifth week of gestation. The intestinal lengthening exceeds the rate of growth of the embryonic body; therefore, it grows outside the abdomen until the 10th week. 7 Failure of the midgut to return to the abdominal cavity before birth results in either an omphalocele or a gastroschisis, depending on whether the amniotic sac is intact. Omphalocele occurs when the abdominal contents herniate through the umbilical ring, often into an intact sac, whereas gastroschisis is present when the herniation is lateral to the ring. The herniation is usually into the right of the umbilicus, and there is never a peritoneal sac. In the normal process of returning to the abdominal cavity, the midgut rotates and becomes fixed to the posterior abdominal wall. If either of these two events does not occur normally, a midgut volvulus may develop and the entire midgut may be IOSt.Bo 9 The average length of the small bowel in the newborn infant ranges from 200 to 300 ern.'? Touloukian and Smith measured the intestine of stillborn and newborn infants from 19 to 40 weeks' gestation. They found that the average length of small bowel between 19 and 27 weeks' gestation was 114 ern. This length was found to be more than double in infants of more than 35 weeks' gestation (average of 248 em), lOa
ETIOLOGY The specific causes of short gut syndrome have changed over the years. The etiology differs in the adult and pediatric population. In adults in the late 1800s and early 451
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1900s, strangulated hernias were the most common cause of massive small bowel resection.'! By 1970, infarction of the small bowel due to mesenteric vascular disease was the primary etiology." In adult patients the causes of short bowel syndrome can be grouped in two general categories: (1) impairment of the blood supply to the bowel causing ischemic necrosis or (2) an inflammatory response in the intestine. Today, Crohn disease is one of the most common causes of short gut syndrome, followed by mesenteric thrombosis, radiation enteritis, volvulus, trauma, and polyposis.P In the pediatric population, one of the earlier reports from the 1970s showed that the most common causes of short bowel syndrome were midgut volvulus or atresias." The etiology in this age group is different, depending on whether patients begin with normal gastrointestinal (GI) anatomy or not." Nowadays, necrotizing enterocolitis accounts for the majority of occurrences of short bowel syndrome in the first group of patients with normal GI anatomy, especially premature infants.i-" Although the etiology of necrotizing enterocolitis is unknown, the immature bowel appears to be susceptible because of a reduced level of secretory immunoglobulin A, fewer gastric hydrogen ions and proteolytic enzymes, decreased GI motility and increased permeability of the epithelial barrier." The area most commonly involved in necrotizing enterocolitis is the distal ileum. Meconium ileus or plugging is another cause that may result in intestinal necrosis due to mechanical distention of the bowel. Causes of short bowel syndrome resulting from congenital anomalies include atresias (isolated or multiples), gastroschisis, and the presence of a shortened small bowel at birth. Gastroschisis may cause a shortened small bowel either congenitally or as a result of resection for ischemia or bowel injury." Functional disorders in which the actual bowel length is normal but the motility and the ability to tolerate enteral nutrition are impaired include long-segment aganglionosis and idiopathic intestinal pseudo-obstruction syndrome. Later in life, Crohn disease, volvulus, and radiation enteritis caused by radiation therapy for neoplastic disease may result in short bowel syndrome.
NUTRIENT EFFECTS AND INTESTINAL ADAPTATION Intestinal adaptation can be defined as a progressive recovery from intestinal insufficiency or failure that follows a loss of intestinal length. After intestinal resection, the adaptive process begins within 12 to 24 hours and may reach a plateau at a certain time. Therapies that are used in an attempt to improve intestinal adaptation could either facilitate a higher plateau phase or reduce the time period until the plateau is reached. 17 Interrelated systems, morphologic changes of the bowel, biochemical/hormonal changes, and neural systems appear to be involved in the intestinal adaptation.
ROLE OF PARENTERAL NUTRITION In the late 1960s, the use of intravenous nutrition allowed patients with extensive resection of the small bowel to gain weight and support the body hydration needs while the residual bowel segment underwent adaptation.t-" Many interactions between total parenteral nutrition (TPN) and bowel adaptation must be considered during patient rehabilitation: (1) The use of intravenous nutrition without enteral feedings has been linked with atrophy or hypoplasia of the intestinal mucosa in normal or resected animals or humans. 19--22 (2) If parenteral nutrition is provided with enteral feedings, bowel adaptation is enhanced compared with that in animals receiving no TPN.23 Parenteral nutrition maintains a normal nutritional state that favors intestinal growth. Finally, (3) Byrne and colleagues.f studying factors that enhance adaptation, found that the longer patients received TPN, the lower the probability of their being weaned from TPN to be supported by enteral feedings alone. Patients receiving TPN are at risk of developing multiple complications. These complications include catheterassociated infection, metabolic complications, anemia, hepatic dysfunction, demineralization of bone, rickets, and progressive renal insufficiency.P-" Because of the fact that parenteral nutrition can be used to maintain patients with short bowel syndrome, but not cure it, several approaches have been proposed as a solution. Research has focused on optimizing intestinal function through dietary, pharmacologic, and surgical interventions. Intestinal transplantation has become part of these solutions, but it still is associated with a high incidence of immunologic difficulties and complications.
ROLE OF ENTERAL NUTRITION
Morphologic Changes and Pathophysiologic Abnormalities Intestinal epithelium is one of the most metabolically active tissues in the body. Beginning as immature crypt cells, enterocytes differentiate and migrate up the crypt villus axis over a period of 2 to 4 days, eventually to be removed by apoptosis." After a mucosal injury, malnutrition, or loss of absorptive area, enterocytes demonstrate accelerated growth and changes in the nutrient transport activity by a process termed adaptation. 29 Adaptation is characterized by an increase in the absorptive surface area of the bowel and/or enhanced nutrient digestive and transport capability by individual cells. On a cellular level, microvilli increase in height and density to augment the absorptive surface of individual enterocytes. Epithelial cells may proliferate more rapidly, resulting in enhanced villus height and crypt depth as well as incremented bowel length and diameter. There are alterations in the rates of crypt cell regeneration and mature enterocyte apoptosis. The cellular transport also changes
SECTION V • Disease Specific
with the formation of de novo transporter synthesis and increased activation of the digestive enzymes and transporters on the brush border membrane.Pr" During intestinal adaptation, the hyperplastic response is greater in the distal small bowel after proximal resection, compared with the proximal bowel after ileal resection. 3D-32 Adaptive response of the jejunum after ileal resection is less notable and variable." Hyperplasia of the colon also occurs after both jejunal and ileal resection,34.:l5 and finally ileal hyperplasia can occur after colectomy.v-" The intrinsic characteristic of the remaining intestine after bowel resection is crucial in determining the functional ability of the bowel to adapt. Motility of the bowel permits nutrients to remain in contact with the intestinal cell and facilitates absorption. Chyme passes through the upper portion of the small intestine in less than one third of the time it takes to pass through the distal portion of the bowel. The ileum notably slows the transit time-an effect called "ileal brake." The motility of the gastrointestinal tract is slowest in the colon." Fluid, electrolytes, and nutrient absorption vary throughout the small and large bowel. In normal adults the intestine is presented with approximately 2 L of ingested fluid and approximately 7 L of secretions from the mucosa of the gastrointestinal tract and associated glands. About 98% of this fluid is reabsorbed (61% by the jejunum, 22% by the ileum, and 15% by the colon) with a daily fluid loss of approximately 200 mL in the stool. 39-4 1 The jejunum is characterized by long villi and large absorptive area. The epithelium is more porous with a relatively large tight junction allowing free and rapid flux of fluids and electrolytes from the vascular to the intraluminal space. In the jejunum, sodium absorption takes place against a small concentration gradient. Absorption is influenced by water movement and stimulated by the presence of glucose, galactose, some amino acids, and to a lesser extent by bicarbonate. In contrast, the ileum is characterized by shorter villi, more lymphoid tissue, less absorptive capacity, and a tighter epithelium. Sodium absorption in the ileum can take place against an electrochemical gradient, is not stimulated by glucose, and is less affected by water flow. In the colon, sodium absorption occurs via sodium channels and takes place even against a high electrochemical gradient. 14,42,43 Therefore, jejunal resection results in less diarrhea because the ileum and the colon absorb the fluid and electrolyte loads. Nutrient absorption is an efficient process. For the most part, the digestion and absorption of fats, proteins, and carbohydrates are accomplished in the first 100 ern of jejunum.iv" Calcium, folate, iron, magnesium, and phosphorus are absorbed in the duodenum and in the proximal jejunum. Vitamin 8 12 (bound to intrinsic factor secreted by the stomach) and bile acids are exclusively absorbed in the distal ileum. The ileum can replace the absorptive capacity of the jejunum through adaptation. However, the jejunum cannot adapt the ileal functions.46-48 In reality, the entire jejunum can be resected without causing permanent malnutrition."
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Removal of the ileocecal valve allows bacteria from the colon to migrate upward into the small bowel, causing bacterial overgrowth. This bacterial invasion can deconjugate any remaining bile salts and worsen steatorrhea.50-52 With the preservation of the ileocecal valve, it would be reasonable to expect that absorption of fluid or nutrients would improve by delaying the transit time of the intestinal contents. This concept has not been supported by experimental evidence. Fich and colleagues'" showed that removal of the valve, while leaving the small bowel intact, does not alter intestinal transit because the valve plays a minor role in controlling intestinal transit. Peptides YY and enteroglucagon are produced by the ileal mucosa; they slow bowel motility and reduce gastric emptying. They are also released when malabsorbed fat reaches the i1eum.47,54 Trophic gastrointestinal hormones such as neurotensin, epidermal growth factor, and insulin-like growth factor (IGF-l) are produced by the ileal mucosa; therefore, ileal resection may decrease the potential for adaptation induced by these hormones.55 With ileal resection, hypergastrinemia is often observed due to inhibition of the normal negative feedback for stopping gastric secretion.
Factors Responsible for Morphologic and Functional Changes Luminal Nutrients and Pancreatobiliary Secretions Although the exact mechanism by which intraluminal nutrients promote adaptation is unknown, it has been suggested that certain preferred substrates may have a direct positive effect on the growth of epithelial cells. Nutrients may stimulate bile and pancreatic secretions that could have a direct effect on the mucosa. 56,57 Nutrients could also have an indirect action through the stimulation and the release of enteric hormones with interconnected effects on intestinal secretion, motility, or growth. Regardless of the mechanism, the importance of enteral nutrition in the adaptation of the small intestine after resection has been confirmed by many studies. 19-22.58 Aggressive luminal feedings during the early adaptive phase of the short bowel syndrome increases the probability of enteral autonomy in patients with relatively short segments of small bowel who might otherwise be dependent on parenteral nutrition.P The optimal diet for patients with a short bowel remains somewhat controversial. A predigested elemental diet is commonly used in the pediatric population. This is based on the idea that an elemental diet requires less digestion and is absorbed over a shorter length of bowel." Continuous feeding is better tolerated in many aspects, reduces emesis, and permits a greater percentage of total nutritional requirements to be delivered by the enteral route. 2,14.47,60 On the other hand, several studies in adults and animals suggested that elemental diets have no beneficial effect on adaptanon.v"
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39 • Short Bowel Syndrome
Proteins Different amino acids have been implicated as factors in intestinal adaptation.' Arginine is an amino acid that plays an important role in the synthesis of urea and protein and is a precursor to polyamines and nitric oxide. Polyamines are organic cations essential for many functions within eukaryotic cells, including growth and differentiation/" Based on the observation that small bowel adaptation is accompanied by increased concentrations of intracellular polyamines, putrescine, spermidine, and spermine are thought to take part in modulating normal and adaptive mucosal growth. 66,67 Blocking of polyamine synthesis results in inhibition of the adaptive response. 66,67 Polyamines have a potential role in modulating apoptosis and altering malignant growth. Future studies may demonstrate therapeutic benefits of polyamines in manipulating the growth of regenerating enterocytes during gut adaptation. The role of nitric oxide in small bowel adaptation is uncertain. The incidence of sepsis and hepatic failure in patients with short bowel syndrome has been associated with bacterial translocation.S'P ln animal models of sepsis and bowel ischemia, nitric oxide plays a role in the maintenance of the intestinal barrier functlon.P'" Welters and colleagues" demonstrate that massive small bowel resection in rats results in increased intestinal permeability. They also found that parenteral arginine supplementation in rats after intestinal resection resulted in a remarkable reduction of intestinal permeability.P With this observation, they suggested that supplementation of arginine in the TPN of patients with short bowel may reduce the incidence of sepsis and hepatic failure. However, the same group found that parenteral arginine supplementation impairs the adaptation process instead of increasing adaptation.P Glutamine, a neutral gluconeogenic amino acid, is the most abundant free amino acid found in the body.74,75 It is a major fuel source for both enterocytes and colonocytes.t-" Glutamine plays an important role in the synthesis of nucleic acids and the proliferation of cells." Glutamine has been implicated in the adaptive response after bowel resection. In animals, the infusion of glutaminase causes a notable reduction in the blood concentration of glutamine and is associated with diarrhea, villous atrophy, and mucosal ulcerations." Parenteral nutrition without glutamine, in animals, results in gut atrophy." which is mitigated by the addition of glutamine in the TPN.8! The addition of glutamine to standard TPN in critically ill patients unable to take enteral nutrition prevents TPN-induced gut permeability.f There are conflicting reports regarding the benefit of oral glutamine. Vagi and colleagues" declared that an elemental diet enriched with glutamine enhances differentiation and proliferation of the residual mucosa in the jejunum. On the other hand, Vanderhoof and co-workers'" were unable to demonstrate a trophic effect with the addition of 5% glutamine to a chow diet after intestinal resection in rats. They thought that the excessive ammonia generated by the supplemented glutamine might be the cause of this negative effect. The same group fed rats with an elemental diet supplemented with glutamine
and again found no enhancing effect on intestinal adaptation." Furthermore, other recent reports of Wiren and associates'<" could not demonstrate a stimulating effect in rats with enteral nutrition supplemented with glutamine. Scolapio and colleagues.f in a placebo controlled study, evaluated the effects of oral glutamine in a patient with short bowel syndrome. They concluded that oral glutamine is not useful for enhancing intestinal adaptation and decreasing TPN requirements.
Triglycerides, Fatty Acids, and Fiber Studies in rats have shown that long-ehain triglycerides are a very strong stimulus of adaptation and are more efficient than protein and polysaccharides.Pf" A highly unsaturated fat source was more effective in increasing mucosal weight, DNA content, and bowel protein content after bowel resection than a diet of less unsaturated fats in an animal model." Free fatty acids appear to be as effective as long-ehain triglycerides in promoting intestinal adaptation.P Medium-ehain triglycerides, which do not require digestion by pancreatic enzymes and are often used clinically to provide fat calories, do not promote the same degree of mucosal adaptation as longchain triglycerides.f Supplementation of enteral nutrition containing the polysaccharides pectin or soy have showed improvement in the adaptive response in rats after extensive small bowel resection. 95,96 A possible mechanism of these observations is an increase in transit time (i.e., prolonged transit). As a result, the contact of the intestinal mucosa with luminal nutrients is augmented, which is thought to increase pancreatic secretion, enteroglucagon release, and gut blood flow." Water-soluble fiber pectin has been shown to induce an antidiarrheal effect in healthy subjects. 98 Fermentable soluble fibers such as pectin may offer additional benefit in the treatment of patients with short bowel syndrome and an intact colon. Anaerobic bacteria of the colon metabolize unabsorbed pectins and carbohydrates to form short-ehain fatty acids. These short-ehain fatty acids are rapidly absorbed by the colonic mucosa, used for energy, and may have trophic effects as well. 99 The latter may involve glucagon-like peptide-2 (GLP-2).
Hormones and Growth Factors The role of specific hormones and peptide growth factors in intestinal adaptation is an area of intense investigation. The presence of a systemic growth factor was supported by the findings of hyperplastic mucosa in an unoperated animal that was in parabiosis with an animal subject to partial enterectorny.l'"
Enteric Hormones Gastrin is released by the presence of gastric distention and protein in the stomach. The trophic action for this hormone is restricted primarily to the parietal cells of the stomach and the duodenum and is probably not a major factor in stimulating intestinal adaptation.P'r'?"
SECTION V • Disease Specific
Pancreatic biliary secretions have shown a hyperplastic response in the intestinal mucosa in both normal animals and animals after intestinal resection.Pv'?' Pancreatic secretions are stimulated by cholecystokinin and secretin. Studies have generated controversies about their role in adaptation. 105,I06 It is possible that the effects of secretin and cholecystokinin in intestinal adaptation are related to the stimulatory effect that these hormones have on pancreatic secretions and other hormones such as enteroglucagon. Enteroglucagon has been implicated in intestinal adaptation in different situations. Tumors producing enteroglucagon are associated with intestinal mucosa hyperplasia.F'J'" Enteroglucagon levels tend to be increased after intestinal resection or jejuno-ileal bypass. 109,110 Enteroglucagon was so-named because it is structurally similar to glucagon. Later it was found that the peptides responsible for the glucagon-like immunoreactivity initially described were glicentin and oxyntomodulin.l'U" but the intestinotrophic mediator has been demonstrated to be GLP-2 in rodents. 113-115 In 1996, Drucker and colleagues'P first demonstrated the trophic effects of GLP-2 on the intestine in an animal model. Parenteral GLP-2 induces crypt cell proliferation and decreases both intestinal motility and enterocyte apoptosis in mice with short bowel syndrorne.!" GLP-2 has also been established as a growth factor for colonic epithelium in unresected animals.!" GLP-2 decreases gastric ernptying.!" increases intestinal transit time, and inhibits sham feeding-induced gastric acid secretion. 119 Intestinal growth adaptation correlates with GLP-2 levels. 120 Jeppesen and co-workers!" reported impaired meal stimulated GLP-2 response in ileal resected short bowel patents without colon. They also reported elevated plasma GLP-l and GLP-2 concentration in patients with an ileal resected short bowel and a preserved colon.l" This observation may explain some of the beneficial effects of the colon on intestinal adaptation in the patients with an ileal resected short bowel. It also raises the possibility of using GLP-2 as a new therapeutic strategy to increase jejunal adaptation in patients with a short bowel and a jejunostomy.
Exogenous Hormones and Growth Factors The growth factors that have received major attention as enhancers of intestinal adaptation after extensive resection are epidermal growth factors (EGFs), growth hormone, and insulin-like growth factors (IGFs). EGFis a polypeptide present universally in bodily fluids such as saliva from submandibular glands (probably the largest contributor to gastric levels), secretions from intestinal Brunner glands, pancreaticobiliary secretions, and breast milk.!" EGF regulates the proliferation and differentiation of an extensive variety of cell types, including enterocytes. When EGF is overexpressed in transgenic mice with short bowel, intestinal adaptation is enhanced in terms of crypt depth, villous height, and total body weight. 124 Mice with a defective EGF receptor (EGFr) reveal a decreased adaptive response.!" EGF
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helps maintain normal mucosal integrity, acting directly on enterocytes, stimulating proliferation and migration, and also stimulates repair when its basolateral receptors are exposed in injured epitheliurn.P" EGF increases sodium-glucose cotransport in the jejunum more than in the ileum, despite a relatively uniform distribution of EGFr. 127This might be due to the high permeability of the jejunal tight junctions, making the EGFr more accessible to luminal EGF.127 Another possibility is that EGF loses potency due to partial digestion and/or dilution as it moves through the GI tract. Although EGFrdistribution is uniform through the intestinal tract, EGFr is enriched in mouse ileum after 50% small bowel resection. 128 EGFalso induces the transport and synthesis of polyamines.!" IGF-l and IGF-2 are also known, respectively, as somatomedin C and somatomedin A. Along with insulin and relaxin, they comprise the insulin family of polypeptide growth factors. Their functions include mediation of growth hormone action, stimulation of insulin activity, and involvement in growth and developrnent.F' IGF-l is trophic for the small intestine and binds to a receptor that is found on gut epithelial cells, and it is especially abundant in the small intestinal crypt region, suggesting that crypt cells may be the primary targets for IGF-l actlon.P' There are conflicting reports in animal studies about IGF-l and its effect on adaptation, as measured by mucosa weight and DNA content, in ileum or jejunum after extensive intestinal resection.130.131 IGF-2 may act as an autocrine or paracrine regulator of epithelial growth. After small bowel resection, intestinal IGF-2 notably increases without corresponding changes in portal venous levels,132 probably because its receptor is more concentrated in rapidly proliferating crypt cells. Human growth hormone (hGH) is secreted primarily by the anterior pituitary. Growth hormone receptors (GHr) are distributed homogeneously along both the jejunoileal axis and crypt villous axiS.133 There is evidence that the effects of hGH can be mediated in vivo through IGF-l and _2. 134 Levels of both IGF-! and -2 are elevated in damaged or inflamed small bowel and in response to hGH administration.P The effect of growth hormone includes the stimulation of intestinal growth and differentiation, as well as promoting water, ion, and amino acid absorption.!" Parenteral administration of the growth hormone increases glutamine and leucine absorption after extensive intestinal resection in rabbits. 137 Treatment of hGH also increases Nat-dependent glucose transport. 136 Many other growth factors might intervene in intestinal adaptation. These include the mesenchymederived hepatocyte growth factor, peptide VY, fibroblastderived keratinocyte growth factor, interleukin-ll and other cytokmes." Recombinant keratinocyte growth factor augments morphologic adaptation in experimental models of short bowel syndrorne.P' Peptide VY reduces GI motility and increases nutrient contact with the intestinal epithelium. Recombinant interleukin-ll prevents villous blunting and bowel shortening in a rat with defunctionalized ileum and improves glycine and galactose absorption in rats after massive small bowel
resection."
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39 • Short
Bowel Syndrome
Adaptation is a complex process, which involves multiple elements such as nutrients, transporters, hormones, and growth factors. The essential value of understanding how all of these factors intervene in intestinal adaptation is in the clinical application of this knowledge to a patient with short bowel syndrome. Despite huge advances in the understanding of the cellular and molecular mechanisms of adaptation after massive small bowel resection, there are not enough answers to apply clinically in these patients. Further studies need to be conducted before our knowledge of intestinal adaptation can be fully used in the treatment of short bowel syndrome.
CLINICAL MANAGEMENT Patients with short bowel syndrome encounter multiple acute and chronic problems. The most common problems are diarrhea, fluid and electrolyte abnormalities, and/or nutrient losses. Multiple therapies must be used to provide the best management to allow intestinal adaptation and for eventual weaning of patients from parenteral nutrition. The care of these patients is complex and ideally requires an interdisciplinary management team including a gastroenterologist, surgeon, dietitian, and nutrition support nurse and pharmacist.
Initial Phase The immediate postoperative state is characterized by a period of intestinal ileus (2 to 5 days) with high gastric output, followed by profuse diarrhea and massive electrolyte loss. An important step in the management of short bowel syndrome is the replacement of fluid losses and the control of diarrhea. At this time, it is crucial to strictly monitor fluid and electrolyte losses. Patients need to be given maintenance fluids plus appropriate replacement solutions. If the patient needs continued ventilator support postoperatively, the amount of maintenance fluids should be reduced by 10% to 20%. Gastric and ostomy losses need to be replaced milliliter per milliliter with a saline solution, according to the blood electrolyte concentrations and/or the electrolyte concentrations of the secreted fluids. Gastric secretions and serum gastrin levels are significantly elevated in patients with short bowel syndrorne.v'" Treatment with histamine H2 antagonists or proton pump inhibitors intravenously may be given in the immediate postoperative state. Gastric hypersecretion tends to be transient, and this therapy can be discontinued at a later time; however, some patients may continue to have gastroesophageal reflux, and the development of peptic ulcers is not uncommon. After the first 24 to 48 postoperative hours, when the patient's condition is more stable, parenteral nutrition should be instituted as a part of the maintenance fluid while replacement fluids are continued in a separate solution. It is important to have a prior evaluation of the patient's nutritional status before parenteral nutrition is started. Parenteral nutrition should replace nutrient and
energy stores depleted during the period of stress before surgery and transient postoperative ileus phase." Parenteral nutrition should be carefully monitored with a continuous nutrition assessment, both clinically and via laboratory parameters, to ensure adequate nutritional rehabilitation. When the ileus disappears and the fluid and electrolyte losses have diminished, enteral feedings should be instituted, ideally by continuous tube feedings. Continuous enteral infusions have numerous advantages over bolus feedings, permitting a greater percentage of total nutritional requirements to be delivered by the enteral route and reducing the tendency for emesis. 14,47 A reduction in thermal energy losses has also been found in normal patients fed continuously compared with patients fed with boluses.!" Use of continuous tube feeding infusions allows the carrier proteins to be constantly saturated, with maximization of the overall functional workload of the intestine. Continuous enteral nutrition should start very slowly and be advanced according to tolerance. Even a minimal amount of 1 mUhr may be beneficial for a newborn baby in the attempt to achieve intestinal adaptation." A marked increase in stool loss by more than 50% or stool output greater than 40 to 50 mUkg/day is an indication to slow the advancement of tube feedings. In patients with an intact large bowel, a decrease in stool pH to less than 5.5 is indicative of carbohydrate malabsorption and osmotic diarrhea. It is important to maintain good hydration in the process of advancing enteral fluids because mild dehydration makes the infant or pediatric patient more prone to emesis and decreased absorption. Many patients with short bowel do not have ostomies; thus, accurate measurement of stool output and adequate replacement of fluid loss is difficult. In these patients, it may be necessary to calculate amounts of fluids on the higher side for pediatric patients, at times delivering 140 to 160 mUkg/day (in total, from enteral and intravenous fluids). Higher amount of fluids (160 to 190 mUkg/day of intravenous plus enteral fluids) should be calculated for neonates and premature infants because of the higher maintenance fluid needs. Patients with a short bowel in general tolerate reasonable amounts of fluids because of the constant fluid losses through the gut, unless they have other dysfunctional systems. Patients with renal dysfunction, respiratory problems, or central nervous system involvement might require more fluid restriction and should be evaluated individually. In the initial phase, hydration is better obtained by continuous, 24-hour parenteral nutrition. Infants (particularly those younger than 4 months of age) usually do not tolerate interruptions of their parenteral nutrition infusions longer than 4 hours daily. The route of enteral nutrition should be selected according to the needs. Nasogastric tube feedings are usually a good temporary option. Nasoduodenal or nasojejunal feeding is an option when delayed gastric or gastroesophageal reflux is present. Frequent dislodgement of the tube and difficulty replacing it make transpyloric feeding less attractive. 141 Children and adults with short bowel syndrome often
SECTION V • Disease Specific
need long-term enteral feedings and benefit from a gastrostomy tube placement. A gastrostomy tube can be converted to a gastrojejunal tube, if necessary. Pediatric patients with a short bowel are initially given elemental or hydrolysate formulas." Elemental (amino acid) formulas are well balanced and are formulated to deliver all necessary nutrients for infants and older children. Protein hydrolysate formulas may also be tolerated, because most protein is absorbed in the formation of di- and tripeptides. Elemental formulas are beneficial in reducing the risk of secondary protein intolerance." which may occur more commonly in children with short bowel syndrome due to conditions that predispose them to enhanced intestinal permeability. Carbohydrates in elemental and hydrolyzed formulas are usually from corn syrup, maltodextrins, hydrolyzed starch, and disacchari des such as sucrose. Although long-chain fatty acids are slightly less well absorbed than medium-chain fatty acids, they are a very strong stimulus of adaptation and are more efficient and calorically dense than protein and carbohydrates'"?' and should constitute a significant percentage of the total enteral caloric intake. In the initial phase, bolus oral feedings in verysmall volumes of the prescribed formula or oral electrolyte solutions are beneficial in stimulating normal development of oral feeding. Pacifier use in infants is not sufficient to meet these needs. Ten to 15 mL of formula two to three times a day might prevent feeding aversion in infants,"
Later Phases As enteral feedings are tolerated, parenteral nutrition should be weaned proportionally. Calculations of the caloric requirements for patients with a short bowel should include the Recommended Daily Allowance for age multiplied by a factor of 1.2 to 1.5 to account for malabsorption. Parenteral nutrition infusion time can be progressively decreased during the day as the child gets older. Careful monitoring of glucose and hydration status throughout this time is important. After the total volume and/or the number of hours infused have been reduced, parenteral nutrition can be eliminated on 1 or 2 nights per week. Progressive advancement of days without parenteral nutrition should be done as the patient continues to tolerate enteral nutrition. This entire process is very gradual and may take months or years to complete. A small number of patients tolerate the necessary enteral feedings to maintain nutritional balance but still need extra fluids for the maintenance of good hydration and electrolyte status. In these patients extra intravenous fluids at night may be used to replace the fluids and electrolytes they need. This fluid/electrolyte deficit could be replaced using the gut. Normal saline or one-half-normal saline can be added to the patient's formula and the tube-feeding rate can be increased accordingly to meet the patient's fluid needs. In children, when growth is achieved, normal processes of eating should be introduced (including both chewing and swallowing) at the appropriate developmental times. Whereas solid food feedings in adults are traditionally initiated with
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high-carbohydrate foods, children with short bowel syndrome respond better with high-fat, high-protein foods. Meats are probably the best food group to start with because they provide less osmotic load to the small bowel and the fat provides an additional stimulant for intestinal adaptation." Simple carbohydrates tend to produce osomotic diarrhea in children with short bowel. At any stage and particularly at the late stage, monitoring of weight gain and growth is the most beneficial tool to evaluate nutritional status and nutrient absorption. At this time, efforts to identify malabsorbed nutrients in the stool are not helpful. It is important to ensure that the patient's weight gain is appropriate for his or her height and not excessive. As the enteral feeding becomes the primary nutritional supply, the child should be monitored more often for micronutrient deficiencies. Macronutrients such as fat, proteins, and carbohydrates are usually absorbed in adequate amounts. Micronutrients such as zinc, magnesium, and fat-soluble vitamins are often deficient in patients with short bowel syndrome patients. The serum zinc concentration is neither a sensitive nor a specific indicator of zinc deficiency. A reduced concentration of zinc in association with a low serum alkaline phosphatase level and/or a normal serum albumin suggests deficiency. Patients have difficulty absorbing fatsoluble vitamins because of the lack of bile salts and loss of absorptive surface. Therefore, they require large doses of vitamins A, D, and E to avoid deficits. Liquid preparations may be necessary, because tablets or capsules are usually excreted intact. Enteral feeding can also be supplemented with the specific deficient micronutrient, although use of magnesium supplements often results in osmotic diarrhea. In this case, frequent small doses or special magnesium preparations may be required.!" During later therapy, the use of many other dietary supplements may be attempted to enhance enteral tolerance. Soluble fiber can be useful for slowing transit time and increasing stool consistency. In addition, aerobic bacteria of the colon metabolize unabsorbed fiber (pectins) to short-ehain fatty acids. These short-ehain fatty acids are rapidly absorbed by the colonic mucosa and used for energy." The use of numerous other additives, such as glutamine and growth hormone, has been attempted with varying degrees of success. Ling and Irving'" reviewed the literature about the effectiveness of growth hormone, glutamine, and a high-earbohydrate, low-fatdiet on the enhancement of intestinal adaptation among patients with short bowel syndrome. They concluded that the benefit of human growth hormone alone, or together with glutamine, with or without dietary modification is marginal.
COMPLICATIONS Early diagnosis and management of complications that occur in children with short bowel syndrome represent an essential part of their care. Extensive bowel necrosis is a catastrophic event and is accompanied by multiple complications during the preoperative period. Acidosis and metabolic abnormalities are common due to the
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39 • Short Bowel Syndrome
massive fluid and electrolyte losses as well as the associated infections. Close monitoring of the fluid losses and electrolyte levels in the blood and the stools are key for adequate replacement. Surgical re-exploration is often necessary, particularly if marginal bowel has not been resected. This strategy is often used in pediatric patients to reduce the amount of intestinal resection. In the immediate postoperative period several problems can occur. Intraperitoneal infection with abscess formation is not uncommon and should be managed by surgical drainage followed by administration of appropriate antibiotics. Intestinal perforation and/or fistula may occur, and treatment should focus on making every effort to preserve all viable bowel. Ostomies may also be created initially, with later closure and more definite bowel reconstruction. Wound infections are also common in these patients and the subcutaneous portion of the abdominal incision can initially be left open, packed, and closed later." In the later phases, dehydration might occur more readily with viral gastroenteritis or environmental exposure to extreme heat. Constant small volumes of fluid intake, as well as avoidance of excessive heat, are also necessary to avoid hospitalization. Keeping extra intravenous solutions on hand for emergency situations may prevent rehospitalization." Watery diarrhea is one of the most common complications of short bowel syndrome, mostly due to the osmotic effect of the enteral formula and/or bacterial overgrowth. A change from bolus to continuous enteral feedings as well as dilution of the formula may be helpful in lessening the diarrhea. Decreasing the carbohydrate content and adding a long chain fatty acid in the formula may also be useful. Somatostatin and its analogue octreotide may lessen diarrhea by increasing the transit time, reducing salt and water excretion, and reducing gastric hypersecretion. Although these therapeutic agents are beneficial in the short term, they have not resulted in long-term benefits, and they may have some potential deleterious effects. They may exacerbate steatorrhea, because of impaired pancreatic exocrine function.lf Other potential adverse effects are the inhibition of intestinal regeneration, which may delay or inhibit intestinal adaptation, and the development of cholelithiasis due to delayed gallbladder emptying, decreased hepatic biliary secretion, and sphincter of Oddi dysfunction.l'
Loperamide has been shown to be safe in the pediatric age group. It prolongs transit time, reduces daily fecal volume, and diminishes loss of fluids and electrolytes. Loperamide also has been effective in reducing the volume of discharge from ileostomies. 150.151 This medication must be used carefully because it can exacerbate bacterial overgrowth. Central venous catheter-related infections are a major cause of morbidity and mortality in the United States. The incidence of central venous catheter-related infections in the pediatric population ranges from 3% to 60%, with rates of 1.7 to 2.4 infections per 1000 catheter-days, depending on the type of device, the age of the patient, and underlying disease. 152 Complications such as sepsis, endocarditis, septic thrombosis, tunnel infection, or metastasis seeding are not uncommon. Causes include intrinsic factors such as bacterial translocation, malnutrition, immune suppression, and extrinsic factors such as the lack of sterile technique or lack of knowledge." Adequate training in the care of central lines is important to prevent extrinsic factors. Yet, bacterial translocation from the gut is more difficult to identify. Small bowel bacterial overgrowth (SBBO) is a fairly common and treatable complication of pediatric short bowel syndrome. SBBO is defined as an excessive increase in the number of bacteria in the upper gastrointestinal tract, leading to the development of symptoms. The bacteria change from predominately oropharyngeal to colorectal species along the length of the intestinal tract.153 Most of the bacteria in the intestine are facultative organisms and have the role of deconjugating bile salts as well as producing some micronutrients, such as vitamin BI2 and folate. However, large numbers of bacteria in the intestine may deplete the bile salt pool and contribute to fat malabsorption. Toxins and metabolites produced by excessive number of bacteria can also cause mucosal inflammation and subtotal villous atrophy, which ultimately alter intestinal functions.47.IS4 Etiologic factors in the development of SBBO include anatomic abnormalities, intestinal dysmotility, prior abdominal surgical procedures, loss of the ileocecal valve, malnutrition of the host, and abnormalities of the immune system.154 Symptoms of SBBO result mainly from nutrient malabsorption. Pain, bloating, diarrhea, dyspepsia, and weight loss are the most common symptoms. Anemia may result from malabsorption, occult blood loss, and vitamin BI2 deficiency. 155 In addition, patients whose conditions had been stable with their enteral nutrition regimen may show failure to advance enteral feedings for a period of time. o-Lactic acidosis is a neurologic complication of SBBO with symptoms of ataxia, delirium, seizures and, eventually, coma. o-Lacticacidosis is a result of bacterial activity and carbohydrate overload to the colon resulting in accumulation of o-lactate in the blood. t-Lactic acidosis should be suspected whenever acidosis with an unexplained anion gap is seen." Systemic distribution of bacterial antigen-antibody complexes may cause rashes, arthritis. and nephritis. I 55 Colitis or ileitis may also occur due to SBBO. This may resemble Crohn disease, although a diffuse inflammatory picture is more comrnon.l'"
SECTION V • Disease Specific
The diagnosis of SBBO is difficult. Tests such as a breath hydrogen test, urine indicans, serum o-lactate level, and endoscopy with culture and colony count of the duodenal fluid may be helpful but results are not always accurate. The nature of the treatment depends on precipitating factors, bacterial species involved, and severity of symptoms. Treatment of SBBO most commonly involves rotating broad-spectrum oral antibiotics, which are often effective in reducing the number of bacteria. Those most often used are metronidazole (20 mg/kg/day), trimethoprim-sulfarnethoxazole (8 mg/kg/day), oral gentamicin (5 mg/kg/day), extended spectrum penicillins, and cephalosporins. When significant intestinal inflammation is present, anti-inflammatory therapy with sulfasalazine or corticosteroids may be used. ISS In older children, who often withhold large volumes of stool, regular toileting, and weekly flushing with polyethylene glycol solution via the enteral feeding tube may help." Normal gastric acid secretion decreases pathogenic bacterial proliferation and, if suppressed, may predispose patients to SBBO. Anatomic abnormalities, such as stricture, fistula, or diverticula, can often be corrected surgically. Probiotic therapy is one of the newest therapies for SBBO. Probiotics (Lactobacillus and Bifidobacterium) are live microorganisms that, when ingested, colonize the intestine, establish themselves as part of its flora, and are beneficial to human health by preventing or treating certain pathologic condittons.!" Several mechanisms of action have been identified with the use of probiotics: production of substances that prevent bacterial proliferation,158 competitive inhibition of bacterial adhesion, 159 competitive consumption of nutrients, modification of toxin receptors through enzymatic mechanisms, and stimulation of the immune system.t'" Lactobacillus species produce nutrients, mainly short-ehain fatty acids, and antimicrobial products such as pyroglutamate. They also remove potentially toxic substances from the intestine."! All of these factors lead to the observation that probiotic therapy in SBBO may be effective in reducing the use of antibiotic therapy and in controlling symptoms related to bacterial overgrowth. The term prebiotic refers to a nondigestible food ingredient that selectively targets the growth and/or activity of one or a limited number of bacteria in the colon and has the potential to improve host health. 162 Fructooligosaccharides, galactooligosaccharides, and inulin are used as prebiotics. The combination of probiotics and prebiotics is called synbiotic therapy and has been used to improve intestinal function and decrease bacterial overgrowth in short bowel syndrome. 162 TPN-associated liver disease is a major cause of death in children with short bowel syndrome. The incidence increases inversely in proportion to age. 163 The etiology appears to be multifactorial and is not well understood. Toxicity of amino acids in parenteral nutrition, competition of amino acids with bile acids for transport across the hepatic canalicular membranes, sepsis, free radical damage, bacterial translocation, production of toxins by unused bowel, absorption of endotoxin, toxicity of unknown substances in the parenteral solution, complete lack of oral feedings, and nonstimulation of
459
gastrointestinal hormones that normally control biliary secretions have all been proposed as possible mechanisms." Aggressive enteral feedings, avoidance of infections and catheter-related sepsis, and prevention of SBBO are all useful in decreasing or preventing TPN-associated liver disease. Hyperoxaluria, caused by increased absorption of oxalate by the colon, is associated with renal stone formation. Bile salts in the colon increase oxalate absorption. Treatment involves measures to decrease fat malabsorption and bind bile salts. Use of a low-oxalate diet and administration of citrate may help prevent stone formation. Low-oxalate diets exclude cocoa, peanut products, tea, coffee, wheat germ, rhubarb, beets, collards, spinach, tofu, and soybeans and restrict citrus drinks, tomatoes, and fruit.142
SURGICAL MANAGEMENT Although the primary management of short bowel syndrome is medical, there are many circumstances in which surgical interventions may offer great therapeutic benefits. The main indications for surgical intervention in short bowel syndrome are failure to progress in enteral feedings and life-threatening complications, such as TPNrelated liver disease and recurrent central line sepsis. Patients with a short bowel may develop high ostomy outputs, anastomotic strictures, and severe bowel dilatation. These patients regularly have problems with recurrent emesis, dysmotility, bacterial overgrowth, and severe diarrhea. Pro-adaptive surgery, such as stoma closure, stricturoplasty, enteroplasty, and tapering or lengthening procedures, may produce dramatic clinical improvement in patients with short bowel syndrome. The choice of operation is influenced by three principal factors: intestinal remnant length, intestinal function, and caliber of the intestinal remnant.' Unpublished preliminary experience of the Intestinal Rehabilitation Program at the Universityof Nebraska suggested that some patients with short bowel syndrome who had advanced TPN-associated liver disease may experience functional and biochemical liver recovery with the appropriate pro-adaptive surgery. This success appears to parallel autologous bowel salvage in many cases. This data imply that even patients with advanced conditions of liver dysfunction, including those with abnormal histologic findings, should be considered for these alternative therapies before intestinal transplantation is considered. With the advent of new immunosuppressive agents, combined liver and bowel transplants and isolated intestinal transplantation have become viable options for some patients with intestinal failure. However, the longterm success of these procedures is still unknown. Preliminary experience has suggested that 1- to 2-year survival after transplantation is about 75%, decreasing to 50% at 3 to 5 years.l'" Although morbidity and mortality rates remain significantly high, this method should be viewed as a therapeutic option for TPN-dependent patients with short bowel syndrome in whom management with standard therapy is failing.
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CONCLUSION Short bowel syndrome is a complex condition that requires a multidisciplinary approach. The length and function of the remaining bowel are determining factors in advancing enteral feedings and thus weaning patients from parenteral nutrition. Aggressive enteral therapies with maintenance of good nutrition and hydration by trained medical staff are important factors in long-term survival. Many controversial issues (method of enteral feeding, type of enteral formula, initiation of enteral/oral feeding, parenteral nutrition additives, and dietary supplements) exist regarding the management of the pediatric patient with short bowel syndrome. Current assessment of efficacy and outcomes of the different medical and surgical treatment options are limited by the small number of patients with short bowel syndrome in anyone center. There is a great need to join efforts between centers to focus on the care of these patients to standardize definitions of the levels of disease severity and establish consistent, beneficial treatment protocols. REFERENCES 1. Welters CFM, Dejong CHC,Deutz NEP,Heineman E: Intestinal adaptation in short bowel syndrome. Aust NZJ Surg 2002;72: 229-236. 2. Vanderhoof JA: Short bowel syndrome. In Walker WA, Durie PR, Hamilton JR, et at (eds): Pediatric Gastrointestinal Disease, 2nd ed. St Louis, Mosby, 1996, pp 830-840. 3. Barksdale EM, Standford A: The surgical management of short bowel syndrome. Curr Gastroenterol Rep 2002;4:229-237. 4. Wilmore DW: Factors correlating with a successful outcome following extensive intestinal resection in newborn infants. J Pediatr 1972;80:88-95. 5. Shanbhogue LK, Molenaar JC: Short bowel syndrome: Metabolic and surgical management. Br J Surg 1994;81:486-499. 6. Affourtit MJ, Tibboel D, Hart AE, et al: Bowel resection in the neonatal phase of life: Short-term and long-term consequences. Z Kinderchir 1989;44:144-147. 7. Gray SW, Skandalakis JE: Embryology for Surgeons: The Embryological Basis for the Treatment of Congenital Defects. Philadelphia, WB Saunders, 1972, pp 129-133. 8. Warner BW,Ziegler MM: Management of the short bowel syndrome in the pediatric population. Pediatr Surg 1993;40:1335-1350. 9. Taylor LA, Ross AJ III: Abdominal Masses. In Walker WA, Durie PR, Hamilton JR, et al (eds): Pediatric Gastrointestinal Disease, 2nd ed. St Louis, Mosby, 1996, p 228. 10. Wilmore OW: Factors correlating with a successful outcome following extensive intestinal resection in newborn infants. J Pediatr 1972;80:88-95. lOa.Touloukian RJ, Smith GJW: Normal intestinal length in preterm infants. J Pediatr Surg 1983;18:720-723. 11. Flint JM:The effect of extensive resections of small intestine. Johns Hopkins Hosp Bull 1912;23:127-144. 12. Sedgwick CE, Goodman AA: Short bowel syndrome. Surg Clin North Am 1971;51:675-680. 13. Westergaard H, Spady DK: Short bowel syndrome. In Sieisenger MH, Fordtran JS (eds): Gastrointestinal Diseases. Philadelphia, WB Saunders, 1992, pp 1249-1256. 14. Vanderhoof JA: Short bowel syndrome. In Walker WA, Watkins JB (ed): Nutrition in Pediatrics, 2nd ed. Hamilton, Ontario, Canada, BC Decker, 1996, pp 609-618. 15. Grosfeld JL, Rescorla FJ, West KW: Short bowel syndrome in infancy and childhood. Am J Surg 1986;151:41-46. 16. Neu J, Weiss MD: Necrotizing enterocolitis: Pathophysiology and prevention. JPENJ Parenter Enteral Nutr 1999;23(5 suppl):SI3-S17. 17. Jeppesen PB, Mortensen PB: Enhancing bowel adaptation in short bowel syndrome. Curr Gastroenterology Reports 2002;4:338-347.
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97. Booth IW: Enteral nutrition as primary therapy in short bowel syndrome. Gut 1994;35(suppl 1):S69-S72. 98. Dilorenzo C, Williams CM,Hajnal F, Valenzuela JE: Pectin delays gastric emptying and increases satiety in obese subjects. Gastroenterology 1988;95:1211-1215. 99. Rombeau JL, Kripke SA: Metabolic and intestinal effects of shortchain fatty acids. JPEN J Parenter Enteral Nutr 1990;14(suppl): 181-185. 100. Loran MR, Carbone JV: The humoral effect of intestinal resection on cellular proliferation and maturation in parabiotic rats. In Sullivan MF (ed): Gastrointestinal Radiation Injury. Amsterdam, Excerpta Medica, 1968, pp 127-139. 101. Lichtenberger L, Miller LR, Erwin DN, Johnson LR: Effect of pentagastrin on adult rat duodenal cells in culture. Gastroenterology 1973;65:242-251. 102. Sager GR, AI-Mukhtar MY, Ghatei MA, et al: The effect of altered luminal nutrition on cellular proliferation and plasma concentrations of enteroglucagon and gastrin after small bowel resection in the rat. Br J Surg 1982;69:14-18. 103. Weser E, Heller R, Tawil T: Stimulation of mucosal growth in rat ileum by bile and pancreatic secretions after jejunal resection. Gastroenterology 1977;73:524-529. 104. Altmann CG: Influence of bile and pancreatic secretions on the size of the intestinal villi in the rat. Am J Anat 1971;132:167-178. 105. Weser E, Bell D, Tawil T: Effects of octapeptide-cholecystokinin, secretin and glucagon on intestinal mucosal growth in parenterally nourished rats. Dig Dis Sci 1981;26:409-416. 106. Dowling RH: Small bowel adaptation and its regulations. Scand J GastroenteroI1982;74(suppl):53-74. 107. Gleeson MH, Bloom SR, Polak 1M, et al: Endocrine tumor in kidney affecting small bowel structure, motility, and absorptive function. Gut 1971;12:773-782. 108. Stevens FM, Flanagan FW, O'Gorman D, et al: Glucagonoma syndrome demonstrating giant duodenal villi. Gut 1984;25:784-791. 109. Kato M,Sasaki I, Naito H, et al: Influence of 50% proximal or distal small bowel resection on gut hormone release after test meal loading in dogs. Nippon Geka Gakkai Zasshi 1991;92:1461-1468. 110. Toda M,Sasaki I, Naito H, et al: Effect of ileo-jejunal transposition (lIT) on gastrointestinal hormones and intestinal structure in dogs. Nippon Geka Gakkai Zasshi 1989;90:1879-1889. Ill. Holst JJ: Evidence that glicentin contains the entire sequence of glucagon. Biochem J 1980;187:337-343. 112. Thim L, Moody AJ: The primary structure of porcine glicentine (proglucagon). Regul Pept 1981;2:139-150. 113. Drucker DJ, Erlich P, Asa SL, et al: Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci USA 1996;93:7911-7916. 114. Tsai CH, Hill M, Drucker DJ: Biological determinants of intestinotrophic properties of GLP-2 in vivo. Am J Physiol 1997; 272:G662-G668. 115. Tsai CH, Hill M, Asa DL, et al: Intestinal growth-promoting properties of glucagon-like peptide-2 in mice. AM J Physiol 1997;273: E77-E84. 116. Jeppesen PB, Hartmann B, Thulesen J, et al: Glucagon-like peptide-2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology 2001;120: 806-815. 117. Litvak DA, Hellmich MR, Evers BM, et al: Glucagon-like peptide-2 is a potent growth factor for small intestine and colon. J Gastrointest Surg 1998;2:146-150. 118. Wodjeman M, Wettergren A, Hartmann B, et al: Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs. Scand J GastroenteroI1998;33:828-832. 119. Wodjemann M, Wettergren A, Hartmann B, et al: Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2. J Clin Endocrinol Metab 1999;84: 2513-2517. 120. Thulesen J, Hartmann B, Kissow H, et a1: Intestinal growth adaptation and circulating levels of glucagon-like peptide 2 (GLP-2) following small bowel resection and jejunoileal transposition in rats. Dig Dis Sci 2001;46:379-388. 121. Jeppesen PB, Hartmann B, Hansen BS,et al: Impaired meal stimulated glucagon-like peptide 2 response in ileal resected short bowel patients with intestinal failure. Gut 1999;45:559-563.
122. Jeppesen PB, Hartmann B, Thulesen J, et al: Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon. Gut 2000;47:370-376. 123. Playford RJ, Macdonald CE, Johnson WS: Colostrum and milkderived peptide growth factors for the treatment of gastrointestinal disorders. Am J Clin Nutr 2000;72:5-14. 124. Erwin CR, Helmrath MA, Shin CE, et al: Intestinal overexpression of EGF in transgenic mice enhances adaptation after small bowel resection. Am J Physiol Gastrointest Liver Physiol 1999;40: G533-G540. 125. Helmrath MA, Erwin CR, Warner BW:A defective EGF-receptor in waved-2 mice attenuates intestinal adaptation. J Surg Res 1997; 69:76-80. 126. Carpenter G, Cohen S: Epidermal growth factor. Annu Rev Biochem 1979;48:193-216. 127. Uribe JM, Barrett KE: Nonmitogenic actions of growth factors-An integrated view of their role in intestinal physiology and pathophysiology. Gastroenterology 1997;113:255-268. 128. Helmrath MA, Shin CE, Erwin CR, et al: Epidermal growth factor up regulates the expression of its own intestinal receptor after small bowel resection. J Pediatr Surg 1998;33:229-233. 129. O'Dell SD, Day IN:Insulin-like growth II (IGF-I1). Int J Biochem Cell Bioi 1998;30:767-771. 130. Ziegler TR, Mantell MP, Chow JC, et al: Intestinal adaptation after extensive small bowel resection-Differential changes in growth and insulin-like growth factor system messenger ribonucleic acids in jejunum and ileum. Endocrinology 1998;139:3119-3126. 131. Gillingham MB, Dahly EM,Carey HV, et al: Differential jejunal and colonic adaptation due to resection and lGF-I in parenterally fed rats. Am J Physiol Gastrointest Liver Physiol 20oo;278:G700-G709. 132. Wiren M, Adrian TE, Amelo U, et al: An increase in mucosal insulin-like growth factor IIcontent in postresectional rat intestine suggests autocrine or paracrine growth stimulation. Scand J GastroenteroI1998;33:1080-1086. 133. Lobie PE, Breipohl W, Waters MJ: Growth hormone receptor expression in the rat gastrointestinal tract. Endocrinology 1990; 126:299-306. 134. Becker K,Stegenga S, Conway S: Role of insulin-like growth factor I in regulating growth hormone release and feedback in the male rat. Neuroendocrinology 1995;61 :573-583. 135. Chen K, Nezu R, Inoue M, et al: Beneficial effects of growth hormone combined with parenteral nutrition in the management of inflammatory bowel disease: An experimental study. Surgery 1997;121:212-218. 136. Tavakkolizadeh A, Shen R, Jasleen J, et al: Effect of growth hormone on intestinal Navglucose cotransporter activity. JPEN J Parenter Enteral Nutr 2001;25:18-22. 137. Iannoli P, Miller JH, Ryan CK, et al: Epidermal growth factor and human growth hormone accelerate adaptation after massive enterectomy in an additive, nutrient-dependent, and site-specific fashion. Surgery 1997;122:721-728. 138. Johnson WF, DiPalma CR, Ziegler TR, et al: Keratinocyte growth factor enhances early gut adaptation in a rat model of short bowel syndrome. Vet Surg 2000;29:17-27. 139. Thompson JS: Management of the short bowel syndrome in the pediatric population. Pediatr Clin North Am 1994;23:403-420. 140. Heymsfield SB, Casper K, Grossman GD: Bioenergetic and metabolic response to continuous vs intermittent nasoenteric feeding. Metabolism 1987;36:570. 141. Marchand V, Baker SS, Baker RD:Enteral nutrition in the pediatric population. Gastrol Endosc Clin North Am 1998;8:669-703. 142. Jeejeebhoy KN: Short bowel syndrome: A nutritional and medical approach. Can Med Assoc J 2002;166:1297-1302. 143. Ling L, Irving M:The effectiveness of growth hormone, glutamine and a low-fat diet containing high-carbohydrate on the enhancement of the function of remnant intestine among patients with short bowel syndrome: A review of published trials. Clin Nutr 2001;20:199-204. 144. Hudson M, Pocknee R, Mowat NA: o-lactic acidosis in short bowel syndrome-An examination of possible mechanisms. Q J Med 1990;74:157-163. 145. Bass BL, Fischer BA, Richardson C, et al: Somatostatin analogue treatment inhibits postresectional adaptation of the small bowel in rats. Am J Surg 1991;161:107-112.
SECTION V • Disease Specific 146. Redfern JS, Fortuner WJ 2nd: Octreotide-associated biliary tract dysfunction and gallstone formation: Pathophysiology and management. Am J Gastroenterol 1995;90:1042-1052. 147. Thompson JS, Nguyen BLT, Harty RF: Somatostatin analogue inhibits intestinal regeneration. Arch Surg 1993;128:385-389. 148. Balistreri WF, A-Kader HH, Ryckman FC, et al: Biochemical and clinical response to UDCA administration in pediatric patients with chronic cholestasis. In Paumgartner G, Stiehl A, Gerok W (eds): Bile Acids as Therapeutic Agents. Lancaster, UK, Kluwer, 1991, pp 323-333. 149. Roslyn JJ, Pitt HA, Mann L, et al: Parenteral nutrition-induced gall bladder disease: A reason for early cholecystectomy. Am J Surg 1984;148: 58-63. 150. Tytgat GN, Huibregtse K, Dagevos J, van den Ende A: Effect of loperamide on fecal output and composition in well-established ileostomy and ileorectal anastomosis. Am J Dig Dis 1977;22: 669-676. 151. King RF, North RT, Hill GL: A double-blind crossover study of the effect of loperamide hydrochloride and codeine phosphate on ileostomy output. Aust N Z J Surg 1982;52:121-124. 152. Mermel LA, Farr BM, Sherertz RJ, et al: Guidelines for the management of intravascular catheter-related infections. Clin Inf Dis 2001;32:1249-1272. 153. Vanderhoof JA: Short bowel syndrome in children and small intestinal transplantation. Pediatr Clin North Am 1996;43:533-550. 154. Sherman PM, Lichtman SN: Bacterial overgrowth. In Walker WA, Durie PR, Hamilton JR, et al (ed): Pediatric Gastrointestinal Disease, 2nd ed. St Louis: Mosby, 1996, pp 816-820. 155. Vanderhoof JA, Young RJ, Murray N, Kaufman SS: Treatment strategies for small bowel bacterial overgrowth in short bowel syndrome. J Pediatr Gastroenterol Nutr 1998;27:155-160.
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156. Taylor SF, Sondheimer JM, Sokol RJ, et al: Noninfectious colitis associated with short gut syndrome in infants. J Pediatr 1991;119:24-28. 157. De Roos NM, Katan MB: Effect of pro biotic bacteria on diarrhea, lipid metabolism and carcinogenesis: A review of papers published between 1988 and 1998. Am J Clin Nutr 2000;71: 405-411. 158. Jack RW, Tagg JR, Ray B: Bacteriocins of gram-positive bacteria. Microbiol Rev 1995;59:171-200. 159. Duffy Le, Zielezny MA, Rieppenhof-Talty M: Effectiveness of Bifidobacterium bifidum in mediating the clinical course of murine rotavirus diarrhea. Pediatr Res 1994;35:690-695. 160. Spanhaak S, Havennar R, Schaafsma G: The effect of consumption of milk fermented by Lactobacillus caseistrain Shirotaon the intestinal microflora and immune parameters in humans. Eur J Clin Nutr 1998;52:899-907. 161. Fuller R: Probiotics in human medicine. Gut 1991;32:439-442. 162. Kanamori Y, Hashizume K, Sugiyama M, et al: Combination therapy with Bifidobacterium breve, Lactobacillus casei, and galactooligosaccharides dramatically improved the intestinal function in a girl with short bowel syndrome-A novel symbiotics therapy for intestinal failure. Dig Dis Sci 2001;46:2010-2016. 163. Dorney SFA, Ament ME, Berquist WE, et al: Improved survival in very short small bowel of infancy with use of long-term parenteral nutrition. J Pediatr 1985;107:521-525. 164. Langnas AN: International small bowel registry. Presented at the 2nd Congress of the International Pediatric Transplant Association, Rio de Janeiro, April 2003.
Enteral Nutrition in Acute Hepatic Dysfunction Abhinandana Anantharaju, MD Sohrab Mobarhan, MD
CHAPTER OUTLINE Introduction Historical Perspective Structure and Functions of Liver Acute Hepatic Dysfunction: Definitions and Etiology Acute Hepatic Dysfunction: Nutritional Implications Nutrition Assessment in Acute Hepatic Dysfunction Nutritional Therapeutics in Acute Hepatic Dysfunction Guidelines for Nutrition Management in Acute Hepatic Dysfunction Future Direction Conclusion
INTRODUCTION The liver is the central metabolic organ of the body. It is involved in metabolism of almost all nutrients. Obviously, liver injury results in derangement of many metabolic systems in the body, resulting in malnutrition. The malnutrition mayor may not be present at the initial evaluation in patients with acute hepatic dysfunction, depending on the etiology of the injury. The association of malnutrition with acute hepatic dysfunction is often neglected in clinical practice. The most common form of acute hepatic dysfunction is caused by alcohol and nearly all patients with acute alcoholic hepatitis (AH) tend to be malnourished. In fact, malnourished patients have poor survival after liver transplantation, and 464
nutritional intervention improves the outcome. Nutritional intervention may help to improve hepatic function, thereby improving the overall prognosis. Most of the studies emphasizing the importance of nutrition in liver disease have been performed in patients with chronic liver diseases. Studies of acute hepatic dysfunction are few and have been performed mainly in patients with AH. Nevertheless, adequate clinical data exist to support aggressive nutritional intervention in patients with acute hepatic dysfunction.
HISTORICAL PERSPECTIVE The importance of nutrition in liver disease was recognized as far back as 400 Be when Hippocrates described the condition, which was later given the name cirrhosis by Laennec.' The pivotal role of nutrition in acute liver disease was first reported in 1945when it was shown that recovery from acute viral hepatitis could be enhanced by a high-fat diet. Unfortunately, the enthusiasm for nutritional therapy in acute liver disease suffered a setback in the 1950s when it was shown that a high-protein intake could precipitate hepatic encephalopathy (HE) in patients with AH.2 Other roadblocks included the fear of fluid overload and hyponatremia. In the 1960sand early 1970s, Lieber and co-workers demonstrated that alcohol was the main culprit for liver injury rather than malnutrition. In the late 1970s, the significance of nutrition in liver disease received even less consideration. In 1980, Nasrallah and Galambos' demonstrated that parenteral nutrition in patients with AH improved survival without significant complications. Subsequently, in 1985, Mendenhall and associates" demonstrated that enteral nutritional supplementation, high in calories, protein, and branched-ehain amino acids (BCAAs), is well tolerated and can improve both parameters of nutrition and liver injury in acute AH.
SECTION V • Disease Specific
465
STRUCTURE AND FUNCTIONS OF LIVER
ACUTE HEPATIC DYSFUNCTION: DEFINITIONS AND ETIOLOGY
The liver is wedge-shaped and is located in the right upper quadrant of the abdominal cavity. The adult liver weighs between 1.8% and 3.1% of body weight in 80% of Individuals." It has two lobes, right and left, and a dual blood supply from the portal vein and hepatic artery. About 85% of the blood supply comes from the portal vein that originates in the gut and the remainder is from the hepatic artery that originates from the celiac trunk. s,6 The portal venous blood mixes with the hepatic arterial blood from the systemic circulation in the liver and ultimately drains into the inferior vena cava via hepatic veins. About 1500 mUmin of blood circulates through the liver. In advanced liver disease, resistance to circulation can be caused by fibrosis, severe inflammation, or hepatic venous thrombosis, resulting in portal hypertension and secondary manifestations. The bile synthesized by hepatocytes drains through biliary channels and ultimately reaches the common bile duct that drains into the duodenum. The liver has an extraordinary ability to regenerate and only 10% to 20% of functioning hepatocytes are required to sustain life. The liver is involved in a variety of metabolic tunctions.v? It stores glycogen, which is released through glycogenolysis as glucose into blood when required. It is also involved in conversion of galactose and fructose to glucose and energy-requiring gluconeogenesis from lactic acid, glycogenic amino acids, and intermediates of the tricarboxylic acid cycle. Transamination and oxidative deamination result in conversion of amino acids to substrates for energy and glucose production. The liver is involved in synthesis of proteins such as albumin, (X- and p-globulins, transferrin, prealbumin, ceruloplasmin, lipoproteins, and some of the clotting factors. It is involved in the clearance of ammonia by formation of urea. The liver is also involved in Ik>xidation of fatty acids, production of ketones (acetoacetate and p-hydroxybutyrate), and metabolism of cholesterol, triglycerides, and phospholipids. The liver is also the major center for storage and metabolism of micronutrients, such as vitamin B12, fatsoluble vitamins (A, D, E, and K), zinc, iron, copper, and magnesium, and synthesizes the transport proteins for vitamin A, iron, zinc, and copper. It is involved in the conversion of folate to 5-methyltetrahydrofolate and of vitamin D to 25-hydroxyvitamin D. 25-Hydroxyvitamin D is further converted to the active form, 1,25-dihydroxyvitamin D, in the kidneys. The liver metabolizes alcohol with the enzyme alcohol dehydrogenase, almost all drugs, and some hormones (aldosterone, estrogen, glucocorticoids, progesterone, and testosterone). It also acts as a highly efficient filter to remove bacteria from blood by specialized macrophages, the Kupffercells, and as a site for extramedullary erythropoiesis in need. Bilirubin-derived from metabolism of heme is conjugated and excreted into the bile. The bile salts are synthesized by hepatocytes and secreted into bile, and this helps in micelle formation and the absorption of fat and fat-soluble vitamins.
Liver disease is said to be acute when its estimated duration is less than 6 months. Hyperacute hepatic failure is the appearance of HE within 7 days of the onset of jaundice," Acute hepatic failure is defined as the appearance of HE between 8 and 28 days after the onset of jaundice. Subacute hepatic failure occurs when HE appears between 5 to 12weeks of the onset of jaundice. Fulminant hepatic failure (FHF) is characterized by the rapid onset of HE and/or coagulopathy within 8 weeks of the onset of jaundice. Itis believed that hepatic failure usually represents a loss of at least 75% of hepatic function." The common causes of acute hepatic dysfunction are alcohol, drugs, and viral hepatitis. However, viral hepatitis is the most common cause of acute and fulminant hepatic failure worldwide and in the United States.P!' In the United States, druginduced hepatic failure, most commonly caused by acetaminophen, is the second leading cause of acute and fulminant hepatic failure. In the United Kingdom, acetaminophen is the leading cause of acute and fulminant hepatic failure. Table 4Q-11ists various causes of acute and fulminant hepatic failure with selected examples.
ACUTE HEPATIC DYSFUNCTION: NUTRITIONAL IMPLICATIONS Initially, because of the rapid development of the disease, severe malnutrition is usually not seen in patients with acute liver disease." Many patients with acute nonalcoholic hepatic failure tend to have good nutritional status at the beginning of the illness. However, in patients with acute alcoholic liver disease, the malnutrition appears to be universal-marasmus-Iike malnutrition being present in up to 86% of patients and kwashiorkor-like malnutrition in 100%.12 In patients with acute AH, the degree of malnutrition correlates with the severity of liver damage and dietary intake. Inadequate dietary intake appears to be the main cause for malnutrition, and malnutrition precedes the recognition of liver disease. Many people do not believe that malnutrition is a factor responsible for progression of liver disease in alcoholic patients.P The presence of malnutrition in patients with AH has _
•.. I
Causes of Acute and Fulminant Hepatic Failure
Toxins-Alcohol, Amanita phalloides, carbon tetrachloride Drugs-Acetaminophen, antituberculous, halothane, salicylates, nonsteroidal anti-inflammatory drugs, some herbal medicines Infections: Viral hepatitis-A, B, C, D, E Other viruses-Epstein-Barr, cytomegalovirus, herpes simplex Leptospirosis Sepsis Others-Autoimmune hepatitis, Wilson disease, ischemic hepatic necrosis, acute fatty liver of pregnancy, Budd-Chiari syndrome, Reye syndrome
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40 • Enteral Nutrition in Acute Hepatic Dysfunction
been attributed to consumption of alcohol as "empty calories"; poor dietary intake; malabsorption of nutrients due to the presence of pancreatitis, poor secretion of bile, or alcohol-induced damage to the enterocytes; increased catabolism; and lack of exercise," Alcohol also enhances catabolism and interferes with the metabolism of many micronutrients including thiamine, folate, pyridoxine, vitamin A,vitamin D, magnesium, phosphorus, zinc, and selenium. The poor dietary intake results from poor appetite, associated with nausea and/or vomiting, which appears to be due to the presence of high levels of proinflammatory cytokines derived from ongoing hepatic damage or associated infection." Patients with alcoholic liver disease also have low immunocompetence, predisposing them to increased occurrence of infections, which can precipitate acute kwashiorkor-type malnutrition." Alcohol provides energy at about 7.1 kcal/g and the efficiency of use of alcohoi for maintenance of metabolizable energy is about the same as that for carbohydrate." However, there is a suggestion that diet-induced thermogenesis may be higher with alcohol than with other substrates," Although the presence of chronic pancreatitis is five times less common in patients with alcoholic liver disease than in alcoholic patients without liver disease, its incidence is higher than that in patients with other forms of liver disease." Patients with FHF are highly catabolic as demonstrated by protein kinetic studies using [l4C] tyrosine. 19 If nutritional supplementation is not provided promptly, they will become malnourished rapidly.
NUTRITION ASSESSMENT IN ACUTE HEPATIC DYSFUNCTION Subjective global assessment (SGA) is used widely and reliably for nutritional assessment in chronic liver disease and liver transplantation." No trials have been conducted to study the usefulness of subjective global assessment in patients with acute hepatic dysfunction. However, in the clinical setting, it is used commonly in acute hepatic dysfunction as well. The presence of jaundice is common in patients hospitalized for acute hepatic dysfunction. These patients also commonly report anorexia, nausea, and/or vomiting, but weight loss is uncommon unless the hepatic dysfunction is due to AH. Also, the weight loss may not be apparent if there is associated fluid retention. Fatigue and poor exercise tolerance are common as well. Patients with AH are invariably malnourished and careful attention should be paid to the presence of micronutrient deficiencies. They tend to have poor fat stores and muscle mass. Skin, nail, and hair changes are uncommon unless liver disease is advanced. Changes in the tongue may reflect associated vitamin deficiencies. Thiamine supplementation should be given routinely to all alcoholic patients to prevent development of Wernicke syndrome and Korsakoff psychosis. Oral health is greatly compromised in patients with alcoholism, and periodontal lesions are especially common in alcoholics with nutritional impairment.P HE is the hallmark of patients admitted with FHF. They also tend to have severe coagulopathy due to acute
decompensation of the liver. Many patients with FHF tend to be have good nutritional status at the onset of the disease. However, the nutritional condition deteriorates rapidly due to accelerated catabolism. Attention should be paid to fluid status and stage of HE. Daily monitoring of weight, urine output, the presence or absence of ascites, arterial blood pressure, central venous pressure, pulmonary capillary wedge pressure, and intracranial pressure will provide valuable information about the fluid status of the patient. Hypoglycemia is common in acute hepatic dysfunction, both alcoholic and nonalcoholic. Patients with FHF, in particular, have profound hypoglycemia that needs close monitoring. The hypoglycemia can be easily corrected with intravenous glucose infusion and/or enteral nutrition. The serum albumin level is usually normal at the onset of acute and fulminant hepatic failure and is usually low in patients with AH. The albumin level declines rapidly within a few days, reflecting both decreased albumin synthesis by the diseased liver, increased protein degradation due to catabolism, and loss of albumin into extravascular spaces rather than as an indicator of overall nutritional status or body protein store." Similarly, the transferrin level declines as well. Lymphopenia and anergy occur commonly in patients with acute hepatic dysfunction and alcoholism. 15,21 The liver contributes to 20% to 30% of whole body energy expenditure.P The resting energy expenditure (REE) is 20% to 30% higher in many patients with FHF compared with that of healthy control subjects and anhepatic liver transplant recipients. 23,24 This has been attributed to the pronounced systemic inflammatory response that accompanies acute hepatic failure. The increase in REE occurs despite patients receiving mechanical ventilation and being sedated." The increase is even more pronounced after one corrects for differences in the core temperatures, but it does not correlate with hemodynamic variables, the requirement for vasoconstrictors, or the presence of renal failure. Respiratory quotient and oxidation rates for major fuels are not significantly different among patients with acute hepatic failure and healthy control subjects.P However, in patients with liver disease without a glucose supply, energy derived from fat is higher and that from carbohydrate is lower than in healthy control subjects. The Harris-Benedict equation appears to be unreliable for estimating energy expenditure in patients with acute hepatic failure." The REE, as measured by metabolic cart, in patients with AH is similar to that in healthy control subjects by using whole body weight." However, when REE per gram of urinary creatinine (indicating lean body mass) is estimated, the patients with AH have 55% higher energy expenditure compared with that of healthy control subjects. 25 This indicates decreased muscle mass with a hypermetabolic state in patients with AH. Practical Issues in Enteral Nutrition has many advantages compared with parenteral nutrition." Enteral nutrition (1) helps to maintain the integrity of the gut mucosa thereby reducing the potential for bacterial translocation, (2) promotes a faster transition to an oral diet, (3) provides additional nutrition through nocturnal or
SECTION V • Disease Specific
continuous feeding, and (4) overcomes the anorexia and poor intake associated with hepatic failure. Enteral feeding tubes can be safely placed in patients with acute hepatic dysfunction despite coagulopathy and esophageal varices." Fine-bore feeding tubes are recommended to prevent the mechanical complications associated with wide-bore tubes. Enteral feeding may have to be withheld if intestinal ileus or gastrointestinal bleeding is suspected." In such patients, short-term parenteral nutrition should be considered. Parenteral nutrition may be associated with increased risk of bloodborne infections, because many patients with acute hepatic failure are immunocompromised. If the patient is able to tolerate enteral feeding, it should be started at a slow rate with the monitoring of clinical condition including mental status. If nasogastric feeding causes recurrent nausea/vomiting, the tip of the feeding tube can be advanced to the duodenum or jejunum either at bedside or under fluoroscopic guidance, and intestinal feeding can be given with good tolerance. Continuous or nighttime pump infusion is better tolerated than intermittent boluses." Electrolyte levels should be closely monitored for refeeding syndrome and corrected if abnormal.
NUTRITIONAL THERAPEUTICS IN ACUTE HEPATIC DYSFUNCTION The primary goal of nutritional support in patients with acute hepatic dysfunction is to provide adequate calories with careful supplementation of proteins to prevent catabolism and hypoglycemia. The nutritional support should also provide essential micronutrients and antioxidants. The secondary goal is to promote hepatic tissue regeneration and improve hepatic function and thereby the overall prognosis. It is also used to improve HE and correct metabolic disturbances. As mentioned earlier, many of the studies of enteral nutrition for acute hepatic dysfunction are performed in patients with AH. However, the underlying cirrhosis is difficult to identify owing to many similarities in presentation." These studies suggest that nutritional support does improve nutritional status but does not influence short-term survival. The effects on the course of the disease are inconclusive. To date there have been five studies evaluating the effect of enteral nutritional therapy in AH: 1. Calvey and co-workers" studied 64 patients with acute AH,with or without underlying cirrhosis, who were randomly assigned to receive a controlled diet or a diet supplemented with 2000 kcal and 10 g of nitrogen per day. The supplemented diet was given orally, nasogastrically, or intravenously as necessary. Positive nitrogen balance was achieved invariably with the diet supplemented with 10 g or more nitrogen except in patients with renal failure and complications related to liver disease. The authors did not note significant changes in prothrombin time, measured nutritional parameters, and mortality. No significant benefit was seen with the use of BCAAs in patients with HE.
467
2. Mendenhall and associates' studied the effect of enteral nutrition therapy alone in patients with moderate to severe AH with protein-ealorie malnutrition. Thirty-four control subjects received a 2500 kcal/day hospital diet, being allowed to eat ad libitum from their prescribed diet. Twenty-three patients received a nutritional supplement containing 2240 kcal/day and protein enriched with BCM and arginine (Hepatic Aid) in addition to a 1000kcal/day hospital diet. Amount of protein and sodium were individualized based on patient's status in both groups. Those receiving supplemental diets consumed higher amounts of calories (a mean of 116.1%) and protein (a mean of 98.3 g). The supplemental diet was well tolerated without increased frequency of HE, and nutritional parameters were significantly improved. The clinical and biochemical parameters of hepatic dysfunction were improved in both the groups. However, there was no significant difference in 30
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40 • Enteral Nutrition in Acute Hepatic Dysfunction
43% of specialists considered using anabolic steroids for alcoholic liver disease in 1992. 34 A systematic review of five randomized clinical trials showed no significant beneficial effects of anabolic-androgenic steroids on overall mortality, liver-related mortality, complications due to liver disease, and other factors (liver histologic findings, hemodynamics, function, and biochernistryj.f The anabolic-androgenic steroids used were oxandrolone orally at 80 rug/day, micronized free testosterone orally at 600 mg/day, and testosterone propionate or methenolone enanthate every other day intramuscularly for duration of 21 days (for oxandrolone), 1 month (for oxandrolone and parenteral testosterone), and 36 months (for oral testosterone). The combination of oxandrolone with prednisolone appears to have a significant beneficial effect on long-term survival without much effect on the short-term survival «30 days)." Mendenhall and associates" studied the effect of oxandrolone therapy combined with enteral nutrition in patients with moderate to severe AH.13 They demonstrated that oxandrolone treatment reduced mortality with adequate calorie intake in patients with moderate malnutrition. However, in patients with severe malnutrition, oxandrolone itself had no effect, but adequate calorie intake significantly reduced mortality. Patients who abuse alcohol or those with alcoholic liver disease have been shown to have a deficiency of hepatic 5-adenosyl-L-methionine (SAMe), polyenylphosphatidylcholine (PPC), and glutathione." Lieber and co-workers'F" showed that supplementation of polyunsaturated lecithins in the diet of baboons can decrease fibrogenesis by impairing the transformation of lipocytes to transitional cells. This is due to an increase in phosphatidylethanolamine methyltransferase and an antioxidant effect." Similarly, supplementation with SAMe in experimental animals can restore mitochondrial glutathione after alcohol exposure." Human studies on the effects of SAMe, PPC, and glutathione in alcoholic liver disease are underway. The number of nutritional intervention studies performed in patients with FHF is limited and randomized trials have not been performed. Many of the conclusions are extrapolated from studies in patients with acute on chronic liver disease. HE is almost universal in FHF. The exact mechanism causing HE is unknown, but it has been attributed mainly to inability of the liver to remove nitrogenous wastes generated during metabolism.'? The portosystemic shunt plays only a minor role, if any, in causation of HE. HE in patients with acute hepatic failure may have identifiable precipitating factors such as gastrointestinal bleeding, infection, renal failure, or electrolyte disturbances, which, when removed, will result in dramatic improvement in HE.39 The proposed hypotheses for the pathogenesis of HE include toxicity from excess ammonia, the presence of an amino acid imbalance with an increase in aromatic amino acids (AAA) (phenylalanine, tyrosine, and tryptophan), relative to the amount of BCAAs (leucine, isoleucine, and valine), the effect of multiple synergistic neurotoxins including generation of false neurotransmitters, and overactivity of "taminobutyric acid neurotransrnission." Some of the other dietary substances that may have a role in the
_ _ Staging of Hepatic Encephalopathy Stages
CooscIOUSOe88
Persooallty
Subclinical (stage 0)
Normal
Stage 1
Confusion, altered sleep pattern
Stage 2 Stage 3
Moderate confusion, lethargy Somnolence
Stage 4
Coma
Mild changes Normal in intellectual function Memory and Constructional mood apraxia, disturbances incoordinatlon, slurred speech, ± asterlxis Disorientation, Asterixls, bizarre ataxia behavior Disorientation, Asterlxls, aggression hyperactive reflexes, positive Babinski reflex, Incoherent speech Unresponsive Decerebrate posture
Neurologic
pathogenesis of HE are zinc deficiency, short-ehain fatty acids, and tryptophan," HE has been classified into four stages depending on the clinical manifestations (fable 40-2). Patients with stage 1 or 2 HE need less intensive management than those with stages 3 or 4 HE. Patients with stages 3 or 4 HE commonly have cerebral edema requiring intracranial pressure monitoring. When cerebral edema is present, total fluid intake should be restricted to prevent worsening of the cerebral edema. The fluid calculation should be based on the patient's renal function, the presence of fluid overload, gastrointestinal losses, and respiratory condition. Considerations for enteral or parenteral nutrition should be based on the principles discussed earlier.
GUIDELINES FOR NUTRITION MANAGEMENT IN ACUTE HEPATIC DYSFUNCTION Nutritional intervention is usually unnecessary with patients with mild abnormalities in hepatic function, but it is essential in patients with HE and FHF. HE in patients with acute hepatic dysfunction is managed similarly to that in patients with chronic liver disease. Lactulose, bowel cleansing, oral antibiotics (metronidazole or neomycin), sodium benzoate, and i-omithine L-aspartate are useful. In general, the amount of protein should be low to begin with and gradually increased as tolerated. The usual recommended initial intake is 0.6 g/kg of body weight. In patients whose HE worsens due to standard proteins, BCAAs can be used with better tolerance," The ratio of AAAs to BCAAs has been shown to influence the amount of tryptophan, a precursor to serotonin, which can cross the blood-brain barrier." BCAAs are involved in shuttling the gluconeogenic amino acids, alanine and glutamine, into the intestinal mucosa and liver as energy
SECTION V • Disease Specific
469
_ _ Enteral Nutritional Formulas Containing Branched-Chaln Amino Acids
Manufacturer Strength Packaging Comments
Hepatic-Aid II
NutrlHep
L-Emental Hepatic
B Braun 36 cal/oz (1.2 kcal/rnl.) Powdered; 86.2 g packet; available in chocolate, eggnog, and custard flavors 46~, BCAA
Nestle 45 cal/oz (1.5 kcal/rnl.) Ready to use; 250 mL can; unflavored
Hormel Health Labs 36 cal/oz (1.2 kcal/rnl.) Powdered; 3 oz packet; available in custard flavor ?
66% of fat is MCT oil; 50% BCAA
Data from Women, Infants, and Children Program, Texas Department of Health: WIC Nutrition Formula Listing, February 2003.
substrates. Leucine and its keto analog, ketoisocaproate, have been shown in animals and in humans to promote muscle and liverstructural and secretory protein synthesis.25 BCAAs are also anticatabolic. BCAAs have been shown to be effective in patients with HE and chronic liver disease. The use of BCAAs need not be continued after HE subsides or a standard amino acid formula is tolerated." Likewise, there is no need to limit protein intake in general after HE subsides or when increasingamounts are tolerated. BCAAs can be given intravenously or enterally. The commonly used BCM-containing enteral formulas are NutriHep, Hepatic-Aid II, and L-Emental Hepatic!' (Table 40-3). Carbohydrate and fat intakes also need attention. Adequate carbohydrate intake is necessary to prevent hypoglycemia, which occurs in up to 40% of patients with acute hepatic failure, due to impaired hepatic gluconeogenesis and hyperinsulinemia.P-" Excessive calorie intake should be avoided because it can result in further impairment of hepatic function from steatohepatitis and cholestasis. Excessive fat infusion has been shown to result in immune incompetence and infusion of fat emulsions containing 75% medium-chain triglycerides (MCTs) and 25% long-chain triglycerides (LCTs) are better utilized during hepatic failure without any effect on reticuloendothelial function." High dietary and intravenous levels of long-ehain fatty acids, particularly 0>-6 polyunsaturated fatty acids, have been shown to encourage infection by prolonged inflammation, enhanced Gram-negative organism survival, reticuloendothelial blockage, immunosuppression, and cytokine depression." LCTs can influence host immunityby altering eicosanoid metabolism and membrane structure and function." The variations in liver function tests are similar with both LCTs and MCTs/LCTs.42 The quantity of fat accumulation decreases when LCTs are partially replaced by MCTs. It has been observed that unbound medium-chain fatty acids are capable of diffusing through the blood-brain barrier and can potentially worsen HE.42 Hydrolysis of MCTs by lipoprotein lipase is much faster than that of LCTs, and hypoalbuminemia can slow the activity of this enzyme. Coadministration of LCTs with MCTs is recommended because LCTs can lessen the toxicityof MCTs. Caloric requirements on the order of 35 to 50 kcal/kg are required to meet REE.43 Protein intake in excess of 1 g/kg/day is necessary to maintain nitrogen balance. Up to 50% of nonprotein calories may be provided as lipid, using a combination of LCTs and MCTs, as tolerated." Hypoglycemia, hypophosphatemia, hypokalemia,
and hypomagnesemia require aggressive replacement therapy." In patients with stage 0 to 1 HE, an oral diet can be consumed, if tolerated, and protein requirements are about 40 to 50 g/day." Vegetable and casein proteinbased diets are recommended because these substances are better tolerated than meat protein." Vegetable and casein proteins are lower in AAAs and higher in BCAAs than meat proteins. A vegetable diet also provides a high amount of fiber, which acts as a substrate forcolonic bacterial fermentation withsubsequent acidification, thereby modifying the colonic environment to decrease bacterial load.6.45 Supplementaldietary fibermay be useful in a similarmanner. In patients withstages 2 to 4 HE, tube feeding is often necessary, and the protein requirement is higher. Performance of nitrogen balance studies is recommended." The nitrogen balance is usually achieved with 1.5 g/kg/day of protein. The recommended initial protein administration is 40 g/day or less and is advanced by 0.25 to 0.5glkg/day, as tolerated.
FUTURE DIRECTION The number of randomized, controlled studies of nutrition management in patients with acute hepatic dysfunction, particularly acute and fulminant hepatic failure, is limited. This provides great opportunities for further exploration and research in this field. The following areas need further investigation: 1. The exact pathogenetic mechanisms that lead to negative nitrogen balance need to be determined and possible pharmacologic and nonpharmacologic interventions to maintain nitrogen balance should be evaluated. 2. Further understanding of HE and its relation to enteral feeding will help to modifythe composition of feeding appropriately for better tolerance. 3. Although animal studies indicate some protectiveeffectof 0>-3 fatty acids in acute hepatitis, human studies are lacking. Their possible protective effect on human liverdisease needs further exploration.
CONCLUSION The liver is involved in numerous metabolic functions that are impaired in acute hepatic dysfunction. More than 70% of hepatic function is believed to decline with acute hepatic failure. Preexisting malnutrition is universal in patients with AH and uncommon in patients with other
470
40 • Enteral Nutrition in Acute Hepatic Dysfunction
forms of drug-induced acute hepatic dysfunction. Enteral nutritional intervention in AH may improve hepatic function and prognosis. Specific nutritional intervention studies in patients with acute and fulminant hepatic failure are lacking. Nutritional intervention in FHF includes fluid restriction and nutritional therapy based on the stage of HE. Enteral nutrition should be the primary modality of nutrition and provided as tolerated. The nutritional support should be considered complementary to standard therapy in patients with acute hepatic dysfunction.
20. Harris C, Warnakulasuriya KA, Gelbier S, et al: Oral and dental health in alcohol misusing patients. Alcohol Clin Exp Res 1997;21:1707-1709. 21. O'Keefe SJ, El-Zayadi AR, Carraher TE, et al: Malnutrition and immuno-incompetence in patients with liver disease. Lancet 1980; 2:615-617. 22. Muller MJ: Hepatic energy and substrate metabolism: A possible metabolic basis for early nutritional support in cirrhotic patients. Nutrition 1998;14:30-38. 23. Schneeweiss B. Pammer J, Ratheiser K, et al: Energy metabolism in acute hepatic failure. Gastroenterology 1993;105:1515-1521. 24. Walsh TS, Wigmore SJ, Hopton P, et al: Energy expenditure in acetaminophen-induced fulminant hepatic failure. Crit Care Med
REFERENCES
25. John WJ, Phillips R, Ott L, et al: Resting energy expenditure in patients with alcoholic hepatitis. JPEN J Parenter Enteral Nutr 1989; 13:124-127. 26. Li SD, Lue W, Mobarhan S, Nadir A, Van Thiel DH, Hagerty A: Nutrition support for individuals with liver failure. Nutr Rev 2000; 58:242-247. 27. Cabre E, Gassull MA: Complications of enteral feeding. Nutrition 1993;9:1-9. 28. Cabre E, Gassull MA: Nutritional therapy in liver disease. Acta Gastroenterol Belg 1994;57:1-12. 29. Calvey H, Davis M, Williams R: Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol 1985;1:141-151. 30. Soberon S, Pauley MP, Duplantier R, et al: Metabolic effects of enteral formula feeding in alcoholic hepatitis. Hepatology 1987;7:1204-1209. 31. Keams PJ, Young H, Garcia G, et al: Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102:200-205. 32. Cabre E, Rodriguez-Iglesias P, Caballeria J, et al: Short- and longterm outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: A multicenter randomized trial. Hepatology 2000;32:36-42. 33. Mendenhall CL: Anabolic steroid therapy as an adjunct to diet in alcoholic hepatic steatosis. Am J Dig Dis 1968;13:783-791. 34. Rambaldi A, Iaquinto G, Gluud C: Anabolic-androgenic steroids for alcoholic liver disease: A Cochrane review. Am J Gastroenterol 2002;97:1674-1681. 35. Mendenhall CL, Anderson S, Garcia-Pont P, et al, Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med 1984;311:1464-1470. 36. Schenker S, Hoyumpa AM: New concepts of dietary intervention in alcoholic liver disease. J Lab Clin Med 1999;134:433-436. 37. Lieber CS, DeCarli LM, Mak KM, et al: Attenuation of alcoholinduced hepatic fibrosis by polyunsaturated lecithin. Hepatology 1990;12:1390-1398. 38. Lieber CS, Robins SJ, Li J, et al: Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon. Gastroenterology 1994;106:152-159. 39. Blackburn GL, O'Keefe SJ: Nutrition in liver failure. Gastroenterology 1989;97: 104~ 1051. 40. Wan JM, Teo TC, Babayan VK, Blackburn GL: Invited comment: Lipids and the development of immune dysfunction and infection. JPEN J Parenter Enteral Nutr 1988;12:435-52S. 41. Women, Infants, and Children Program, Texas Department of Health: WIC Nutrition Formula Listing, February 2003. 42. Bach AC, Storck D, Meraihi Z: Medium-ehain triglyceride-based fat emulsions: An alternative energy supply in stress and sepsis. JPEN J Parenter Enteral Nutr 1988;12:825-88S. 43. Riordan SM, Williams R: Fulminant hepatic failure. Clin Liver Dis 2000;4:25-45. 44. Mizock BA: Nutritional management of hepatic failure. Acute Care 1988-89;14-15:71-90. 45. Mullen KD, Dasarathy S: In Schiff ER, Sorrell MF, Maddrey WC (eds): Schiff's Diseases of the Liver. Philadelphia, Lippincott Williams & Wilkins, 1999, vol 1, pp 570-571.
20oo;28:64~54.
1. Wicks C: Nutrition and liver disease. In Payne-James J, Grimble GK, Silk DBA (eds): Artificial Nutrition Support in Clinical Practice, 2nd ed. London, Greenwich Medical Media, 2001, pp 49~51O. 2. Morgan TR, Mendenhall CL: Nutritional therapy for alcoholic hepatitis: Are we there yet? Hepatology 1992;16:845--848. 3. Nasrallah SM, Galambos IT: Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2:1276-1277. 4. Mendenhall C, Bongiovanni G, Goldberg S, et al: VA Cooperative Study on Alcoholic Hepatitis. 1I1: Changes in protein-ealorie malnutrition associated with 30 days of hospitalization with and without enteral nutritional therapy. JPEN J Parenter Enteral Nutr 1985;9:590-596. 5. Wanless IR: Physioanatomic considerations. In Schiff ER,Sorrell MF, Maddrey WC (eds): Schiff's Diseases of the Liver. Philadelphia, Lippincott Williams & Wilkins, 1999,vol 1, pp 3-37. 6. Hasse JM, Matarese LE: Medical nutrition therapy for liver, biliary system, and exocrine pancreas disorders. In Mahan LK, EscottStump S (eds): Food, Nutrition, and Diet Therapy, 10th ed. Philadelphia, WBSaunders, 2000, pp 695-721. 7. Fan S, Poon RT: Liver disease and parenteral nutrition. In Rombeau JL, Rolandelli RH (eds): Clinical Nutrition: Parenteral Nutrition, 3rd ed. WB Saunders Company, 2001, pp 392-406. 8. O'Grady JG, Schalm SW, Williams R:Acute liver failure: Redefining the syndromes. Lancet 1993;342:273-275. 9. Hiyama DT, Fischer JE: Nutritional support in hepatic failure: Current thought in practice. Nutr Clin Pract 1988;3:96-105. 10. Sherlock S, Dooley J: Acute liver failure. In Diseases of the Liver and Biliary System, 11th ed. Oxford, UK, Blackwell Science, 2002, pp 111-126. 11. Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N: Fulminant hepatic failure: Summary of a workshop. Hepatology 1995;21: 240-252. 12. Mendenhall CL, Anderson S, Weesner RE, et al: Protein-ealorie malnutrition associated with alcoholic hepatitis. Veterans Administration Cooperative Study Group on Alcoholic Hepatitis. Am J Med 1984;76:211-222. 13. Mendenhall CL, Moritz TE, Roselle GA, et al: A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: Results of a Department of Veterans Affairs Cooperative Study. Hepatology 1993;17:564-576. 14. Hoek JB, Pastorino JG: Ethanol, oxidative stress, and cytokineinduced liver cell injury. Alcohol 2002;27:63-68. 15. Watson RR, Borgs P, Witte M, et al: Alcohol, immunomodulation, and disease. Alcohol Alcohol 1994;29:131-139. 16. Rumpler WV, Rhodes DG, Baer DJ, et al: Energy value of moderate alcohol consumption by humans. Am J Clin Nutr 1996;64:108-114. 17. Raben A, Agerholm-Larsen L, Flint A, et al: Meals with similar energy densities but rich in protein, fat, carbohydrate, or alcohol have different effects on energy expenditure and substrate metabolism but not on appetite and energy intake. Am J Clin Nutr 2003;77:91-100. 18. Dreiling DA, Koller M:The natural history of alcoholic pancreatitis: Update 1985. MtSinai J Med 1985;52:340-342. 19. O'Keefe SJ, Abraham R, EI-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. Gastroenterology 1981;81: 1017-1024.
III Enteral Nutrition in Renal Disease Wilfred Druml, MD William E. Mitch, MD
CHAPTER OUTLINE Introduction Metabolic Alterations in Uremia Energy Metabolism Protein and Amino Acid Metabolism Carbohydrate Metabolism Lipid Metabolism Electrolytes Micronutrients Metabolic Impact of Renal Replacement Therapy Nutrient Requirements in Uremia Energy Substrates Proteins Electrolytes Micronutrients Gastrointestinal Complications in Uremia Potential Advantages of Enteral Nutrition in Renal Failure Nutritional Strategies General Considerations Patient Classification The Practice of Enteral Nutrition Feeding Tubes Enteral Formulas Enteral Nutrient Administration Parenteral Nutrition Conclusion
INTRODUCTION The label of malnutrition is often applied to patients with chronic renal failure (CRF) because a low serum albumin level and a decrease in body weight are
common. There are two problems with this label. First, the definition of malnutrition encompasses abnormalities that are related to an insufficient diet or a diet that is imbalanced. This implies that the abnormality can be overcome by simply increasing the quantities of foods eaten. In the patient with CRF, however, ability to excrete the products resulting from metabolism of the food eaten is limited. If this capacity is exceeded, then accumulated toxic products arising from the metabolism of protein will accumulate, yielding symptoms of uremia. In some ways, the defect in the patient with CRF is similar to those of patients with chronic liver disease or patients with inborn errors of metabolism; feeding excess protein to such patients will lead to symptoms. Consequently, the diet of patients with CRF must be carefully planned and controlled. Second, patients with renal insufficiency can experience losses of protein stores if they develop acidosis because of decreased kidney function or these patients can show active protein catabolism because of diabetes or insulin resistance or an inflammatory illness.' The dialysis procedure itself can activate protein degradation. Consequently, the assumption that protein stores can be regained simply by the patient's eating more food can lead to increased occurrence of complications. Enteral nutrition has become the preferred type of artificial nutritional support for patients with renal disease, and tube feeding is performed routinely in many institutions, particularly in patients with acute renal failure (ARF). The reason for using this strategy is the beneficial effect from delivery of nutrients into the gastrointestinal tract. Nevertheless, few systematic evaluations have been conducted in this field, and most reviews of artificial nutritional support for patients with kidney failure have focused on parenteral nutrition. There is even a paucity of information from the manufacturers of specialized enteral formulas about the use of enteral nutrition in kidney failure. This scarcity of information on the use of enteral nutrition for patients with kidney disease reflects the heterogenous spectrum of disorders accompanied by 471
472
41 • Enteral Nutrition in Renal Disease
renal dysfunction, ranging from stable advanced CRF to ARF with multiple organ dysfunction. In short, the goals of nutritional therapy, the requirements for nutrients, and the types of enteral formulas differ widely among patients. The divergent aims of nutritional therapy for various patient groups have created inconsistent recommendations for enteral nutrition. Enteral nutrition basically may be indicated in three groups of patients with renal failure: 1. Patients with catabolism and a superimposed illness and ARF or CRF or those treated by regular hemodialysis or chronic ambulatory peritoneal dialysis (CAPO), or other renal replacement therapy (RRT). In these catabolic patients, an optimal nutrient intake rather than a minimal level of nutrients should be provided to meet the demands caused by the hypercatabolic disease state while preventing the loss of lean body mass and stimulating wound healing and immunocompetence. The primary goal is to maintain good nutrition, and nutrients should be administered as needed to achieve this goal. For such patients, fluid and electrolyte disorders and the accumulation of metabolic waste products are treated by adjusting the intensity of RRT. 2. Patients with stable CRFwho are not treated by dialysis. (This group includes small children with congenital or acquired forms of renal dysfunction and malnourished, mostly elderly patients with CRF.) In sharp contrast to that for acutely ill patients, nutritional support for these subjects is focused on minimizing toxicity of uremia, retarding progression of renal disease, and delaying the time until dialysis will become necessary while maintaining protein stores and lean body mass and/or stimulating growth. 3. Patients treated by RRT but who have no complicating illness. (This group may include patients who do not have adequate oral nutrition such as small infants or elderly patients.) Loss of protein stores occurs often in this group of patients and is a major cause of morbidity (especially infections) and mortality. Meal supplements are given to replete and maintain body protein stores, to improve visceral protein synthesis, to stimulate immunocompetence and growth, and to improve quality of life and physical well-being. In this chapter, we will review the metabolic alterations caused by kidney disease, the impact of dialysis therapies on metabolism and nutrient balances, the alterations of gastrointestinal function in kidney disease, and the nutrient requirements for different patient groups. We also will analyze the types of enteral formulas and the techniques of nutrient application and summarize the few publications concentrating on enteral nutritional support of patients with kidney disease. The concepts of oral nutritional supplements of essential amino acids and/or keto acids and an analysis of the impact of nutrition on the progression of renal disease have been reviewed elsewhere.P
METABOLIC ALTERATIONS IN UREMIA Patients with kidney disease exhibit characteristic metabolic ebnormalitles'v (Table 41-1). These metabolic alterations are modified by the extent of kidney dysfunction, by the type and intensity of dialysis, by the degree of depletion of protein stores, and by intercurrent diseases. In patients with ARF, the underlying disease processes causing kidney damage and associated complications, such as severe infections and additional organ dysfunctions, also influence metabolism.
Energy Metabolism In animal experiments, kidney failure is associated with decreased oxygen consumption even when hypothermia and acidosis have been corrected (uremic hypometabolism). In contrast, oxygen consumption by patients with various forms of kidney failure is unchanged or even slightly elevated/" Energy expenditure, however, can be sharply increased in patients with acute illnesses such as sepsis so that the underlying illness and its complications are more relevant in defining energy metabolism than renal failure per se."
Protein and Amino Acid Metabolism In the patient with stable CRF who has no acute illness or acidosis, the ability to adjust protein and amino acid metabolism normally is not impaired and no excessive protein catabolism is seen.B--JO However, patients with kidney failure and another condition, such as an infection, acidosis, or cancer, will develop excessive protein catabolism and sustained negative nitrogen balance.''!' A number of factors contribute to protein catabolism (Table 41-2). Amino acids are redistributed from skeletal muscle to the liver and hepatic extraction of amino acids from the circulation increases as do gluconeogenesis (and ureagenesis) from amino acids. An increase in hepatic synthesis of acute-phase proteins is also seen, but albumin synthesis is not sufficient to maintain
• . , •
Characteristic Metabolic Alterations In Patients with Non-Nephrotic Rena' Disease
Peripheral Insulin resistance Impairment of lipolysis Metabolic acidosis Hyperparathyroidism, uremic bone disease Impairment of vitamin D activation Impairment of potassium disposal-hyperkalemia Chronic inflammatory reaction C"microinflammation") Activation and potentiation of protein catabolism in the presence of additional catabolic factors, such as trauma, acidosis, Infection, or malnutrition
SECTION V • Disease Specific
DmIJD
Contributing Factors to Protein _ _ Catabolism in Renal Failure Impairment of metabolic functions by uremic toxins Endocrine factors Insulin resistance Increased secretion of catabolic hormones (catecholamines, glucagon, glucocorticoids) Hyperparathyroidism Suppression of release/resistance to growth factors Metabolic acidosis Chronic microinflammation Acute intercurrent disease/acute-phase reaction-systemic inflammatory response syndrome (activation of cytokine network) Release of proteases Increased formation of reactive oxygen species Malnutrition Inadequate supply of nutritional substrates Renal replacement therapy Loss of nutritional substrates Induction of an inflammatory reaction
normal stores of albumin. In this case, the defect is not malnutrition but the consequence of the change in proteins being synthesized by the liver.I Consequently, imbalances in amino acid pools in plasma and in the intracellular compartment develop, leading to a distinct plasma amino acid pattern.l-" Protein and amino acid metabolism in renal failure are also affected by the loss of metabolically active kidney tissue. This has an impact on the amino acids that are synthesized or metabolized by the kidneys, including cysteine, tyrosine, arginine, and serine. The result is that some amino acids that are usually termed nonessential or dispensable (e.g., tyrosine, arginine, or histidine) can become conditionally indispensable in renal failure." An important cause of catabolism in kidney failure is insulin resistance. In muscle, the maximal rate of insulinstimulated protein synthesis is depressed and protein degradation is increased. There seems to be a common defect in protein and glucose metabolism that is associated with a higher rate of protein breakdown, leading to interruption of the normal control of protein turnover. IS Other endocrine factors are implicated in the accelerated protein degradation occurring in response to uremia.i-' Secondary hyperparathyroidism may stimulate protein breakdown. Plasma levels of the "catabolic hormones," catecholamines, glucagon, and corticosteroids are elevated. Inflammatory molecules, such as interleukins and tumor necrosis factor-a (TNF-a.) can mediate hypercatabolism in acute disease states. This mechanism may also be operating in patients with otherwise stable CRF who have a chronic inflammatory reaction identified by a persistent elevation of C-reactive protein ("microinflammation"): 16 Finally, it has been proposed that circulating proteases released from granulocytes may stimulate catabolism of proteins in patients undergoing dialysis or those with hypercatabolic ARF.17 Metabolic acidosis is common in patients with kidney disease. The severity of acidosis is directly related to the function of the remaining kidney tissue and also to the
473
amount of protein eaten or catabolized. The latter occurs because certain amino acids (e.g., the sulfurcontaining amino acids) are converted to acid. The development of acidosis is relevant to nutritional therapy for another reason, namely that it is an important cause of muscle protein breakdown and growth retardation. Metabolic acidosis activates the catabolism of protein through the ubiquitin-proteasome system." By correcting the metabolic acidosis, the increase in muscle protein degradation associated with kidney failure can be eliminated and nutritional status improved.P:" These findings together with the effects of acidosis on inhibitors, lipolysis, causing insulin resistance, erythropoietin resistance, and aggravating hyperparathyroidism, have made alkali therapy a cornerstone of the treatment of renal failure. Aside from catabolic stimuli, such as acidosis, inflammation, infection, or trauma, an inadequate diet can increase protein breakdown. However, exogenously supplied substrates can only reduce, but will not eliminate, accelerated protein breakdown and gluconeogenesis in a catabolic patient with acute or chronic renal failure and a superimposed illness. In attempts to suppress protein breakdown more completely, various endocrinemetabolic interventions such as therapy with thyroxin, growth hormone, or insulin-like growth factor-l have been evaluated in acutely ill patients with kidney failure. Results from clinical trials have been disappointing, and growth factors are no longer used in adult patients with renal failure and superimposed illness. 19,2o In the patient treated by dialysis whose metabolism is stable, the use of anabolic steroids may improve the nutritional state."
Carbohydrate Metabolism Kidney failure is associated with an impairment in glucose tolerance, principally due to resistance to insulin in peripheral tissues, especially muscle." Maximal insulin-stimulated glucose uptake by skeletal muscle is decreased by 50%, and glycogen synthesis in muscle is impaired. The insulin concentrations causing halfmaximal stimulation of glucose uptake and glucose metabolism are normal, pointing to a postreceptor defect rather than to impaired insulin sensitivity as the cause of defective glucose metabolisrn.P In patients with acute kidney disease or CRF or in patients treated by dialysis with an intercurrent illness, another feature of abnormal glucose metabolism is accelerated hepatic gluconeogenesis mainly from conversion of amino acids released during protein catabolism. In such patients, hepatic extraction of amino acids, their conversion to glucose, and urea production are all increased and are not suppressed by glucose infusion.t' Again, the circulating catabolic hormones, hyperparathyroidism, metabolic acidosis, and release of inflammatory mediators such as interleukins and TNF-a. can all contribute to the insulin resistance of uremia. Moreover, alterations of glucose and protein
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41 • Enteral Nutrition in Renal Disease
metabolism in ARF are interrelated: impaired cellular glucose availability and utilization accelerate protein catabolism. 15 Insulin metabolism is also grossly abnormal in uremia: insulin secretion is reduced in the basal state and in response to glucose infusion.F' The kidney is a major organ that degrades insulin, but insulin degradation by the liver is also consistently reduced (at least in ARF). Consequently, the plasma insulin concentration is high and insulin requirements diminish in insulindependent diabetic subjects with advancing renal failure.
Lipid Metabolism In terms of nutritional therapy, the most relevant alteration of lipid metabolism of the non-nephrotic patient with kidney failure is impairment of lipolysis.26•27 A reduction in the activities of both peripheral lipoprotein lipase and hepatic triglyceride lipase are implicated in defective lipoprotein catabolism. 28•29 Total triglyceride content and the triglyceride content of plasma lipoproteins, especially very low-density and low-density lipoproteins, are increased and intermediate-density lipoprotein remnants accumulate. In contrast, total serum cholesterol levels have been reported to be increased, normal, or even decreased, but plasma highdensity lipoprotein cholesterol levels are uniformly low in patients with ARF or CRFor patients treated by dialysis. Additionally, the protein composition of lipoproteins becomes abnormal, concentrations of apoproteins AI and All are low, and the ratio of lipoprotein CII (an activator molecule of lipoprotein lipase) to lipoprotein CIII (an inhibitor of lipolysis) is decreased. Metabolic acidosis can contribute to the impairment of lipolysis by further inhibiting lipoprotein lipase activity. Impaired lipolysis affects the hydrolysis of LCTs and MCTs. During intravenous infusion of fat emulsions, the hydrolysis of MCTs and LCTs is equally delayed." Inhibition of lipolysis plus delayed intestinal absorption of fat results in a retarded and augmented postprandial rise in plasma triglycerides in patients treated by dialysis compared with that in healthy adults. Whether increased hepatic secretion of triglycerides contributes to altered lipid metabolism in kidney failure is controversial but in nephrotic patients or patients treated by CAPO (with a dialytic glucose intake) hepatic triglyceride formation is stimulated. 31•32 In patients treated by dialysis, chronic heparin administration also leads to depletion of lipoprotein lipase stores and aggravates the development of hypertriglyceridemia. Camitine deficiency reportedly contributes to lipid abnormality in patients with CRF and particularly in patients receiving dialysis. Use of a camitine supplement has been advocated, and enteral diets for nutritional support of kidney failure patients are often enriched in camitine. In contrast, plasma carnitine levels are increased in ARF because of increased release from muscle tissues during catabolism plus activation of hepatic carnitine synthesis."
Electrolytes Potassium Kidney failure can be complicated by hyperkalemia because of impaired excretion of electrolytes and increased potassium release during accelerated protein catabolism; there also is an altered distribution between intra- and extracellular spaces caused by the uremic state per se, by acidosis, or by drugs such as digitalis glycosides or ~antagonists.34 It must be noted, however, that whole body potassium is decreased in most patients with CRF or patients receiving dialysis. This reflects principally a loss of lean body mass. Consequently, patients undergoing dialysis or even patients with ARF may exhibit a low serum potassium concentration requiring potassium replacement during artificial nutntton."
Phosphate Serum phosphate increases in uremic patients not only because of decreased excretion but also because phosphates are released from cells during catabolism and metabolic utilization is diminished when cells are rebuilding and finally because phosphates are mobilized from bone because of hyperparathyroidism and/or acidosis. Like potassium, whole body phosphate is decreased in many patients because of a decrease in lean body mass. Occasionally, patients receiving dialysis (and especially those treated with phosphate-binding agents), who are treated with low-phosphate diets will develop hypophosphatemia. Moreover, more than 20% of patients with ARF will have hypophosphatemia on admission to the hospital." These observations plus the consequences of use of enteral or parenteral fluid solutions with low electrolyte contents explain why hypophosphatemia and hypokalemia may develop in patients. 36,37
Calcium Patients with kidney failure often have hypocalcemia because of a reduction in both protein-bound and ionized fractions of calcium. The major reasons for this finding are reduced calcium absorption from the gastrointestinal tract as a result of reduced synthesis of 1,25-dihydroxy vitamin 0 3, hyperphosphatemia, and skeletal resistance to the calcemic effect of parathyroid hormone." Aluminium toxicity can also contribute to a decrease in serum calcium levels. Hypercalcemia can develop during treatment with calcitriol, with calcium-containing antacids, with a high dialysate calcium concentration, with immobilization, and/or with hyperparathyroidism. In ARF, a persistent elevation of the serum calcitriol level may result in a rebound hypercalcemia during the diuretic phase of ARF.
Magnesium The serum magnesium level may be high in patients with uremia, but this rarely has clinical relevance. Symptomatic
SECTION V. Disease Specific
hypennagnesemia can develop with the ingestion of magnesium hydroxyl antacid gels or magnesium-eontaining cathartics. Hypomagnesemia, on the other hand, may occur with gastrointestinal disorders and steatorrhea during the diuretic phase of ARFor in patients after renal transplantation during treatment with cyclosporine."
Micronutrients
Vitamins Serum levels of the water-soluble vitamins are often decreased in patients with kidney failure because of losses associated with dialysis and/or very restricted diets. 40,41 With the exception of calcitriol, serum levels of fat-soluble vitamins are usually not decreased in patients with stable CRF or patients receiving dialysis. The serum levels of vitamins A and Kare high whereas vitamin Kdeficiency only occurs in patients receiving certain antibiotics." Plasma and erythrocyte concentrations of the antioxidant vitamin E (a-tocopherol) have been found to be decreased, normal, or even increased in patients with CRF or patients receiving dialysis; whereas in most patients with ARFplasma levels of vitamin E are low." As with patients with CRF, in patients with ARF, the plasma calcitriol concentration is decreased because of reduced activation of vitamin 0 3.42
Trace Elements Trace element metabolism in uremic subjects is complicated." The cause and stage of kidney disease and the type of tissue in which the concentration of an element is measured must all be considered in the interpreting of these reports. Many of the findings such as decreases in the plasma concentrations of iron or zinc or an increase in serum copper are probably nonspecific alterations related to the acute-phase reaction rather than to a deficiency or toxicity state." Geographic and therapeutic influences such as the content of trace elements in tap water, the type of therapy, and, especially, contamination of dialysis fluids with trace elements may profoundly affect trace element balances. Because of the high degree of protein binding, most trace elements are not eliminated by dialysis, so variations in intake become critically important in determining the cause of a deficiency or a toxic condition. With the exception of aluminum, the contributions of trace element toxicity or deficiency to the symptoms of kidney disease have not been established. Decreased levels of zinc in various tissues in patients with CRFor patients undergoing dialysis have been linked to several symptoms of uremia including loss of appetite, an altered sense of taste and smell, and impaired sexual function. Selenium concentrations in plasma and erythrocytes are uniformly decreased in patients with kidney failure, and selenium deficiency has been implicated in lipid peroxidation abnormalities, cardiomyopathy and ischemic heart disease, malignancy, and impaired immune function." In critically ill patients with ARF, plasma selenium concentrations are more
475
depressed and lipid peroxidation product levels are higher compared with those in patients without ARF.46 Fortunately, iron overload is a rare problem for patients with kidney disease because of the effectiveness of erythropoietin therapy. However, erythropoietin therapy increases iron requirements and overt iron deficiency can develop. Micronutrients are an important part of the organism's defense mechanisms against oxygen free radicalinduced injury to cellular components. Impaired antioxidant status has been reported in studies of patients with ARF or CRF and patients receiving dialysis. 45,46 Experimentally, antioxidant deficiency (decreased vitamin E and/or selenium levels) exacerbates ischemic renal injury, worsens the course of disease, and increases mortality. These findings suggest that the generation of excessive reactive oxygen species and peroxidation of lipid membrane components playa crucial role in initiating and/or mediating tissue injury.
METABOLIC IMPACT OF RENAL REPLACEMENT THERAPY The impact of renal replacement therapies on metabolism and nutrient balances is manifold (Table 41-3). Several water-soluble substances, including amino acids and vitamins are lost during hemodialysis.P"' Amino acid elimination accounts for about 4 g of amino acids/hr of dialysis therapy, and approximately 4 g of peptidebound amino acids plus blood losses in the extracorporeal dialysis tubing contribute to the negative nitrogen balance measured during dialysis." Likewise, during CAPOlosses of total free amino acids average about 3 to 4 glday, but there is an additional loss of about 9 g of total protein/day that includes 6 g of albumin/day." These losses are not the sole cause of negative nitrogen balance during dialysis; accelerated protein breakdown also occurs." Various mediators of protein degradation have been proposed: the release of leukocyte-derived proteases, an activation of the complement system, or inflammatory mediators (TNF-a and interleukins) related to interactions of blood with dialysis membranes or induced by endotoxin.w'? Dialysis has also been shown to inhibit protein synthesis in muscle. Finally, hemodialysis promotes the generation of oxygen radicals that • . . Metabolic Side Effects of Renal . . Replacement Therapy Induction of anorexia Loss of nutritional substrates Impairment of oxygen scavenger system Loss of antioxidants Activation of reactive oxygen species Induction of an Inflammatory reaction Induction of protein catabolism Impairment of protein synthesis Heat loss (CRRD Excessive load of substrates (lactate, citrate) (CRRD Loss of peptides (hormones/proteins) (CRRT, CAPO) CRRT, continuous renal replacement therapy.
476
41 • Enteral Nutrition in Renal Disease
could contribute to tissue injury, accelerated atherosclerosis, and impaired Immunocompetence." Continuous RRTs, such as continuous hemofiltration and hemodialysis, are being used for critically ill patients with ARF. Because of the high fluid turnover and the continuous mode of therapy, these continuous RRTs are associated with a broad pattern of metabolic consequences in addition to renal replacement (see Table 41-3).51 One major consequence is the elimination of small- and medium-sized molecules. For example, amino acids have a sieving coefficient of 0.8 to 1.0, so amino acid losses can be estimated from the volume of the filtrate and the average plasma concentrations's and usually will amount to approximately 0.2 gil of filtrate or loss of 5 to 15 g of amino acid/day which is about 10% to 15% of amino acid intake. With membranes that have a high molecular size cut-off, peptide/protein losses can also amount to 1.2 to 7.5 g/day.53 Similarly, water-soluble vitamins, (e.g., folic acid, vitamin B6, and vitamin C) are eliminated." For this reason a higher daily intake than usually recommended is required to maintain plasma concentrations of these vitamins in patients treated by continuous RRT.19
NUTRIENT REQUIREMENTS IN UREMIA Prescribing an optimal intake of nutrients in patients with kidney failure requires consideration of the nature and degree of kidney dysfunction, the extent of catabolism experienced by the patient, and the type and frequency of dialysis.'? Patients with renal failure are an extremely heterogeneous group of subjects with widely differing nutrient requirements, and, in addition, requirements for an individual patient can vary widely during the course of disease.
Energy Substrates As detailed earlier, kidney failure per se has little impact on oxygen consumption so energy requirements are largely determined by the underlying illness. Adverse effects and dangers are associated with exaggerated nutrient intakes so that energy supply in a patient with an acute catabolic disease should cover but not exceed actual energy consumption." The same recommendation holds for patients with CRF and patients with a superimposed catabolic illness who are also receiving dialysis. Overall, energy requirements will rarely exceed 130% of the calculated basal energy requirement even in hypermetabolic conditions associated with kidney failure,such as sepsis or multiple organ failure. In patients with CRF and stable metabolism or patients without an acute illness who are receiving dialysis, physical activityis often reduced so their energy intake should not exceed 30 to 35 kcallkg/day (i.e., about 40% above their basal energy requirement). This intake will maintain lean body mass. If caloric intake is restricted for patients with CRF, energy expenditure does not adapt and will impair compensatory mechanisms that protect against loss of protein stores.54
Proteins The optimal intake of protein or amino acids for patients with ARF or CRF or patients receiving dialysis who also have an intercurrent catabolic illness has not been extensively studied." In nonhypercatabolic patients during the recovery phase of ARF, a protein intake of 1.0 to 1.3 g/kg of body weight (b.wt.)/day was required to improve nitrogen balance. In patients requiring dialysis (hemodialysis, peritoneal dialysis, or continuous hemofiltration), protein or amino acid intake should be increased by 0.2 g/kg b.wt./day to compensate for substrate losses associated with the therapy. For the hypercatabolic patient with ARF treated by continuous hemofiltration, the protein requirement may rise to 1.3 to 1.5 g/kg of b.wt./day based on estimates of the protein catabolic rate and nitrogen balance studies, respectively.55 On the other hand, it must be stressed that hypercatabolism and loss of lean body mass cannot be controlled simply by increasing protein or amino acid intake. In patients with stable CRFwithout an intercurrent illness, 0.6 g of protein/kg b.wt./day (or alternatively 0.3 g of protein/kg of b.wt./day supplemented with essential and/or keto acids) is sufficlent." A low-protein dietary prescription must be monitored during artificial nutrition to avoid complications, including the loss of protein mass. However, this type of therapy was successful during long-term therapy of patients with advanced CRF.57 With a low-protein diet, the tendency to develop metabolic acidosis is lowered because the intake of amino acids that are metabolized to yield protons is reduced. If acidosis does appear, it should be corrected to prevent the accelerated muscle protein breakdown that occurs concurrently.f The protein requirements of patients receiving dialysis are higher than the requirements for normal adults or patients with stable CRF.56.59 The recommended amount is at least 1.2 g/kg of b.wt./day and even more for patients with low body weight, anthropometric evidence of a decrease in muscle mass, or a low serum albumin level. 1 For patients treated by CAPD, an intake of 1.4 g of protein/kg of b.wt.lday is recommended to compensate for losses of amino acids and especially proteins into the peritoneal dialysate.
Electrolytes Electrolyte requirements for any patient with kidney failure are highly variable. Usually, intake of potassium and/or phosphate is limited in enteral products that are specifically designed for uremic patients. It must be kept in mind, however, that some patients will have electrolyte deficiencies and that the use of a phosphateand/or potassium-free parenteral or enteral nutritional supplement will cause a drop in plasma levels of potassium and phosphate.v-" This is due to the effects of insulin (stimulated by carbohydrate administration) and the synthesis of new tissues so the decrease in these minerals may be profound in patients who have depleted
SECTION V • Disease Specific
body pools of electrolytes. For example, in one report patients with kidney failure and high plasma phosphorus levels at the beginning of therapy required supplements of 10 mmol of phosphate/lOOO kcal/day to prevent the development of hypophosphatemia."
Micronutrients Although requirements of water-soluble vitamins for uremic patients are increased." ascorbic acid (vitamin C) intake should be limited to approximately 250 mg/day because it is a precursor of oxalic acid and an excess may cause secondary oxalosis." Forfat-soluble vitamins, vitamin A levels in plasma are increased by kidney failure so its requirement is low; the same may be true for vitamin K. There are conflicting reports about vitamin E stores in uremic patients, but an adequate amount should be givento patients with ARF or CRF and an associated acute illness because vitamin E reportedly can prevent vascular complications in patients treated by dialysis." Supplementation of vitamin D is complicated because it increases intestinal absorption of phosphates as well as calcium, but it can also suppress parathyroid hormone secretion. The decision to prescribe a supplement of vitamin D must be made in conjunction with extensive information about the mineral and bone status of the patient; this type of decision should be made individually for each patient. The requirements forselenium and zinc are unsettled. Supplementation of selenium (200 ~g of sodium selenite intravenously after each dialysis session) reportedly led to an increase in the plasma and erythrocyte concentrations of selenium, enhanced glutathione peroxidase activity, and decreased lipid peroxidation products in patients treated by dialysis." In critically ill patients, selenium supplements reduced the number of patients with ARF who required dialysis therapy and improved clinical outcorne.F Note that most enteral diets contain the Recommended Daily Allowances of vitamins and trace elements and oral or parenteral multivitamin/multi-trace element preparations may be given. Unfortunately, parenteral administration of trace elements in patients with kidney failure carries the risk of inducing toxicity because the main regulators of trace element homeostasis (i.e., the gastrointestinal absorption and excretion by the kidney) are bypassed by intravenous infusion.
DmIIIII
477
GASTROINTESTINAL COMPLICATIONS IN UREMIA Abnormalities of structure and function of virtually every segment of the gastrointestinal tract have been described in patients with kidney failure (fable 41-4).63,64 Findings are contradictory because investigations include patients with different stages and types of renal insufficiency and differences between the responses of animal models and patients. To summarize, alterations in gastrointestinal functions associated with uremia that are relevant to enteral nutrition and digestive and absorptive insufficiency are probably of little clinical importance for the assimilation of substrates. Malabsorption of fat and especially of LCTs may be the most important abnormality because it can influence the type of enteral formula prescribed (predominantly LCTs and MCTs).65 The most important consequence of kidney failure in terms of enteral feeding is impaired gastrointestinal motility, both of gastricemptyingand intestinal peristalsis. Even in the early stages of kidney failure, small bowel motility and colonic transit time are slowed." In patients with ARF, gastric emptying is impaired and in critically ill patients, the maximalserum creatinine level predicts the degree of impaired intestinal motility." Concomitant chronic diseases, such as diabetes mellitus, or medications can aggravate the negative impact of kidney failure on gastrointestinal motility. In uremic patients with diabetes mellitus, in particular, a profound gastroparesis often is present. In critically ill patients, opiates or catecholamines can further impair gastrointestinal motility and early administration of prokinetic drugs can improve the tolerance to oral or enteral feeding." Some patients still will require positioning of the feeding tube tip in the jejunum to facilitate enteral nutrient administration. Multiple organ dysfunction syndrome is associated with edema of the intestinal mucosa, impaired mucus production, and enzyme synthesis plus altered peristalsis. These not only contribute to intestinal paralysis but also can impair the absorption of nutrients and increase intestinal permeability and promote bacterial translocation." The presence of ARF or CRF can aggravate these conditions. There also is concern about injury to the intestinal mucosa because ARF is a leading risk factor for gastrointestinal hemorrhage." This is not a reason to avoid enteral nutrition because it can help to prevent or reversethe development of erosions and ulcerations and gastrointestinal bleeding episodes.
Gastrointestinal Side Effects of Uremia
Oral cavity: Stomatitis. gingivitis, parotitis, mucosal ulcerations, and bleeding episodes; altered taste Esophagus: Esophagitis, gastroesophageal reflux, bacterial colonization, fungal infections, virus infections
Stomach: Reduced acid secretion in chronic renal failure, acid hypersecretion after institution of regular dialysis therapy, mucosal edema. scattered petechiae. hemorrhagic infarction, pseudomembrane formation, ulceration, hemorrhagic gastritis, gastric bleeding. increase in gastric mucosal permeability, delay in gastric emptying, gastroparesis Pancreas: Mild degree of pancreatic insufficiency, elevated plasma levels of amylase, trypsinogen, and lipase Small intestine: Mild impairment of digestion and adsorption of carbohydrates and proteins/amino acids, fat malad sorption. increased fecallat loss. increased intestinal loss of albumin, mucosal edema and/or uremic enterocolitis, maladsorption of calcium, folate, and iron, telangiectasia, amyloidosis Colon Increased incidence of colonic ulcers and pseudomembranous colitis, angiodysplasias of the colonic mucosa, impaired motility. constipation, diarrhea. alterations of colonic flora, increased secretion of potassium
478
41 • Enteral Nutrition in Renal Disease
POTENTIAL ADVANTAGES OF ENTERAL NUTRITION IN RENAL FAILURE Enteral nutrition should be the first line of artificial nutrient application in all patients including those with kidney failure. Enteral nutrients can have specific advantages for the kidney. Parenterally infused or enterally provided protein or amino acids increases kidney perfusion and excretory function (renal functional reserve). However, the beneficial effects of nutrients on kidney function depend on the route of administration. In rats with ischemic ARF, enteral nutrition was found to be superior to parenteral nutrition in limiting the extent of renal injury and enhancing recovery from ARF.71,72 Unfortunately, it is not known whether this beneficial effect will limit injury and improve kidney function in humans. At least in the animal model of ARF, enteral nutrition increased renal perfusion, limited renal breakdown, and improved prognosis." No systematic investigations addressing the potential beneficial effects of enteral nutrition on renal function and patient outcome in humans have been performed. However, in one study of the prognostic factors in 839 patients with ARF, enteral but not parenteral nutrition was associated with improved survival.P The clinician must recognize that provision of all nutrient requirements exclusively by the enteral route may be impossible, and supplementary parenteral nutrition may be necessary. Even in this case, provision of small amounts of enteral formula regularly (i.e., 50 mL six times per day) can help to support intestinal functions in patients with severely compromised intestinal motllity." It has been suggested that dietary fiber can reduce uremic toxin accumulation by inhibiting colonic bacterial ammonia generation and increasing fecal nitrogen excretion." Although this benefit is limited, enteral diets should contain fiber to stimulate motility, improve blood glucose control, and reduce serum cholesterol levels. Systematic studies evaluating the potential beneficial effects of probiotics in patients with kidney failure have not been reported. Several actions of probiotics such as inhibition of potential pathogens, improvement in barrier function, reduction of blood ammonia levels, production of vitamins and digestive enzymes, and reduction of antibioticinduced diarrhea or colitis might be beneficial in patients with kidney failure, but their use requires further study."
NUTRITIONAL STRATEGIES
General Considerations Some initial questions to ask before nutritional support is initiated are the following: Which patient needsnutritional support? The decision to initiate nutritional support is influenced by the following: • The ability of the patient to obtain nutritional requirements by oral nutrition. For example, small infants, patients with neurologic disabilities, those with mechanical obstructions in the upper gastrointestinal tract, anorectic elderly patients, or critically ill patients may require artificial nutritional support.
• The nutritional state of the patient (as determined from serum albumin and transferrin concentrations, anthropometric measurements, and clinical judgment). All patients with an acute illness and evidence of insufficient protein stores should receive nutritional intervention early in the course of the disease, even if it is believed that the patient may soon begin to eat. • The degree of accompanying catabolism (severity and type of accompanying complications and underlying illness). When excessive protein catabolism is present, nutritional support should be initiated early. When should nutrition be started? The greater the extent of catabolism, the earlier nutrition should be initiated to prevent the development of deficiencies and hospital-acquired malnutrition.
At what degree of kidney dysfunction should the nutritional regimen be adapted? Experimental and clinical studies have shown that metabolic alterations associated with kidney failure occur when creatinine clearance falls to less than approximately 50 mt/rnin." Thus, when the serum creatinine concentration is more than 3 mg/dL and/or creatinine clearance is less than 40 mUmin, nutritional regimens should be designed to counteract the specific metabolic abnormalities of kidney failure (see earlier discussion).
Patient Classification Ideally, an individual nutritional program should be designed for each patient with kidney failure because nutritional needs can differ tremendously among patients, making the standardization of nutrition protocols impossible. We suggest that there are three general categories of patients:
The noncatabolic patient with ARF or the patient with stable CRF. This group includes patients without excess catabolism. Their urea nitrogen appearance is less than 5 g of nitrogen above nitrogen intake/day (fable 41-5). In patients with stable CRF, nutritional repletion generally requires a diet designed by a skilled dietitian to achieve a balance between minimizing toxicity of uremia! retarding progression of renal disease and promoting recovery of protein stores.
The patient with a stablecondition treated by hemodialysis or CAPD. Malnutrition has been observed in 10% to 50% of patients treated by regular dialysis or CAPO. Besides disturbances in protein and energy metabolism, muscle wasting is related to hormonal derangements, metabolic acidosis, infections or other superimposed illness, losses of nutrients during dialysis, and the catabolic effect induced by dialysis per se.' In these patients, food intake and especially caloric intake may be inadequate because of anorexia, nausea, vomiting, and psychosocial factors such as loneliness, addiction, or depression.
The patient withARFor CRF orthepatient receiving RRT with superimposed acute illness. In these patients, the primary goal is to maintain protein stores; fluid and electrolyte disorders or accumulation of waste products can be treated by adjusting the intensity of dialysis or hemofiltration. The aim of nutritional therapy should not be to avoid dialysis or reduce its frequency. However, providing
SECTION V • Disease Specific
BED
479
Patient Classification and Substrate Requirements ARF, CRF, RDT/CAPD + Superimposed Catabolic Illness
Patient CIlllI8iftcation Excess urea appearance (above Nintake) (g) Route of nutrient administration Energy recommendations
Noncatabollc ARF or Stable CRF ± Malnutrition
Stable RDT/CAPD ± Malnutrition
Moderate Catabolism
Severe Catabolism
0-(-5)
0-(-5)
6-12
>13
Oral/enteral
Oral/enteral
25-35
30-40
Enteral and/or parenteral 25-35
Enteral and/or parenteral 30-40
0.6-0.8 EAA
1.2-1.4 EAA+ NEAA
0.8-1.2 EAA+NEAA
1.0-1.5 EAA+ NEAA
(keel/kg/day)
Protein (g/kg/day) Nutrients used Oral/enteral Parenteral
Enteral formulas: Enteral formulas: Food or specific enteral Enteral formulas: formulas ± EAA/KA supplements specific/standard specific/standard specific/standard EAA solution Glucose 200/.,-40% plus EAA + NEAA solution (adapted or standard) supplements of vitamins, trace Glucose 50%-70% and fat emulsion 10%-20% elements, and electrolytes as required
ARF, acute renal failure; CAPO, chronic ambulatory peritoneal dialysis; EAA, essential amino acids; KA, keto acids of EAA; NEAA, non-essential amino acids; ROT, regular dialysis therapy.
excessive amounts of protein and calories will not block the processes that are stimulating protein breakdown." The decision of how much protein to prescribe can be based on an analysis of the urea nitrogen appearance (see following discussion). The clinician must also remember that the dialysis process itself stimulates catabolism of muscle protein. Consequently, frequent dialysis may correct fluid and electrolyte abnormalities but cause further loss of protein stores. In clinical practice, these acutely ill catabolic patients can be identified from the extent of protein breakdown associated with their underlying disease. The first category consists of patients with evidence of moderate hypercatabolism having a urea nitrogen appearance that exceeds nitrogen intake by 6 to 12 g of nitrogen/day (see Table 41-5). These patients are those with complicating infections or peritonitis or those who have sustained moderate injury or undergone major surgery and also have associated kidney dysfunction. Tube feeding and parenteral nutrition are generally required and dialysis or hemofiltration often becomes necessary to limit waste product accumulation. A second category of patients with kidney failure are those with hypercatabolism complicating severe trauma, burns, or an overwhelming infection. Their urea nitrogen appearance is markedly elevated to more than 12 g of nitrogen above nitrogen intake. Treatment strategies are usually complex and include enteral or parenteral nutrition and hemodialysis or continuous hemofiltration, in addition to blood pressure and ventilatory support. To avoid protein depletion, nutrient requirements are high, and dialysis is needed to maintain fluid balance and a blood urea nitrogen concentration less than 80 mg/dL (see Table 41-5). Mortality in this group of patients exceeds 60% to 80%. However, kidney dysfunction is not the only cause for the poor prognosis, the superimposed hypercatabolism and the severity of underlying illness and its complications also are contributing factors.
THE PRACTICE OF ENTERAL NUTRITION
Feeding Tubes Percutaneous endoscopic gastrostomy (PEG) should be considered when the need for enteral nutritional support is prolonged as in nursing home patients, confused patients, or those with neurologic disabilities and/or mechanical obstruction of the upper gastrointestinal tract. PEG is contraindicated for patients treated by peritoneal dialysis because of the risk of inducing a gastric leak or peritonitis or external leaking of dialysis fluid.78.79 With special precautions and a prolonged time interval between positioning of the gastrostomy tube and initiation of peritoneal dialysis, a stable seal between the stomach and abdominal wall can form and be used effectively. PEG can be used in children and selected adults treated by CAPO. In infants treated by CAPO, in particular both conventional PEG tubes and gastrostomy button devices were successfully used for long-term feeding.8o•81 Alternatively, an open gastrostomy can be attempted. Soft, fine bore feeding tubes should be used exclusively to prevent the development of pressure ulcerations in the esophagus. Usually, it is sufficient that the tip of the tube is positioned in the stomach, but with prolonged impairment of gastric emptying and vomiting due to gastroparesis, paralytic ileus, duodenogastric and/or gastroesophageal reflux, the tip of the tube should be advanced into the small intestines, preferably in the jejunum.
Enteral Formulas The basic difficulty in designing an enteral diet for patients with kidney failure arises from the diversity of individual needs. Enteral diets for patients with kidney failure represent a compromise between standardized
480
41 • Enteral Nutrition in Renal Disease
nutrient formulations and the requirements of the individual patient. Because enteral diets are not subject to strict regulation by the Food and Drug Administration, systematic investigations of most commercially available diets are lacking.82 Three types of enteral formulas (i.e., those not including supplements of essential amino acids or ketoacids) have been used to treat uremic patients.
Newer types of elemental diets for patients with CRF are the modular diets that integrate protein and energy components (see Table 41-6). To some extent, these diets can be adapted to the needs of a specific patient by altering the number and types of components. The main disadvantages of these powder diets are the time needed to prepare them and the risk of contamination and, thus, elemental powder diets largely have been replaced by ready-to-use high molecular liquid diets.
1. Elemental diets for patients withCRFand noncatabolic patients with ARF. The concepts underlying the low-
2. Ready-to-use high molecular liquid diets for patients with stable CRF and noncatabolic patients with ARF.
protein diet supplemented with essential amino acids for treating patients with CRF have been extended to the field of enteral nutrition. These earlier diets (Table 41-6) contained the eight classic essential amino acids plus histidine and are often incomplete because they must be supplemented with energy substrates, vitamins, and trace elements. The major disadvantages of these enteral diets are not only the limited spectrum of nutrients, but also the high osmolality of the nutrient solution plus the problems of dealing with a powdered diet. Because they contain only essential amino acids, they can be used as a dietary supplement for patients with CRF but for total enteral nutrition, a more complete formula should be used.
BEll
Several ready-to-use formulas are marketed for patients with stable CRF or noncatabolic patients with ARF (Table 41-6). They can be used as an oral supplement or as the sole source of enteral nutrition and are characterized by reduced contents of protein and electrolytes and often contain additives, such as histidine or carnitine. To increase palatability when used as oral supplements, these preparations are available in various flavors. 3. Ready-to-use high molecular liquid diets for stable patients treated by dialysis or catabolic patients with ARF. Several liquid ready-to-use formulas that are adapted to the nutrient requirements of patients treated with RDT or
Enteral Diets for Patients with Chronic Renal Failure
Volume (ml) Calories (kcal) (cal/ml) Proteln:fat:carbohydrates (0/,,) Nitrogen (g) (kcal/gN) Nonprotein (kcal/gN) Osmolar (mOsmol/kg) Protein (g) EAAs (0/,,) NEAAs (0/,,) Hydrolysate (%) Total protein (0/,,) Carbohydrate (g) Mono-disaccharides (0/,,) Oligosaccharides (%) Polysaccharides (%) Fat (g) LCTs(%) Essential FAs (0/,,) MCTs (%) Sodium (mrnol/L) Potassium (rnrnol/L) Phosphorus (rng/L) Vitamins Trace elements
Travaaorb Renal (ClinTec)*
Salvtpeptlde Nephro (ClinTec)t
Survlmed Renal (Fresenlus Kabl).
Replena (Suplena) (Rou)§
Renalcal (Nestle)1I
Renllon 4.0 (Nutrlcla)1
1000
1000
1000
1000
1000
1000
1333.3 1.35 7:12:80
2000 2 8:22:69
1320 1.32 6:10:83
2000 2 6:43:50
2000 2 6.9:35:58.0
2000 2 8:45:47
3.42 389:1 363:1 590 22.9 60 30
6.4 313:1 288:1 507 40 23 20 23 34 350 3 8 69 48 50 31 50 7.2 1.5
3.32 398:1 374:1 600 20.8
4,8 417:1 393.1 600 30
5,9 360:1 340:1 600 34.4 67 33
6,3 319:1 293:1 640 40
100 256 10
29D.4
235 51
a a
a a
270.5 100 17.7 30 18 70 N/A N/A N/A a** b
100 276 100 15.2 70 52 30 15.2 8
90 95.7 100 22 34 29 728 a a
82.4 30
183 100 20
70 N/A N/A N/A a a
14 4 40 a a
*lnstant diet: 3 bags + 810 mLof water =1050mL. 'Instant diet: (I x component I + 1 x component II + 350 mLof water) x 2 = 1000mL. 'Instant diet: 4 bags + 800 mLof water =1000mL. §Complete nutrition, low protein and electrolytes, taurine + carnitine supplement; 8 fl oz cans (237 mL). 11250 mLcans. ~125 mLTetra Pak; carnitine and taurine supplements. **a, 2000kcal/day for RDAs of vitamins and trace elements; b, have to be supplied. EAA, essential amino acids; FA, fattyacids; LCTs, long-chain triglycerides; MCTs, medium-ehain triglycerides; N/A, information not available; NEAAs, nonessential amino acids; RDAs, Recommended DailyAllowances.
--
SECTION V • Disease Specific
481
Enteral Diets for Patients Treated by Regular Dialysis or Chronic Ambulatory Peritoneal Dialysis
Volume (ml) Calories (kcal) (cal/rnl) Protein:fatcarbohydrates (%) Nitrogen (g) (kcaljgN) Nonprotein (kcal/gN) Osmolar (mOsmolkg) Protein (g) Total protein (%) Carbohydrate (g) Mono-disaccharides (%) Oligosaccharides ('X,) Polysaccharides ('X,) Fat (g) LCTs(%) Essential FAs (Yr.) MCTs ('X,) Sodium (rnmol/L) Potassium (mrnol/L) Phosphorus (mg/L) Vitamins Trace elements
Restorlc Nephro Intenslv
Nepro (Ross)*
Nova Source Renal (Novartis)t
Magnacal Renal (Mead Johnson)*
Renilon 7.5 (Nutrlcla)8
1000
1000
1000
1000
1000
2000 2 14:43:43
2000 2 15:45:40
2000 2 15.3:45:40
2000 2 15:45:40
2000
11.2 179:1 154:1 635 69.9 100 215.78 12
12.2 164:1 140:1 700 74'
11.8 170:1 145:1 575 75
12 166:1
200
11.8 169:1 144:1 570 75 100 200
100 86
101 80
36.1 27 695
14 43.5 20.8 650
20 35 32 800
26 3 58
21 49 34.8 28.1 96
a' a
a a
a a
a a
a a
88 95.6 100 20
200 51 149 100 19.5
(Vltasyn)~
2 15:43:42
400 76 208 42 166 96
*Complete nutrition, fluid, high protein, low electrolytes, taurine + Carnitine supplement: 8 fI oz cans. '8 fI oz Tetra Brik Paks; 1000 mL RTH (ready to hang). 18 fI oz cans. §125 mL Tetra Pak; carnitine and taurine supplements. 11500 mL bottle carnitine and taurine supplements. ~Includes protein from caseinatesand L-arginine. a, 2000 kcal/day for RDA of vitamins and trace elements.
CAPO are available. These diets have a higher protein and calcium content but low potassium and phosphate concentrations and a high specific energy content of 1.5 to 2 kcallmL to limit volume intake (see Table 41-7) and may be supplemented with histidine, taurine, or carnitine. Originally designed for oral supplementation, these diets are also available in different flavors. They can be used as the sole source of enteral nutrition and also for hypercatabolic patients with ARF in the intensive care unit. Also available are standard enteral formulas designed for nonuremic patients. In most patients with kidney dysfunction in critical care units, standard enteral formulas are being used. The disadvantages of these conventional diets are their fixed composition that prevents any adaptation to individual needs. Generally, they have a high content of protein and electrolytes, especially potassium and phosphate. Whether diets enriched with various immunomodulating substrates such as glutamine, arginine, ro-3-fatty acids, or nucleotides might be advantageous also in patients with ARF remains to be seen.
Enteral Nutrient Administration The techniques for using enteral nutrition for patients with kidney failure are identical to those used for other patients. Because many patients with kidney failure have
impaired gastric emptying and intestinal motility (often aggravated by diabetes or drugs containing opiates), positioning of the feeding tube into the jejunum may be required. Feeding solutions can be administered intermittently or continuously into the stomach or continuously into the jejunum, preferably by pump. If solutions are given continuously, the stomach should be aspirated every 2 to 4 hours until adequate gastric emptying and intestinal peristalsis are established. This practice will prevent vomiting and reduce the risk of bronchopulmonary aspiration. To avoid osmotic diarrhea, the formula (especially elemental diets with free amino acids and a high osmolality) could be diluted initially. The amount and concentration of the solution should be gradually increased over several days until nutritional requirements are met. Undesired but potentially treatable side effects include nausea, vomiting, abdominal distension, and cramping and diarrhea. Besides reducing the intestinal side effects of enteral nutrition, a program consisting of a gradual increase in amount and concentration of solution will help avoid metabolic derangements in patients with reduced tolerance to nutrients. In malnourished patients treated by dialysis, nocturnal enteral nutrient supplementation via a nasogastric feeding tube has been advocated. Disadvantages of this method include the necessity for repeated placement of a feeding tube, the risk of displacement (intrabronchially), and possible inadvertent
482
41 • Enteral Nutrition in Renal Disease
removal by a confused patient whose enthusiasm for this type of nasogastric feeding has diminished; for these reasons a PEG tube would be preferred. It should be stressed again that even if sufficient nutrient administration cannot be achieved by the enteral route, provision of small amounts of nutrients plus parenteral nutrition will help to maintain intestinal function.
Clinical Experience with Enteral Nutrition in Renal Disease Remarkably few investigations on enteral nutrition in patients with kidney disease have been reported, and these mostly comprise only a few patients. Most of these reports have focused on the feasibility and tolerance of enteral diets whereas data about the nutritional efficiency or a comparison of different diets is rarely provided.
Enteral Nutrition in Acute Renal Failure In recent years, enteral nutrition has become the standard nutritional support for critically ill patients and patients with ARF.19,83,84 Despite the fact that enteral nutrition has become the routine clinical procedure worldwide, systematic investigations have not been performed. In most intensive care units, standard formulas designed for nonuremic patients are used for patients with ARF. However, specific formulas designed for patients who are treated by dialysis and based on a moderate amount of protein might also be advantageous for patients with ARF (see Table 41-7). The first systematic investigation on the safety and efficacy of enteral nutrition in patients with ARF, Fiaccadori and colleagues evaluated nutrition-related complications and adequacy of nutrient administration during 2525 days of artificial nutrition in 68 patients with ARF not requimg RRT and 114 patients requiring RRT as compared to 65 patients with normal renal function." Most ARF patients received a disease-specific formula. Gastric residual volumes and frequency of tube obstruction were higher and withdrawal of enteral nutrition because of complications was more frequent in patients with ARF. Administered volume was inadequate but above 90% of the prescribed in all groups. Protein intake was below the recommended for patients on RRT. The authors conclude that enteral nutrition is safe and effective in patients with ARF but that additional parenteral supplementation may be required in ARF patients on RRT.
Enteral Nutrition in Chronic Renal Failure Nutritional support is obligatory for the preterm infant, the small infant, or the young child with CRD, and, hence, most published studies about enteral nutrition patients for patients with CRF have been performed in pediatric patients. Ledermann and co-workers's reported on their experience with enteral nutrition in 29 children with a mean glomerular filtration rate of 12.1 mt/min." Long-termenteral nutrition prevented or reversed weight
loss and growth retardation, and the children achieved significant catch-up growth if therapy was started before the age of 2 years. Experience with enteral nutrition in adults with CRFis very limited, but the population for whom enteral nutrition would be obligatory (i.e., neurologically compromised patients or patients in nursing homes who do not eat enough protein or calories) is small." Several of the studies have used enteral diets as oral supplements in patients who could eat spontaneously. Abras and Walser" conducted a study of continuous nasogastric feeding in four patients with advanced CRF using an experimental low-nitrogen diet composed of amino and keto acids and oligosaccharides. The subjects were permitted to consume unlimited quantities of an oral diet, but about 70% of their intake was delivered by a feeding tube. Despite the extremely small amount of nitrogen in the formula, nitrogen balance became positive in all subjects, body weight was maintained, and plasma protein concentrations remained stable. For the newer, ready-to-use liquid formulas, only feasibility studies are available. A reduced protein formula was tested in 18 patients with CRF over 4 weeks. The patients ate normally and added the supplement at a rate of approximately 10 kcal/kg of b.wt./day, yielding recommended intake levels of protein and energy, stable blood chemistry values in all patients, and gastrointestinal tolerance."
Enteral Nutrition in Patients Receiving Regular Renal Replacement Therapy Enteral nutrition has been used in pediatric patients treated by dialysis. The use of nasogastric feeding facilitates the provision of adequate nutrients and seems to result in improved patient outcome in the majority of published reports. 90·9] In adults, experience with enteral nutrition in patients treated by dialysis is much more limited. 92 Douglas and colleagues'" used nasogastric feeding of conventional diets providing 44 g of protein and 2060 kcal for the treatment of malnourished patients treated by dialysis. In some, enteral feeding was given only for 8 hours at night and provided 55 g of protein and 1450 kcal. Plasma protein levels improved. Cockram and associates" compared three different enteral formulas in 79 patients treated by hemodialysis: a standard formula, a formula adapted for patients with kidney failure, or this adapted formula supplemented with dietary fiber (fructooligosaccharides). The formulas were infused at a rate to yield about 35 kcal/kg/day and 1.25 g of protein/kg/day, respectively, and were the sole source of nutrition during 10 days. The adapted formula improved serum electrolyte concentrations (phosphorus, potassium, and calcium), whereas this formula plus dietary fiber caused less constipation. Several subjects, however, developed hypercalcemia, but this also was common when standard diets were infused. Holley and Kirk36 retrospectively analyzed the efficacy of enteral tube feeding in 10 adult patients treated by hemodialysis (8 were fed via a PEG tube); an improvement in serum albumin levels was seen, but 8 of 10 patients
SECTION V • Disease Specific
developed hypophosphatemia during tube feeding. Such findings are also common with total parenteral nutrition therapy in patients with kidney failure in whom infusion of a phosphate-free nutrition solution can result in hypophosphatemia." Several authors have investigated enteral diets used as oral supplements for malnourished patients treated by dialysis. In 18 patients treated by hemodialysis, Kuhlmann and associates'" used a low-phosphate diet given at two rates (1.4 g of protein/kg/day, 45 kcal/kg/day vs. 1.2 g of protein/kg/day, 35 kcal/kg/day); the control group was fed a diet supplemented with 10% of mean protein and energy intake (1.1 g of protein/kg/day, 28 kcal/kg/day) over 3 months. In the group with the highest energy intake, increases in weight and serum albumin levels were seen. Weight gain correlated with dietary energy intake but not with protein intake.
Intradialytic Enteral Nutrition In malnourished patients treated by hemodialysis who have a reduced spontaneous nutrient intake, there may be a role for an enteral formula during hemodialysis therapy. A supplement of one unit (237 mL) containing 16.6 g of protein, 22.7 g of fat, and 53 g of carbohydrates in 85 patients treated by hemodialysis who were followed for 6 months led to higher serum protein concentrations (albumin and prealbumin) and a higher subjective global assessment score plus a minor increase in body mass index." However, 20% of the patients did not comply with the treatment regimen. This intervention is promising and much less expensive than intradialytic parenteral nutrition. Sharma and co-workers" compared two diets: a homemade preparation and a commercially available supplement (500 kcal, 15 g of protein) given after each hemodialysis session. The control group received no supplement during 1 month of observation." Both of the groups receiving supplements showed an improvement in dry body weight and body mass index, an increase in serum albumin level, and an improvement in functional scoring. No intolerance was reported. Some have suggested that enteral nutrition be stopped during hemodialysis because splanchnic blood flow might decrease and precipitate gastrointestinal symptoms. Ifa patient can tolerate intradialytic nutrient supply, nutrients can be provided during treatment.
Complications and Monitoring of Enteral Nutrition Side effects and complications of nutritional support in patients with kidney failure do not differ from those observed in other patient groups, except for the intolerance to administration of fluid and electrolytes; however, an exaggerated protein or amino acid intake will precipitate symptoms of uremia. In addition, uremic patients can develop glucose intolerance and decreased fat clearance with hyperglycemia and hypertriglyceridemia, respectively. Thus, nutritional therapy in patients with renal failure requires a tight schedule of monitoring to
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avoid the development of metabolic complications of nutritional intervention.
PARENTERAL NUTRITION Extensive reviews of the use of parenteral nutrition for patients with kidney failure are available.'? We believe that parenteral nutrition should not be viewed as an alternative but rather as a complementary method of nutritional support for patients whose nutritional requirements cannot be met by the enteral route alone. Because ARFcan occur in patients with severe gastrointestinal dysfunction or pancreatitis or in hypercatabolic patients with multiple organ dysfunction, total or supplementary parenteral nutrient support may become necessary. For selected dialysis patients with overt malnutrition in whom oral or enteral nutritional supplementation has failed, intradialytic parenteral nutrition could be tried to improve the nutritional state.
CONCLUSION Enteral nutrition has become the preferred type of artificial nutritional support in patients with kidney failure as well as in many intensive care units, in pediatric nephrology, or for malnourished patients receiving dialysis. Whenever possible, nutrients should be supplied orally or enterally, and even if nutritional needs are not provided by the enteral route alone, small amounts of luminal nutrients may help to maintain gastrointestinal function and integrity. Unfortunately, there are few systematic studies of the efficacy of this type of therapy. The optimal type and composition of enteral diets remain to be specified, and more work is needed to define the requirements of various groups of patients with uremia. The heterogeneity of patient groups, the diverging aims of nutritional support, and the differences in individual requirements hamper the design of standardized enteral diets. In the future, nutritional therapy must be focused on a more qualitative type of metabolic intervention, taking advantage of specific effects of various nutrients on physiologic functions ("pharmaconutrients"). These functions include protein metabolism and immunology. With this approach, the efficiency of nutritional support should improve while morbidity in patients with kidney failure requiring artificial nutrition is reduced. REFERENCES 1. Mitch WE: Malnutrition: A frequent misdiagnosis for hemodialysis patients. J Clin Invest 2002;110:437-439. 2. Maroni B, Mitch WE: Role of nutrition in prevention of the progression of renal disease. Annu Rev Nutr 1997; 17:435-455. 3. Mitch WE, Walser M: Nutritional support of patients with kidney disease. In Brenner BM (ed): Brenner & Rector's The Kidney, 7th ed. Philadelphia, WB Saunders, 2004. 4. Bailey JL,Mitch WE: Pathophysiology of uremia. In Brenner BM (ed): Brenner & Rector's The Kidney, 7th ed, Philadelphia, WB Saunders,
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5. Mitch WE, Klahr S (eds): Handbook of Nutrition and the Kidney. Philadelphia, Lippincott Williams & Wilkins, 2002. 6. Schneeweiss B, Graninger W, Stockenhuber F, et al: Energy metabolism in acute and chronic renal failure. Am J Clin Nutr 1990;52:596-601. 7. Neyra R, Chen KY, Sun M, et al: Increased resting energy expenditure in patients with end-stage renal disease. JPEN J Parenter Enteral Nutr 2003;27:36-42. 8. Lim VS, Kopple 10: Protein metabolism in patients with chronic renal failure: Role of uremia and dialysis. Kidney Int 2000;58:1-10. 9. Mitch WE, Price SR: Mechanisms activated by kidney disease and the loss of muscle mass. Am J Kidney Dis 2001;38:1337-1342. 10. Goodship TH, Mitch WE, Hoerr RA,et al: Adaptation to low-protein diets in renal failure: Leucine turnover and nitrogen balance. J Am Soc Nephrol 1990;1:66-75. 11. Price SR, Reaich D, Marinovic AC, et al: Mechanisms contributing to muscle wasting in acute uremia: Activation of amino acid catabolism. J Am Soc NeuroI1998;9:43~43. 12. Ivarsen P, Tietze IN, Pedersen EB: Nutritional status and amino acids in granulocytes and plasma in patients with chronic renal disease and varying residual renal function. Nephron 2001;88: 224-232. 13. Druml W, Fischer M, Liebisch B, et al: Elimination of amino acids in renal failure. Am J Clin Nutr 1994;60:41~23. 14. Laidlaw SA, Kepple JD: Newer concepts of indispensable amino acids. Am J Clin Nutr 1987;46:593--605. 15. Clark AS, Mitch WE: Muscle protein turnover and glucose uptake in acutely uremic rats. J Clin Invest 1983;72:836-845. 16. Bistrian BR: Interaction between nutrition and inflammation in end-stage renal disease. Blood Purif 2000;18:333-336. 17. Horl WH, Heidland A: Enhanced proteolytic activity-Cause of protein catabolism in acute renal failure. Am J Clin Nutr 1980;33: 1423-1427. 18. Franch HA, Mitch WE: Catabolism in uremia: The impact of metabolic acidosis. J Am Soc Nephrol 1998;9(12suppl):S78-S81. 19. Druml W: Nutritional support in patients with acute renal failure. In Molitoris BA, Finn WF (eds): Acute Renal Failure [A companion to Brenner & Rector's The Kidney]. Philadelphia, WB Saunders, 2001, pp 465-489. 20. Hirschberg R, Kopple J, Lipsett P, et al: Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. Kidney Int 1999;55:2423-2432. 21. Johansen KL, Mulligan K, Schambelan M: Anabolic effects of nadrolone decanoate in patients receiving dialysis. JAMA 1999;281: 1275-1281. 22. Sechi LA, Catena C, Zingaro L,et al: Abnormalities of glucose metabolism in patients with early renal failure. Diabetes 2002;51: 1226-1232. 23. May RC, Clark AS, Goheer MA, Mitch WE: Specific defects in insulin-mediated muscle metabolism in acute uremia. Kidney Int 1985;28:490-497. 24. Cianciaruso B, Bellizzi V, Napoli R, et al: Hepatic uptake and release of glucose, lactate and amino acids in acutely uremic dogs. Metabolism 1991;40:261-290. 25. Cianciaruso B, Sacca L,Terracciano V, et al: Insulin metabolism in acute renal failure. Kidney Int 1987;23(suppl 27):109-112. 26. Wanner C: Lipids in end-stage renal disease. J Nephrol 2002;15: 202-204. 27. Tsumura M, Kinouchi T, Ono S, et al: Serum lipid metabolism abnormalities and change in lipoprotein contents in patients with advanced-stage renal disease. Clin Chim Acta 2001;314:27-37. 28. Mordasini R, Frey F, Flury W, et al: Selective deficiency of hepatic triglyceride lipase in uremic patients. N Engl J Med 1977;297: 1362-1366. 29. Druml W, Zechner R, Magometschnigg D, et al: Post-heparin lipolytic activity in acute renal failure. Clin Nephrol 1985;23:289-293. 30. Druml W, Fischer M,Sertl S, et al: Fat elimination in acute renal failure: Long chain versus medium chain triglycerides. Am J Clin Nutr 1992;55:46~72.
31. Moberly JB, Attman PO, Samuelsson 0, et al: Alterations in lipoprotein composition in peritoneal dialysis patients. Perit Diallnt 2002; 22:220-228. 32. Kaysen GA: Nephrotic hyperlipidemia: Primary abnormalities in both lipoprotein catabolism and synthesis. Miner Electrolyte Metab 1992;18:212-216.
33. Wanner C, Riegel W, Schaefer RM, Horl WH: Camitine and camitine esters in acute renal failure. Nephrol Dial Transplant 1989;4: 951-956. 34. Ahmed J, Weisberg LS: Hyperkalemia in dialysis patients. Semin Dial 2001;14:348-356. 35. Druml W, Lax F, Grimm G, Schneeweiss B, et al: Acute renal failure in the elderly 1975-1990. Clin Nephrol 1994;41:342-349. 36. Holley JL, Kirk J: Enteral tube feeding in a cohort of chronic hemodialysis patients. J Ren Nutr 2002;12:177-182. 37. Kleinberger G, Gabl F, Gassner A, Lochs H, Pall H, Pichler M: Hypophosphatemia during parenteral nutrition in patients with renal failure. Wien Klin Wochenschr 1978;90:169-172. 38. Ritz E, Matthias S, Seidel A, et al: Disturbed calcium metabolism in renal failure-Pathogenesis and therapeutic strategies. Kidney Int 1992;38(suppI38):S37-S42. 39. Shaah GM, Kirschenbaum MA: Renal magnesium wasting associated with therapeutic agents. Miner Electrolyte Metab 1991;17:58-64. 40. Descombes E, Hanck AB, Fellay G: Water soluble vitamins in chronic hemodialysis patients and need for supplementation. Kidney Int 1993;43:1319-1328. 4I. Story DA, Ronco C, Bellomo R: Trace element and vitamin concentrations and losses in critically ill patients treated with continuous venovenous hemofiltration. Crit Care Med 1999;27: 22Q-223. 42. Druml W, Schwarzenhofer M, Apsner R, Horl WH: Fat soluble vitamins in acute renal failure. Miner Electrolyte Metab 1998;24: 22Q-226. 43. Smythe WR, Alfrey AC, Craswell PW, et al: Trace element abnormalities in chronic uremia. Ann Intern Med 1992;96:302-310. 44. Okada A,Takagi Y, Nezu R, et al: Trace element metabolism in parenteral and enteral nutrition. Nutrition 1995;11:106-113. 45. Konig JS, Fischer M, Bulant E, et al: Antioxidant status in patients on chronic hemodialysis therapy: Impact of parenteral selenium supplementation. Wien Klin Wochenschr 1997;109:13-19. 46. Metnitz PGH, Fischer M, Bartens S, et al: Impact of acute renal failure on antioxidant status in patients with multiple organ failure. Acta Anaesthesiol Scand 2000;44:236-240. 47. IkizlerTA, Flakoll PJ, Parker RA, Hakim RM: Amino acid and albumin losses during dialysis. Kidney Int 1994;46:830-837. 48. Ikizler TA, Pupim LB, Brouillette JR, et al: Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation. Am J Physiol 2oo2;282:EI07-EI16. 49. Caglar K, Peng Y, Pupim LB,et al: Inflammatory signals associated with hemodialysis. Kidney Int 2002;62:1408-1416. 50. Jackson P, Loughrey CM, Lightbody JH, et al: Effects of hemodialysis on total antioxidant capacity and serum antioxidants in patients with chronic renal failure. Endocrinol Metab 1995;41:1135-1138. 51. Druml W: Metabolic aspects of continuous renal replacement therapies. Kidney Int 1999;56(suppl 72):S56-S61. 52. Frankenfeld DC, Badellino MM, Reynolds N, et al: Amino acid loss and plasma concentration during continuous hemofiltration. JPEN J Parenter Enteral Nutr 1993;17:551-561. 53. Mokrzycki MH, Kaplan AA: Protein losses in continuous renal replacement therapies. J Am Soc Nutr 1996;7:2259-2263. 54. Kopple 10, Monteon F, Shaib J: Effect of energy intake on nitrogen metabolism in nondialyzed patients with chronic renal failure. Kidney Int 1988;29:734-742. 55. Chima CS, Meyer L, Hummell AC, et al: Protein catabolic rate in patients with acute renal failure on continuous arteriovenous hemofiltration and total parenteral nutrition. J Am Soc Nutr 1993;3: 1516-1521. 56. Kopple 10: Dietary protein and energy requirements in ESRD patients. Am J Kidney Dis 1998;32:S97-S104. 57. Aparicio M, Chauveau P, De Precigout V, Bouchet JL, Lasseur C, Combe C: Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet. J Am Soc NephroI2000;11:708-716. 58. Pickering WP, Price SR, Bircher G, Marinovic AC, Mitch WE, Walls J: Nutrition in CAPD: serum bicarbonate and the ubiquitinproteasome system in muscle. Kidney Int 2002;61:1286-1292. 59. K1DOQI Clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 2oo0;35:SuppI2:S1-S140. 60. Mashour S, Turner JF Jr, Merrell R:Acute renal failure, oxalosis, and vitamin C supplementation: a case report and review of the literature. Chest 2000;11:561-563.
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61. Boaz M, Smetana S, Weinstein T, et al: Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): Randomised placebo-controlled trial. Lancet 2000;356: 1213-1218. 62. Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R: Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care Med 1999;27:1807-1813. 63. Kang JY: The gastrointestinal tract in uremia. Dig DisSci 1993;38: 257-268. 64. Etemad B: Gastrointestinal complications of renal failure. Gastroenterol Clin North Am 1998;27:875-892. 65. Drukker A, Levy E, Bronza N, et al: Impaired intestinal fat absorption in chronic renal failure. Nephron 1982;30:154-160. 66. Lefebvre HP, FerreJP, WatsonAD, et al: Small bowel motility and colonic transit are altered in dogs with moderate renal failure. Am J PhysioI2001;281:R230-R238. 67. Silva AP, Freire CC, Gondim F deA, et al: Bilateral nephrectomy delays gastric emptying of a liquid meal in awake rats. Ren Fail 2002;24:275-284. 68. Silang R, Regalado M, Cheng TH, Wesson DE: Prokinetic agents increase plasma albumin in hypoalbuminemic chronic dialysis patients with delayed gastric emptying. Am J Kidney Dis2001;37: 287-293. 69. Alexander JW: Bacterial translocation during enteral and parenteral nutrition. Proc NutrSoc 1998;57:389-393. 70. Fiaccadori E, Maggiore U, Clima B, et al: Incidence, risk factors, and prognosis of gastrointestinal hemorrhage complicating acute renal failure. Kidney Int 2001;59:1510-1519. 71. Mouser JF, Hak EB, Kuhl DA, et al: Recovery from ischemic acute renal failure is improved with enteral compared with parenteral nutrition. CritCare Med 1997;25: 1748--1754. 72. Roberts PR, Black KW, Zaloga GP: Enteral feeding improves outcome and protects against glycerol-induced acute renal failure in the rat. Am J RespirCritCare Med 1997;156:1265-1269. 73. Metnitz PGH, Krenn CG, SteltzerH, et al: Effect of acute renal failure requiring renal replacement therapyon outcome in critically ill patients. Crit Care Med 2002:30:2051-2057. 74. Ohta K, Omura K, Hirano K, et al: The effectsof an additive small amount of a low residual diet against total parenteral nutritioninduced gut mucosal barrier. Am J Surg2003;185:79-85. 75. Bliss DZ, Stein TP, SchleiferCR, Settle RG: Supplementation with gum arabic fiber increases fecal nitrogen excretion and lowers serum urea nitrogenconcentration in chronic renal failure patients consuminga low-protein diet. AmJ ClinNutr 1996;63:392-398. 76. Chow J: Probiotics and prebiotics: A brief overview. J Ren Nutr 2002; 12:76-86. 77. Shaw JH, Wildbore M, Wolfe RR: Whole body protein kinetics in severelyseptic patients.The response to glucose infusion and total parenteral nutrition. AnnSurg 1987;205:288--294. 78. Fein PA, Madane SJ, Jorden A, et al: Outcome of percutaneous endoscopic gastrostomy feeding in patients on peritoneal dialysis. Adv Perit Dial 2001;17:148--152.
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79. Fein PA: Safetyof PEG tubes in peritoneal dialysis patients. Semin Dial 2002;15:213-214. 80. O'Regan S, Garel L: Percutaneous gastrojejunostomy for caloric supplementation in children on peritoneal dialysis. Adv Perit Dial 1990;6:273-275. 81. Watson AR, Coleman JE, Taylor EA: Gastrostomy buttons for feeding children on continuous cycling peritoneal dialysis. Adv Perit Dial 1992;8:391-395. 82. Talbot JM: Guidlinesfor the scientific review of enteral food products for special medical purposes. JPEN J Parenter Enteral Nutr 1991;15(suppl):995-174S. 83. Seidner DL, Matarese LE, SteigerE: Nutritional care of the critically ill patient with renal failure. Semin Nephrol 1994;14:53-63. 84. Leverve X, Bamoud 0: Stressmetabolismand nutritionalsupport in acute renal failure. Kidney Int Suppl 1998;66:S62-S66. 85. Fiaccadori E, Maggiore U, Giacosa R, et al: Enteral nutrition in patients with acute renal failure. Kidney Int 2004;65:999-1008. 86. LedermannSE, Shaw V,Trompeter RS: Long-term enteral nutrition in infants and young children with chronic renal failure. Pediatr NephroI1999;13:87Q-875. 87. Gretz N, Jung M, Scigalla P, Strauch M: Tube feeding in patients suffering from renal failure. In Giovanetti S (ed): Nutritional treatment of chronic renal failure. Boston, Kluwer Academic, 1989, pp 339-342. 88. Abras E, Walser M: Nitrogen utilization in uremic patients fed by continuous nasogastricinfusion. Kidney Int 1982;22:392-397. 89. Cockram DB, MooreLW, Acchiardo SR: Response to an oral nutritional supplement for chronic renal failure patients. J Ren Nutr 1994;4:78-85. 90. Warady BA: Gastrostomy feedings in patients receiving peritoneal dialysis. Perit Dial1nt1999;19:204-206. 91. Ledermann SE, Spitz L, Moloney J, et al: Gastrostomy feeding in infants and children on peritoneal dialysis. Pediatr Nephrol 2002; 17:246-250. 92. Wolfson M: Use of nutritional supplements in dialysis patients. Semin Dial 1992;5:285-290. 93. Douglas E, LomasL, Prygrodzka F,et al: Nutrition and malnutrition in renal patients: The role of nasa-gastric nutrition. Proc Eur Dial TransplantAssoc 1982;11:17-20. 94. Cockram DB, HensleyMK, Rodriguez M, et al: Safetyand tolerance of medical nutritional products as sole sources of nutrition in people on hemodialysis. J Ren Nutr 1998;8:25-33. 95. Kuhlmann MK, Schmidt F, Kohler H: High protein/energy vs. standard protein/energy nutritional regimen in the treatment of malnourished hemodialysispatients.MinerElectrolyte Metab1999; 25:306-310. 96. CaglarK, FedjeL, Dimmitt R,et al:Therapeutic effectsof oral nutritional supplementation during hemodialysis. Kidney Int 2002;62: 1054-1059. 97. Sharma M, Rao M, Jacob S, Jacob CK: A controlled trial of intermittent enteral nutrient supplementation in maintenance hemodialysis patients. J Ren Nutr2002;12:229-237.
Enteral Nutrition in Human Immunodeficiency Virus Infection Gabriellonescu, MD Donald P. Kotler, MD
CHAPTER OUTLINE Introduction Effects of Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome on Nutritional Status Macronutrients Micronutrients Pathogenesis of Malnutrition during Disease Progression Alterations in Food Intake Malabsorption Metabolic Alterations Nutritional Support General Issues Enteral and Parenteral Therapies Oral Enteral Supplements Appetite Stimulants Nonvolitional Feeding Adjunctive Therapies Conclusion
INTRODUCTION Malnutrition has been recognized as part of late-stage human immunodeficiency virus (HlV) infection and results of studies, such as The Multicenter AIDS Cohort Study, showed weight loss to be an independent predictor of mortality in persons with marked CD4+ lymphocyte depletion.' The Centers for Disease Controland Prevention recognizes malnutrition as an acquired immunodeficiency syndrome (AIDS)-defining disease complication." Early studies reflected the natural history of HIV infection, in which malnutrition and wasting were the rule. The development of highly active antiretroviral therapy (HAARD has profoundly affected the course of HIV infection and sharply decreased mortality.' In the Western
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world, the application of HAART led to a fall in the number of severely malnourished patients. However, malnutrition remains a significant problem in the United States because in up to one third of HIV-infected people, the condition is undiagnosed, some patients do not take antiretroviral drugs, and others harbor viruses that are resistant to therapy. In this chapter we will review the effects of HIV infection and AIDS upon nutritional status, both of macronutrients and micronutrients. The pathogenesis of proteinenergy malnutrition will be discussed. Updates on the effects of nutritional support will be reviewed with an emphasis on studies using oral supplements, appetite stimulants, and nonvolitional enteral feeding. The chapter will not include any discussion of the recently described condition, often called lipodystrophy, that is characterized by body fat redistribution and metabolic changes because this condition is not associated with proteinenergy malnutrition.
EFFECTS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND ACQUIRED IMMUNODEFICIENCY SYNDROME ON NUTRITIONAL STATUS
Macronutrients Clinical disease progression and the development of opportunistic infections often were found to follow or coincide with the noticeable weight loss (>10% of premorbid weight).' A cross-sectional study analyzed the composition of weight lost by patients with AIDS compared with control subjects." Body cell mass (BCM) , as reflected by total body potassium content, was markedly reduced in men with AIDS, whereas body fat content was similar to that of homosexual male control subjects. The loss in weight was less profound than the loss in
SECTION V • Disease Specific
BCM. Intracellular water volume depletion directly correlated with BCM loss, whereas relative extracellular water volumes were increased. The increase in extracellular water content, along with the relative lack of fat depletion, diminished the measured change in weight. Thus, malnutrition often was more severe than the weight loss suggested. In addition, normal weight did not necessarily equate with adequate nutritional status. The composition of weight loss in the AIDS patients who were studied suggested a stressed rather than a starved condition. The loss of BCM evinces a proteinwasting state, which was corroborated in a follow-up study showing depletion of the total body nitrogen concentration." Other studies have revealed visceral protein depletion via analysis of serum protein levels5•7,8 as well as decreased muscle protein synthesis despite increased whole-body protein turnover." Further analyses of body composition by Ott and colleagues'? confirmed the depletion of BCM in HIV-infected patients, even relatively early in the disease course. In contrast, some AIDS patients do not have BCM depletion, implying that the presence of immune deficiency alone does not determine the existence or degree of malnutrition. The composition of weight loss differs in men and women. The cross-sectional study cited earlier" revealed that HIV-infected women had greater relative losses of body fat than BCM, similar to findings in people with eating disorders, such as anorexia nervosa. These findings were confirmed in a study by Kotler and associates, II who described different effects of HIV infection on body composition in the two sexes. They found a pronounced lean body mass (LBM) loss and relative fat gain in Hlv-positive males in contrast to relatively preserved LBM and loss of fat mass in HIV-positive females. The sex differences were similar in Caucasian and African cohorts. The explanation for the sex-specific differences may be the HIV-related alterations of the hormonal milieu: a reduction in testosterone level resulting in BCM depletion in men in contrast to decreased estrogen and progesterone levels leading to fat loss in women. Alternatively, these differences may be related to baseline body composition. Grinspoon and co-workers'! showed that as HIV infection progressed through early to late stages in women, their fat mass decreased, followed later by LBM losses. These changes were paralleled by decreases in free testosterone, dehydroepiandrosterone, follicle-stimulating hormone, and luteinizing hormone levels, and increases in blood glucose level and resting energy expenditure; growth hormone level was not different from that of a control group. Also, total serum testosterone concentrations tended to correlate with CD4+ counts. To examine the consequences of malnutrition in patients with AIDS, the relationship between BCM depletion and death in patients not receiving nutritional support was examined." Normalized BCM was lower in patients close to death, with an extrapolated BCM at death of about 50% of normal (Fig. 42-1). Extrapolated body weight was about one third below ideal. The results imply that the timing of death from wasting in AIDS patients is related to the degree of BCM depletion
487
95
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o z
70
1 --:::--
_-=::::::
.,e. 45 20+------r-----..., 100
50
0
Time from death-days FIGURE 42-1. Comparison of the relationships of normalized total-body (TB) potassium content and body weight as a percent of ideal body weight (I B) to the timing of death. (Adapted from Kotler DP, Wang J, Pierson RN: Studies of body composition in patients with the acquired immunodeficiency syndrome. Am J Clin Nutr 1985;42:1255-1265.)
rather than the specific cause of the wasting process. Other measures of malnutrition also are associated with increased mortality in AIDS patients. \'7,8.13 Longitudinal studies of nutritional status conducted in clinically stable outpatients with AIDS were performed to determine whether progressive wasting is a constant phenomenon in AIDS patients." Patients with stable AIDS demonstrated normal food consumption and mild to moderate malabsorption of sugars and fats, with a compensatory decrease in resting energy expenditure compared with control subjects.l-" Macallan and colleagues" found that weight loss was episodic, with frequent reversals, either spontaneously or in response to treatment of a specific disease complication. Systemic infections commonly produced acute weight loss, whereas intestinal diseases more often manifested with subacute, progressive wasting. Failure to reverse weight loss predicted a terminal course. Such findings underscore the hypothesis that wasting accompanies disease complications and is not an intrinsic characteristic of AIDS per se.
Micronutrients Micronutrient deficiencies occur in HIV-infected individuals, often relatively early in the disease course. A comparison of the relative rates of development and progression of macronutrient and micronutrient deficits is not available. The most commonly recognized micronutrient deficiency is that of vitamin B12• Several studies conducted in the pre-HAART era showed a prevalence of vitamin BI2 concentrations of about one third of normal. One study showed absent intrinsic factor secretion in some patients, whereas several have documented abnormal Schilling test results including part 2 (vitamin BI2 complexes to intrinsic factor), implying abnormalities in ileal absorption. Serum levels of other water-soluble vitamins also have been reported to be low, despite apparent normal intake." Deficiencies of fat-soluble vitamins also occur, especially in patients with fat malabsorption. Decreased serum zinc and selenium concentrations have been reported.Pj? Studies have shown that serum zinc levels correlate with development of AIDS in HIV-infected subjects," but a cause-and-effect relationship
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42 • Enteral Nutrition in Human Immunodeficiency Virus Infection
has not been demonstrated. Selenium deficiency has been associated with an increased mortality risk.22 Cardiomyopathy" and decreased selenium contents were found on autopsies of cardiac muscle from patients who died of AIDS in one study.24 The implications of these micronutrient deficiencies are unclear. It is risky to base therapy on serum levels of zinc and selenium because serum concentrations may fall as a result of the acute-phase response and may indicate extravascular sequestration rather than a deficiency. On the other hand, a recent study did identify neuropsychologic changes associated with low serum vitamin B12 concentrations and normalization as a result of specific supplementation." Studies in HIV-infected subjects have revealed glutathione depletion" believed to reflect increased antioxidant requirements. The finding of an increased rate of HIV replication in cells undergoing oxidative stress and the inhibition of this HIV replication by N-acetyli-cysteine suggest a possible association between a specific nutritional deficiency and disease progression."
PATHOGENESIS OF MALNUTRITION DURING DISEASE PROGRESSION The progression of HIV disease can be categorized into three basic stages: early, intermediate, and late, each with distinct nutritional needs. HIV seropositivity alone, without clinical or immunologic evidence of immune deficiency, represents early disease. Few nutritional studies have been performed in patients at this stage of disease. Laboratory evidence without clinical evidence of immune deficiency or any AID5-specific symptoms represents the intermediate stage of disease. This phase is associated with nutritional alterations, although progressive wasting is rare. Studies have shown mild-tomoderate depletion of BCM,1O mild elevations in resting energy expenditure.P-" and serologic evidence of a chronic, systemic inflammatory disorder. 3o.31The specific causes of these metabolic abnormalities are uncertain but are felt to be epiphenomena of HIV replication's and the anti-HIV immune response. The erythrocyte sedimentation rate is elevated and so are serum ~fmicro globulin, urinary neopterin, and serum a-interferon levels.P It also is possible that metabolic abnormalities occur in response to occult infections." Cell marker studies of peripheral blood lymphocytes" and studies of cytokine expression in lymphoid tissues 36•37both showed evidence of immune activation. Nutritional deficiencies may be severe and progressive in late stages of HIV and are multifactorial in etiology, evolving from alterations in food intake, nutrient absorption, or intermediary metabolism. Intake, absorption, and metabolism are highly regulated and interrelated, so that any disease may affect all three simultaneously.
Alterations in Food Intake Oral, pharyngeal, or esophageal pathologic conditions (Fig. 42-2), medications, and psychosocial and economic
FIGURE 42-2. Barium esophagram demonstrating characteristic diffuse involvement of the esophagus by Candida albkans (arrow).
factors may act alone or in combination to reduce food intake. Diagnosis can be based upon an algorithmic approach (Fig. 42-3). In addition, food intake may be reduced in response to intestinal malabsorption'" or systemic disease." Cytokines mediate the anorexia of systemic infection," whereas the precise mediators of changes in appetitive behavior related to malabsorption are unknown. Regardless of the primary cause of disease, decreased food intake may contribute to wasting. As a corollary, effective therapy should produce a return of appetite. This point was clearly demonstrated in a longitudinal study of HIV-infected and AIDS patients with and without systemic infection." Increased resting energy expenditure was demonstrated in all HIVinfected groups, and results were comparable in AIDS patients with and without infections. In another study, short-term weight loss was documented in AIDS patients with infections and correlated with decreased food intake, rather than increased energy expenditure.f Other studies have demonstrated higher metabolic rates in HIV-infected patients with active infection."
SECTION V • Disease Specific
1. Diet History 2. Calorie Count 3. Availability of Food Normal
Low
t No Offending Medication
1t
r- • I
Offending Medication
Discontinue I
No Local Pathologic Condition
• t
Local Pathologic Condition
I
Treat
NoCNS Disease
~ Evaluate for
CNS Disease
JI
1
----. Nontreatable Malabsorption, Metabolic Process
Nonvolitional Feeding
Reevaluate
l
Treatable
1
Treat
FIGURE 42-3. Clinical evaluation of food intake. CNS, central nervous system.
Malabsorption Chronic diarrhea is a very common complaint of HIVinfected individuals in the United States and in developing countries." Abnormalities in absorption have been noted repeatedly and range from occult to clinically severe. These were most apparent in the pre-HAART era and still are characteristic of the situation in developing countries. An opportunistic infection can be demonstrated in most patients with severe malabsorption (Fig. 42-4).45 In the absence of opportunistic infections, small intestinal structure and function may be normal.45,46 Clinically important malabsorption is limited mainly to patients with severe immune depletion (CD4+ count <100 cells/mrn"). These findings imply that small intestinal damage results from a disease complication and is not an intrinsic characteristic of AIDS. Given that infections such as cryptosporidiosis are often acquired through ingestion of contaminated water," accounting for a substantial percentage of occurrences of malnutrition associated with HIV in countries without effective public health measures is difficult.
489
Intracellular pathogens that cause conditions such as cryptosporidiosis, microsporidiosis, and isosporiasis are the most common organisms found on clinical evaluation of small intestinal disease," leading to excess losses of enterocytes and hyperplastic villus atrophy. Mycobacterium species, such as Mycobacterium aviumintracellulare complex, also may cause an enteropathy characterized by marked fat malabsorption associated with evidence of systemic infection." Malabsorption may result from infiltration of the lamina propria, submucosa, and intestinal lymphatics with macrophages containing mycobacteria, leading to an exudative enteropathy due to lymphatic blockade by infected macrophages. Diarrhea also may be the result of infection by enteroadherent bacteria. Adherence is associated with cytoskeletal alterations and epithelial cell cytotoxicity, especially in the ileum. 50 Some cryptosporidial infections also are localized in the ileum." Some authors have suggested that small intestinal alterations may reflect the response to aT-ceil-mediated reaction, including, possibly, the response to infection with HIV itself.52 In recent series, 15% to 25% of comprehensive evaluations (Fig. 42-5) for intestinal malabsorption revealed no pathogenic organisms." Intraluminal bacterial overgrowth has been suggested as a pathogenic factor in malabsorption.P Although elevations in colony counts to the degree seen in scleroderma and other such motility disorders are not seen in AIDS patients, some bacterial overgrowth may occur due to the presence of hypochlorhydrla.sv" Ileal dysfunction may occur as an isolated phenomenon or in association with diffuse intestinal disease and other signs of malabsorption. The spectrum of enteric pathogens responsible for ileal dysfunction has yet to be elucidated in full. Clinically, bile salt malabsorption affects the net absorption of water, ions, and fat. Intraluminal bile salts may act as secretagogues in the colon, inducing active chloride secretion in the right colon via cyclic adenosine monophosphate-mediated pathways.56 The degree of fat malabsorption is determined by the quantitative defect in bile salt absorption, as it is for ileal resections related to inflammatory bowel disease."
Metabolic Alterations Metabolic alterations occur in HIV infection and mayor may not be associated with hypermetabolism. Systemic infections, including Pneumocystis carinii pneumonia, mycobacterial infections, and cytomegalovirus infections, cause derangements of intermediary metabolism and produce protein wasting," Metabolic alterations, in addition to changes in energy expenditure, are found in HIV-infected people. HIV-infected men and women may develop hypogonadism at some point during the disease course.P Although hypogonadism primarily affects a man's sexual function, the decreased testosterone level may also promote protein wasting, because testosterone is an anabolic hormone as well as an androgen. Fasting hypertriglyceridemia is another metabolic alteration associated with AIDS, and its presence has been associated with elevated levels of circulating
E FIGURE 42-4. Infections that promote nutrient malabsorption. A, Partial villus atrophy and crypt hyperplasia in ajejunal biopsy from a patient with microsporidiosis (original magnification x2S0). The crypt villus junction is shown by the arrow. B, Cryptosporidia involving jejunal enterocytes. Note their location at the luminal membrane (arrow). Most of the organisms actually are intracellular in location (original magnification x400). C, Transmission electron micrograph of enterocytes containing spores of Enterocytozoon bieneusi (xIS,OOO). D, Transmission electron micrograph of enterocytes containing spores of Encephalitozoon imestinalis (x9000). E, Transmission electron micrograph of a sloughing enterocyte infected with Enterocytozoon bienensi.
SECTION V • Disease Specific
491
FIGURE 42-4. (cont'd) F, Microgametocytes of Isospora belli located in a jejunal villus epithelial cell (original magnification x400). C, Trophozoites of Giardia lamblia located in the intervillus space (original magnification x250). H, Mycobacterium avium-intracellutare infection of the small intestine, with villus distortion due to the accumulation of foam cells containing bacilli (original magnification x250). I, Transmission electron micrograph of bacilli adhering to the luminal membrane of ileal enterocytes and producing an "attaching and effacing" lesion (x5000).
a-interferon. 33,59 This association appears to directly relate a metabolic alteration due to immune activation. Increased de novo fatty acid synthesis and esterification into triglycerides as well as decreased clearance of circulating triglycerides both contribute to hypertriglyceridernia.P'" Elevated de novo lipogenesis in AIDS patients with wasting emerged as a surrogate marker of cytokine-related structural protein loss62 but could not be correlated with opportunistic infections. Hypertriglyceridemia was not associated with progressive wasting in one study; thus, its implications are unclear." In contrast, Zangerle and co-workers's showed that
weight loss in HIV infection is associated with immune activation, although the specific mechanism was not defined in that study.
NUTRITIONAL SUPPORT
General Issues The rationale for providing nutritional support to AIDS patients is that nutritional status can be enhanced to the patient's advantage. Improvement in immune function
492
42 • Enteral Nutrition in Human Immunodeficiency Virus Infection
Enteral and Parenteral Therapies
Clinical History I Not cotpatible
comtatible
~
I
>t
.
D-Xylose Test
Stool EvaluatlOfl
t
Diagnostic
~
Treat
~
Reevaluate
I
t
+
Low
Normal
t
t
GI Workup for Jejunal Disease
~
Fecal Fat I
~
Elevated
Normal
~
~
GI Workup Malabsorption for Ileal Disease Ruled Out FIGURE 42-5. Clinical evaluation of malabsorption. GI, gastrointestinal.
and resistance to other antimicrobial agents, in "quality of life," in physical and mental performance, and in longevity, as well as avoidance of costs of supportive, custodial care, are all possible advantages of adequate nutritional support. No study has demonstrated reversibility of cell-mediated immune deficiency in AIDS via nutritional repletion. On the other hand, cell-mediated immune deficiencies due to uncomplicated malnutrition are reversed by nutritional repletion. The lack of reversibility in AIDS probably is due to the HIV-associated CD4+ cell loss. Attempts to recover immune function along with cytokine and metabolic modulation have generated trials with macronutrient and adjuvant supplementation,64-li6 with mixed results. The indications for nutritional support for HIVinfected patients are the same as those for nutritional support in other chronic diseases. They include progressive wasting producing objective evidence of morbidity and little likelihood of self-eorrection and occurring in a patient with the potential for a prolonged, comfortable life. Several approaches have been tried in AIDS patients. The most straightforward involves treating the underlying disease complication responsible for malnutrition. A longitudinal study of patients with cytomegalovirus-induced colitis demonstrated the impact of successfully treating underlying disease complications." Progressive wasting in such patients was demonstrated before the availability of effective therapy, accounted for by decreased food intake.f whereas patients treated with the antiviral agent, ganciclovir (Syntex Laboratories, Palo Alto, CA), regained body weight, BCM, and body fat without the addition of formal nutritional support. Thus, effective disease treatment can reverse wasting. As a corollary, nutritional supplementation may be futile in the presence of untreated, serious disease complications.
Nutritional therapy falls into two broad categories. The first is intended to promote nutritional repletion chiefly by providing a balanced diet, whereas the second uses supraphysiologic or pharmacologic doses of specific macronutrients or micronutrients to affect the underlying disease process. The best results with food-based strategies of nutritional support are often achieved by creating a diet composed of the individual's own preferred foods. The intended dietary intake is between 25 and 35 kcal/kg of body weight. If intake is not hindered by active disease complications, many people can adjust their intake and achieve caloric balance, so that weight gain68 or maintenance is possible. Several publications offer practical guidelines for food-based nutritional therapy/"
Oral Enteral Supplements Although the use of food supplements is often advised, data to support their usefulness are limited." The list of commercial nutritional formulas, which differ widely in composition and palatability, continues to grow. Standard polymeric diets have a nutrient composition similar to that of food-based diets. Their advantage is simply their ease of preparation and administration. Some formulas are low in residue, others are modified to be lactose-free or to contain high contents of medium-ehain triglycerides (MCTs) rather than long-chain triglycerides (LCTs) to avoid malabsorption, others are semielemental or elemental for patients with severe malabsorption, and some also contain enhanced quantities of specific nutrients to serve a pharmacologic role. Each type of diet might have a role in the AIDS patient, depending upon the clinical circumstances. However, in trials with elemental diets, improvements in fat and nitrogen retention were documented, accompanied by decreased gastrointestinal symptoms, such as diarrhea. Salomon and associates" documented improvements in stool fat excretion and a decrease in the number of diarrheic stools in subjects given the full amount of a formula containing MCTs and hydrolyzed whey protein. One half of the study subjects maintained their weight, whereas 11 of 12 reported marked decreases in stool frequency. Craig and colleagues" randomly assigned AIDS patients with wasting and proven malabsorption to receive a supplement containing MCTs or a supplement containing LCTs. They documented a decrease in fat and nitrogen fecal excretion, along with an improvement in diarrhea frequency but no change in weight in the group receiving MCTs compared with baseline. Stack and co-workers" studied the effects of a high protein/calorie (1.5 kcal/mL) supplement on HIV-infected subjects with weight loss at various stages of disease. Mean weight gain in subjects who did not develop opportunistic infections was 2.1 kg, whereas subjects who subsequently developed secondary infections lost a mean weight of 0.2 kg. Elemental diets were compared with a whole protein, whole fat supplement and a MCT supplement, in
SECTION V • Disease Specific
weight-stable subjects with C04+count of less than 200.74 Subjects who were able to maintain a high caloric intake (>2300 kcal/day) gained up to 1% of their prestudy weight, with a convergent change in their BCM, by bioelectrical impedance analysis, thus leading to the conclusion that weight maintenance in subjects with an intact gastrointestinal tract and free of opportunistic infections is related to general caloric intake. Special consideration has been given to 00-3 fatty acid supplementation, owing to its anticytokine effects." Chlebowski and associates" studied a peptide-based enteral formula, which contained MCTs, j3-carotene, or3 fattyacids, selected vitamins (B6, B12, C, and E), minerals (iron, zinc, and selenium), and soluble fiber, in HIVinfected individuals and found evidence of benefit compared with a standard polymeric diet." Although the amount of weight gained was small and no objective improvement in immune function was detected, hospitalizations in the experimental group appeared to fall. Suttmann and colleagues" showed that 4-month supplementation with a-linolenic acid (total of 1.8 g of polyunsaturated fatty acids/day) and L-arginine significantly raised body weight and soluble tumor necrosis factor (TNR) receptor concentrations; the latter are seen as neutralizing agents that may limit TNF-mediated induction of HIV expression compared with the effects of a standard, isocaloric formula. No improvements in host defense and hospitalization rates were seen. Pichard and co-workers" found that an arginine/or3 fatty acid-eontaining supplement increased body weight, fat-free mass, and fat mass compared with a standard formula. In both groups the recommended caloric intake was exceeded, with most of the increase being attributed to higher protein consumption. There were no significant differences between groups or within the same group at the end of supplementation for immunologic parameters and quality of life. An improvement was noted in gastrointestinal symptoms, such as anorexia. LBM repletion and the anticytokine effects of 00-3 fatty acids were evaluated in an open-label trial." Nonsignificant weight gain was observed in subjects given supplements compared with a nonsupplemented group. Metabolic studies revealed an anticytokine effect on the liver, characterized by a significantly decrease in de novo lipogenesis and serum triglyceride levels in the supplemented group, suggesting that or3 fatty acids are weak anticytokine agents, effective for stabilizing or increasing weight in subjects with stable AIDS. Micronutrient deficiency has been directly linked to mortality in HIV disease." Multivitaminsupplementation improved gestational weight gain in pregnant Tanzanian women, with no change in immunologic parameters." Also, a vitamin B supplement delayed development of AIDS and death in South African HIV-positive subjects.P Oxidative stress, induced by the production of reactive oxygen species, contributes to HIV replication through nuclear factor-eli activation. In vitro addition of antioxidant vitamins to the system blocked this activation and inhibited HIV replication.P Allard and associates" initiated the first randomized, controlled trial of vitamin C and E supplementation, achieving a significant
493
decrease in oxidative stress indices (plasma malondialdehyde and breath pentane output) and a trend toward a reduction in HIV viral load. Carnitine is an essential amino acid that has been associated with significant enhancement of phytohemagglutinin-driven lymphoproliferative responses. Earlier data documented carnitine depletion in azidothymidine-treated AIDS patients. Immunopharmacologic studies, in which 6 g of L-earnitine/day was provided for 2 weeks in azidothymidine-treated AIDS patients, showed increased in vitro mitogen-stimulated peripheral blood mononuclear cell proliferation; unfortunately, this change was not accompanied by an increase in the number of C04+ lymphocytes." HIV-infected pediatric patients also may benefit from enteral alimentation. Extremely ill infants with AIDS and multiple medical problems were given an intensive oral regimen of a standard formula and exhibited a clinically significant gain in weight."
Appetite Stimulants The appetite stimulants, megestrol acetate (Megace, Bristol-Myers Squibb, New York, NY) and dronabinol (Marinol, Unimed Pharmaceuticals, Marietta, GA), have been shown to promote weight gain. 86.87 Appetite stimulation is most beneficial in the absence of local pathologic lesions affecting chewing and swallowing, malabsorption syndromes, and active systemic infections. Because megestrol acetate is a progestational agent, it may interfere with gonadotropin secretion and effects. Women may become amenorrheic or develop other menstrual irregularities. There is a high incidence of impotence in men treated with megestrol acetate, which is felt to be due to suppression of gonadotropin release. A suppressant effect upon serum testosterone concentration was shown, which could explain the proclivity of megestrol acetate to promote weight gain via increases in body fat content, while limiting LBM deposition due to its antianabolic effect.88 Dronabinol (!J.9. tetrahydrocannabinol) is the principal psychoactive substance present in Cannabis sativa (marijuana). Additional benefits include the drug's antiemetic effect and its purported ability to improve mood. The effect of dronabinol on the composition of weight gained, i.e., fat versus lean mass, has yet to be reported. Cyproheptadine (Periactin, Merck & Co., Whitehouse Station, NJ) has received little formal study. It was found to have a mild stimulatory effect upon food intake in one study."
Nonvolitional Feeding When supplements and appetite stimulants fail to moderate wasting, aggressive nutritional support regimens may be required for improvement. The effect of total parenteral nutrition (TPN) upon body composition was assessed in AIDS patients with diverse gastrointestinal and systemic dlseases." The clinical efficacy of TPN was largely dictated by the underlying clinical problem. In patients with eating disorders or malabsorption
494
42 • Enteral Nutrition in Human Immunodeficiency Virus Infection
syndromes, repletion of BCM was noted. On the other hand, progressive depletion of BCM occurred despite TPN in patients with systemic infections, whereas accumulation of body fat occurred. Recognizing the potential for TPN to prolong survival in patients with refractory malabsorption and progressive wasting is intuitive, although survival of AIDS patients receiving TPN for longer than 1 year is uncommon. Catheter sepsis is a commonly encountered complication in patients receiving TPN, with Gram-positive cocci being most typically isolated." The relative efficacies of TPN and oral intake of a semielemental diet in AIDS patients with severe malabsorption were compared in a prospective, randomized, open-label trial by Kotler and associates.f The semielemental diet consisted of oligosaccharides, oligopeptides, and MCTs in an electrolyte, vitamin, and mineral texture. The TPN group had a higher mean caloric intake, gained more weight, and had higher BCM and significantly more body fat than did the semielemental diet group. The use of TPNwas fourfold more expensive and was associated with greater morbidity and a decrease in physical functioning than was the semielemental diet. Melchior and colleagues" found increases in LBM and in functional status after 2 months of TPN, but similar survival, compared with that with placebo, in AIDS patients with wasting. In AIDS patients with primary eating disorders and no objective evidence of severe malabsorption or systemic infection, tube feeding (Fig. 42-6) might be expected to replete BCM. This was shown in a prospective case series using a formula diet administered through a percutaneous endoscopic gastrostomy tube for 2 months." In addition to increases in BCM, body fat content, serum
Duration
~
~«2 Weeks)
Indefinite (>2 Weeks)
Temporary
Tube Enterostomy
Nasoenteric Tube
I
I
+
Risk for Aspiration
• •
I
•
•
Yes
No
No
Yes
~
~
~
~
Nasojejunal Nasogastric Percutaneous Percutaneous Tube Tube Endoscopic Endoscopic Gastrostomy Jejunostomy FIGURE 42-6. Decision tree for enteral nutrition.
albumin concentration, and serum iron binding capacity, the last a reflection of transferrin, also increased. Thus, the enteral feeding regimen repleted both somatic and visceral protein compartments. Of note, repletion succeeded despite the persistence of systemic infection in several patients. In this study, total lymphocyte counts in peripheral blood increased significantly during the period of nutritional support, associated with an increase in the number of T suppressor cells (CD8+), although no changes were noted in the number of helper CD4+ lymphocytes. Functional improvement, including subjective improvements in cognitive function, was seen in patients receiving nutritional support. In other studies of percutaneous endoscopic gastrostomy tube feeding, weight gain was also documented."
Adjunctive Therapies Several clinical trials have been conducted to test various anabolic agents as adjuncts in the treatment of wasting. Recombinant growth hormone has been shown in short-term studies (7 days to 3 months) to produce positive nitrogen balance" and repletion of fat-free mass." Schambelan et al98 showed an average of 3-kg LBM accretion, accompanied by a 1.7-kg decrease in body fat, after a 3-month course of recombinant human growth hormone (average dose 6 rug/day or 0.1 rug/kg/day) in AIDS patients with wasting. This was associated with an increase in treadmill work output, but quality of life and days of disability remained the same compared with those for the placebo control group. Cytokine inhibitors, such as pentoxifylline (frental, Aventis, Bridgewater, NJ) and thalidomide, also have been proposed as a treatment of malnutrition associated with HIV infection. Thalidomide accelerates the degradation of TNF-a messenger RNA, making it a potential candidate for immune and nutritional modulation. In a 3-month, placebo-controlled trial,65 thalidomide use was associated with significant weight and muscle mass increases of an average 4.5 kg and 1 kg, respectively. No effects on viral burden or CD4+ counts were noted. Progressive resistance exercise (PRE) has been advocated as a non pharmacologic approach designed to restore LBM and muscle strength." Two months of supervised PRE produced a gain of an average of 2.8 kg of LBM in wasted subjects compared with 1.4 kg in the weightstable group. Fat mass also increased in wasted subjects and decreased in the weight-stable group, probably due to a higher caloric intake in the former group. The magnitude of LBM increase was comparable to the 3-kg increase in LBM and 1.7-kg decrease in fat mass, shown by Schambelan et al,98 after 3 months of recombinant growth hormone treatment in AIDS patients with wasting. These results are similar to those seen by Engelson and coworkers'?' with 12weeks of testosterone therapy producing a gain of 1.2kg of LBM and a 0.2-kg decrease in fat mass by bioelectrical impedance analysis. Gold and associates'?' found an increase of 3 kg in LBM after 16weeks of nandrolone decanoate, with no changes in fat mass.
SECTION V • Disease Specific
Anabolic and nutritional therapies were compared with PRE in a number of trials. Thus, Agin and colleagues!" found that adding supplemental whey protein extract to a PRE regimen did not increase BCM in excess of gains observed with PRE only, whereas whey protein only had an effect on LBM. Bhasin and co-workers'P showed that in hypogonadal AIDS patients with wasting, the effects of 16 weeks of a combination of testosterone and PREwere not additive and that PRE and testosterone replacement were both associated with gains in LBM. These findings were confirmed by Grinspoon and associates'?' in a placebo-controlled trial in which PRE and supraphysiologic testosterone replacement (200 mglwk) yielded similar LBM gains, compared with combined intervention, in eugonadal men with AIDS and wasting. Potential safety concerns (a decrease in high-density lipoprotein or alterations in liver function test results) limit the long-term use of testosterone replacement. In contrast, Strawford and colleaguesl" found that with addition of 20 mg/day of oxandrolone to PREand 100 mg/wk of testosterone, LBM and muscle strength increased significantly, compared with PRE and physiologic testosterone replacement in eugonadal, weight-stable subjects.
CONCLUSION Proper nutritional management can have a positive impact upon the clinical course of HIV infection. Further information is required to assign nutrition its proper priority in the clinical management of HIV-infected individuals. The respective roles of macronutrients and micronutrients remain unclear, as is the role of intestinal dysfunction in general. Metabolic alterations, including hypogonadism, which can be easily treated, and hypermetabolism, which may be cytokine-driven, may play important roles in the pathogenesis of malnutrition associated with HIV infection. These subjects require further study. The role of nutritional supplements in altering the progression of HIV infection and in limiting the severity of the clinical immune deficiency is poorly understood. The overall impact of malnutrition and of nutritional support upon clinical outcomes in addition to nutritional status must be studied. The question as to whether the development of progressive malnutrition can be prevented by early intervention with nutritional therapies remains to be answered. Acknowledgments The authorsare indebted to RichardN. Pierson. Jr.,Jack Wang, and the staffof the Body Composition Unit for continuing contributions to the research programon nutritionin AIDS.
REFERENCES 1. Palenicek JG, Graham NMH, He YH, et al: Weight loss prior to clinical AIDS as a predictor of survival. J Acquir Immune Defic Syndr1995;10:366-373. 2. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR Morbid Mortal Weekly Rep 1987;36:3-15.
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3. Palella FJJr, DelaneyKM, MoormanAC, et a1: Declining morbidity and mortalityamong patients with advanced human imrnunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853-860. 4. Greene JB: Clinical approach to weight loss in the patients with HIVinfection. GastroenterolClinNorth Am 1988;17:573-586. 5. Kotler DP, Wang J, Pierson RN: Studies of body composition in patientswith the acquired immunodeficiencysyndrome.AmJ Clin Nutr 1985;42:1255-1265. 6. Kotler DP, Tierney AR, Dilmanian FA, et al: Correlation between total body potassium and total body nitrogen in patients with acquired immunodeficiencysyndrome. Clin Res 1991;39:649A. 7. Chlebowski RT, Grosvenor MB, Bernhard NH, et al: Nutritional status, gastrointestinal dysfunction, and survival in patients with AIDS. Am J Gastroenterol 1989;84:1288-1293. 8. Guenter P, Muurahainen N, Simons G, et al: Relationships among nutritional status,disease progression, and survival in HIV infection. J AIDS 1993;6:1130-1138. 9. Yarasheski KE, ZachwiejaJJ, GischlerJ, et al: Increased plasma GIn and Leu R. and inappropriately low muscle protein synthesis rate in AIDS wasting. Am J Physiol 1998;275:E577-E583. 10. Ott M, Lambke B,Fischer H, et al: Early changes of body composition in human immunodeficiencyvirus-infected patients: Tetrapolar body impedance analysis indicates significant malnutrition. Am J Clin Nutr 1993;57:15-19. 11. Kotler DP, Thea DM, Heo M, et al: Relative influences of sex, race, environment, and HIV infection on body composition in adults. AmJ Clin Nutr 1999;69:432-439. 12. Grinspoon S, Corcoran C, Miller K, et al: Body composition and endocrine function in women with acquired immunodefi· ciency syndrome wasting. J Clin Endocrinol Metab 1997;82: 1332-1337. 13. Kotler DP, Tierney AR, Wang J, Pierson RN Jr: The magnitude of body cell mass depletion determines the timing of death from wastingin AIDS. Am J Clin Nutr 1989;50:444-447. 14. Kotler DP, TierneyAR, BrennerSK, et al: Preservation of short-term energy balance in clinically stable patients with AIDS. Am J Clin Nutr1990;57:7-13. 15. Trujillo EB, Borlase BC, Bell SJ, et al: Assessment of nutritional status, nutrient intake, and nutritionsupport in AIDS patients.J Am Dent Assoc 1992;92:477-478. 16. SharkeySJ,SharkeyKA, Sutherland LR, et al: Nutritional status and food intake in human immunodeficiency syndrome. J Acquir Immune Defic Syndr 1992;5:1091-1098. 17. Macallan DC, Noble C, Baldwin C, et al: Prospective analysis of patterns of weight change in stage IV human immunodeficiency virusinfection. Am J ClinNutr 1993;58:417-424. 18. Beach RS, Mantero-Atienza E,Shor-Posner G,et al:Specificnutrient abnormalities in asymptomatic HIV infection. AIDS (London, England) 1992;6:701-708. 19. FalutzJ, Tsoukas C, Gold P: Zinc as a cofactor in human imrnunodeficiency virus-induced immunosuppression. JAMA 1988;259: 2850-2851. 20. Dworkin BM, Rosenthal WS, Wormser GW, et al:Selenium deficiency in the acquired immunodeficiency syndrome. JPEN J Parenter EnteralNutr 1986;10:405-407. 21. Graha NMH, Sorenson D, Odaka N, et al: Relationship of serum copper and zinc to HIV·l seropositivity and progression to AIDS. J Acquir Immune Defic Syndr 1991;4:976-980. 22. Baum MK, Shor-Posner G, Lai S, et al: High risk of Hlv-related mortality is associated with selenium deficiency.J Acquir Immune Defic Syndr Hum Retrovirol 1997;15:370-374. 23. Johnson RA, Baker SS, Fallon IT, et al: An accidental case of cardiomyopathy and selenium deficiency. N Engl J Med 1981; 304:1210-1212. 24. Dworkin BM, Antonecchia PP, Smith F, et al: Reduced cardiac selenium content in the acquired immunodeficiency syndrome. JPEN J Parenter Enteral Nutr 1989;13:644-647. 25. Beach RS, Morgan R, Wilkie F, et al: Plasma cobalamin levelsas a potentialcofactorinstudiesof HIV·l relatedcognitive changes.Arch Neurol 1992;49:501-506. 26. Staal FWT, Ela SW, Roederer M, et al: Glutathione deficiency and human immunodeficiency virus infection. Lancet 1992;339: 909-912.
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27. Roederer M, Staal FIT, Raju PA, et al: Cytokine-stlrnulated human immunodeficiency virus replication is inhibited by N-acetylL-cysteine. Proc NatlAcad Sci USA 1990;87:4884-4888. 28. Hommes MIT, Romijn JA, Endert E,Sauerwein HP: Resting energy expenditure and substrate oxidation in human immunodeficiency virus (HIV)-infected asymptomatic men: HIV affects host metabolism in the early asymptomatic stage. Am J Clin Nutr 1991;54: 311-315. 29. Hommes MIT, Romijn JA, Godfried MH, et al: Increased resting energy expenditure in human immunodeficiency virus-infected men. Metabolism 1990;39:1186-1190. 30. GriecoMH, ReddyMM, Kothari HB, et al: ElevatedB{microglobulin and lysozyme levels in patients with acquired immune deficiency syndrome. Clin ImmunollmmunopathoI1984;32:174-178. 31. Eyster ME, Goedert JJ, Poon M-e, et al: Acid-labile interferon: A possible preclinical marker for the acquired immunodeficiency syndrome in hemophilia. N EnglJ Med 1983:309:583-587. 32. Mulligan K,Tai VW, Schambelan M: Energyexpenditure in human immunodeficiencyvirus infection. N EnglJ Med 1997;336:70-71. 33. Grunfeld C, Kotler DP, Shigenga JK, et al: Circulating interferon alpha levels and hypertriglyceridemia in the acquired immunodeficiencysyndrome. AmJ Med 1991;90:154-162. 34. LangeM, Klein E,Kornfield H,et al: Cytomegalovirus isolation from healthy homosexual men. JAMA 1984:252;1908-1910. 35. Giorgi N, DetelsR: T-cell subset alterations in HIV-infected homosexual men. NIAID MulticenterAIDS Cohort Study. Clin Immunol ImmunopathoI1989;52:10-18. 36. RekaS, Garro ML, KotlerDP: Variation in the expression of human immunodeficiency virus RNA and cytokine mRNA in rectal mucosa during the progression of HIV infection. Lymphokine Cytokine Res 1994;13:391-398. 37. Reka S, Garro ML, KotlerDP: Evaluation of cytokine expression in lymph nodes of HIV-infected individuals by RNA in situ hybridization [abstract].In Proceedingsof the Ninth International Conference on AIDS, Berlin, Germany. 1993;1:171. 38. Sclafani A, Koopmans HS, Vasselli J, Reivhman M: Effects of intestinal bypass surgery on appetite, food intake, and body weight in obese and lean rats. AmJ Physiol 1978;234:E389-E398. 39. Fong Y, Moldower LL, Marono M, et al: Cachectin/TNf or IL-1a induces cachexia with redistribution of body proteins.AmJ Physiol 1989;256:R659-R665. 40. Moldawer LL, Anderrson C, Gelin J, Lundholm KG: Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. AmJ PhysioI1988;254:G45Q-G456. 41. Grunfeld C, Pang M, Shimizu L, et al: Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiencyvirusinfectionand AIDS. AmJ ClinNutr1992;55: 455-460. 42. Macallan DC, Noble C, Baldwin C, et al: Energy expenditure and wasting in human immunodeficiencyvirus infection. N Engl J Med 1995;333:83-88. 43. Melchior J-e, Salmon 0, Rigaud D, et al: Resting energy expenditure is increased in stable, malnourished HIV-infected patients. Am J Clin Nutr 1991;53:437-441. 44. Piot P, Quinn T, Taelman H, et al: Acquired immunodeficiency syndrome in a heterosexual population in Zaire. Lancet 1984;2: 65-79. 45. Kotler DP, Francisco A,Clayton F,et al: Small intestinal injuryand parasitic disease in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990;113:444-449. 46. Kotler DP, Reka S, Chow K, Orenstein JM: Effects of enteric parasitoses and HIV infection upon small intestinal structure and function in patients with AIDS. J ClinGastroenterol 1993;16:10-15. 47. Hayes EB, Malte TO, O'BrienTR, et al: Largecommunity outbreak of cryptosporidiosis due to contamination of a filtered public water supply. N EnglJ Med 1989;320:1372-1376. 48. Kotler DP, Orenstein JM: Prevalence of intestinal microsporidiosis in HIV-infected individuals referred for gastroenterological evaluation. AmJ Gastroenterol 1994;89:1998-2002. 49. Roth RI, Owen RL, Keren OF, Volberding PA: Intestinal infection with Mycobacterium avium in acquired immunodeficiency syndrome (AIDS): Histological and clinicalcomparison withWhipple's disease. DigDisSci 1985;30:497-500. 50. KotlerDP, GiangTT, ThiimM, et al: Chronic bacterial enteropathy in patients with AIDS. J Infect Dis 1995;171:552-558.
51. Clayton FC, Heller TH, Reka S, KotlerDP: Variation in the distribution of cryptosporidiosisin AIDS. J Clin PathoI1994;102:420-425. 52. Hodges JR, Wright R: Normal immune responses in the gut and liver. ClinSci 1982;63:339-347. 53. Budhraja M, Levandoglu H, Kocka F, et al: Duodenal mucosal T cell population and bacterial culture in acquired immunodeficiency syndrome. AmJ Gastroenterol 1987;82:427-433. 54. Wolfe MM, Soil A: The physiologyof gastric acid secretion. N Engl J Med 1988;319:1707-1712. 55. Lake-Bakaar G, Quadros E, Beidas S, et al: Gastricsecretory failure in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;109:502-504. 56. Hofmann AF: The syndrome of ileal disease and the broken enterohepatic circulation: Choleretic enteropathy. Gastroenterology 1967;52:752-757. 57. Hofmann AF, Poley JR: Role of bile acid malabsorption in the pathogenesis of diarrhea and steatorrhea in patients with ileal resection. Gastroenterology 1967;52:752-757. 58. Coodley GO, Loveless MO, Nelson HD, Coodley MK: Endocrine function in the HIV wasting syndrome. J Acqic Immunodef Syndr 1994;7:46-51. 59. Grunfeld C, Kotler DP, Hamadeh R, et al: Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1989;86: 27-31. 60. Grunfeld C, Pang M, Doerrler W, et al: Lipids, lipoproteins, triglyceride clearance and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74:1045-1052. 61. Hellerstein MK, Grunfeld C, Wu K, Christiansen M, Kaempfer S, Kletke C, Shakleton CHL: Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. J. Clin Endo Metab 1993;7:559-565. 62. Hoh R, Pelfini A, Neese RA, et al: De novo lipogenesis predicts shot-term body-composition response by bioelectrical impedance analysis to oral nutritional supplements in HIV-associated wasting. AmJ Clin Nutr 1998;68:154-163. 63. Zangerle R, Reibnegger G, Wachter H, Fuchs 0: Weight loss in HIV infection is associated with immune activation. AIDS 1993;7: 175-181. 64. De Simone C, Famularo G, TztanzogluS, et al: Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: Effectof oral carnitine. AIDS 1994;8:655-660. 65. Reyes-Teran G, Sierra-Madero JG, Martinez del Cerro V, et al: Effects of thalidomide on HIV-associated wasting syndrome: A randomized, double-blind, placebo-eontrolled trial. AIDS 1996;10: 1501-1507. 66. Dezube BJ, Pardee AB, Chapman B,et al: Pentoxifylline decreases tumor necrosis factor expression and serum triglyceridesin people with AIDS. J AIDS 1993;6:787-794. 67. Kotler DP,Tierney AR, Altilio 0, et al: Body mass repletion during ganciclovir therapy of cytomegalovirus infections in patients with the acquired immunodeficiency syndrome. Arch Intern Med 1989;149:901-905. 68. BurgerB,Ollenschlager G,Schrappe M, et al: Nutritionalbehaviour of malnourished HIV-infected patients and intensified oral nutritional intervention. Nutrition 1993;9:43-44. 69. Newman CF: Practical dietary recommendations in HIV infection. In Kotler DP (ed): Gastrointestinal and Nutritional Consequences of AIDS, pp 247-277. New York, Raven Press, 1991. 70. Burger B, Olenschlager G, Schrappe M, et al: Nutrition behavior of malnourished HIV-infected patients and intensified oral nutritional intervention. Nutrition 1993;9:43-44. 71. Salomon S, Jung J, Voss T, et al: An elemental diet containing medium-chain triglycerides and enzymatically hydrolyzed protein can improve gastrointestinaltolerance in people infected with HIV. J Am Diet Assoc 1998;98:460-462. 72. CraigGB, DarnellBE, WeinsierRL, et al: Decreased fat and nitrogen losses in patients with AIDS receiving medium-chain-triglycerideenriched formula vs those receiving long-chain-triglyceridecontaining formula.J Am Diet Assoc 1997;97:605-611. 73. Stack JA, Bell SJ, Burke PA, Forse AR: High-energy, high-protein, oral, liquid, nutrition supplementation in patients with HIV infection: Effecton weight status in relation to incidence of secondary infection. J Am Diet Assoc 1996;96:337-341.
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74. Gibert CL, Wheeler DA, Collins G, et al: Randomized, controlled trial of caloric supplements in HIV infection. J AIDS 1999;22: 253-259. 75. Dinarello CA, Marnoy SO, Rosenwasser U: Role of arachidonate metabolism in the immunoregulatory function of human leukocytic pyrogen/lymphocyte-activating factor/interleukin 1. J Immunol 1983;130:890-895. 76. Chlebowski RT, Beall G, Grosvenor M, et al: Long-term effects of early nutritional support with new enterotropic peptide-based formula vs. standard enteral formula in HIV-infected patients: Randomized prospectivetrial. Nutrition 1993;9:507-512. 77. Suttmann U, Ockenga J, Schneider H, et al: Weight gain and increased concentrations of receptor proteins for tumor necrosis factorafter patients withsymptomatic HIV infection received fortified nutrition support. J Am DietAssoc 1996;96:565-569. 78. Pichard C,Sudre P, Karsegard V, et al: A randomized double-blind controlled study of 6 months of oral nutritional supplementation with arginine and n-3 fatty acids in HIV-infected patients. AIDS 1998; 12:53-.Q3. 79. Hellerstein MK, Wu K, McGrath M, et al: Effects of dietary n-3 fatty acids supplementation in men with weight lossassociated with the acquired immune deficiency syndrome: Relation to indices of cytokineproduction. J AIDS 1996;11:258-270. 80. Baum MK, Shor-Posner G: Micronutrient status in relationship to mortality in HIV-l disease. NutrRev 1998;56(1 Pt 2):SI35-S139. 81. Villamor E, Msamanga G, Spiegelman D, et al: Effect of multivitamin and vitamin Asupplements on weight gain during pregnancy among HIV-l infected women. AmJ ClinNutr2002;76:1082-1090. 82. Kanter AS, Spencer DC, SteinbergMH, et al: Supplementalvitamin B and progression to AIDS and death in black South African patients infected with HIV. J AIDS 1999;21:252-253. 83. Harakeh S, Jariwalla RJ: Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV-infected cells. Am J Clin Nutr 1991;54(6 suppl): 1231S-1235S. 84. Allard JP, Aghdassi E, Chau J, et al: Effects of vitamin E and C supplementation on oxidativestress and viralload in HIV-infected subjects.AIDS 1998;12:1653-1659. 85. Fennoy I, LeungJ: Refeeding and subsequent growth in the child with AIDS. NutrClinPract 1990;5:54-58. 86. Von RoennJH, Armstrong D, Kotler D, et al: A placebo-controlled trial of rnegestrol acetate in patients with AIDS-related anorexia and cachexia. Ann InternMed 1994;121:400-408. 87. GorterR, SeefriedM, Volberding P:Dronabinoleffectson weightin patientswith HIV infection. AIDS 1992;6:127. 88. Engelson ES, Pi-Sunyer FX, KoUer DP: Effects of megestrol acetate therapyon body compositionand circulatingtestosteroneconcentrationsin patients with AIDS. AIDS 1995;9:1107-1108. 89. Summerbell CD, YouleM, McDonald V, et al: Megestrol acetate vs cyproheptadine in the treatment of weight loss associated with HIV infection. IntJ STD AIDS 1992;3:278-280.
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90. KoUer DP, Tierney AR, Wang J, Pierson RN Jr: Effect of home total parenteral nutrition upon body composition in AIDS. JPEN J Parenter EnteralNutr 1990;14:454-458. 91. Raviglione MO, Battan R, Pablos-Mendez A, et al: Infections associated with Hickman catheters in patients with acquired immunodeficiencysyndrome. AmJ Med 1989;86:780-786. 92. Kotler DP, FogelmanL, TierneyAR: Comparison of total parenteral nutrition and an oral, semielemental diet on body composition, physical function, and nutrition-related costs in patients with malabsorbtion due to acquired immunodeficiency syndrome. JPEN J Parenter Enteral Nutr 1998;22:120-126. 93. MelchiorJC, ChastangC, Gelas P, et al: Efficacy of 2-month total parenteral nutrition in AIDS patients: A controlled randomized prospective trial. The French Multicenter Total Parenteral Nutrition CooperativeGroup Study. AIDS 1996;10:379-384. 94. Kotler DP, Tierney AR, Ferraro R, et al: Effect of enteral feeding upon body cell mass in AIDS. AmJ ClinNutr 1991;53:149-154. 95. Cappell MS, Godil A: A multicenter case controlled study of percutaneous endoscopic gastrostomy in HIV seropositive patients. AmJ Gastroenterol 1993;88:2059-2066. 96. Mulligan K, Grunfeld C, Hellerstein MK, et al: Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab 1993;77:956-962. 97. Schambelan M, Mulligan K, Grunfeld C, et al: Recombinant human growth hormone in patients with HIV-associated wasting. Ann Intern Med 1996;125:873-882. 98. Schambelan M, Mulligan K, Grunfeld C, et al: Recombinant human growth hormone in patients with HIV-associated wasting. Ann Intern Med 1996;125:873-882. 99. RoubenoffR, McDermott A, WeissL, et al: Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiencyvirus. AIDS 1999; 13:231-239. 100. Engelson ES, Rabkin JG, RabkinR, KoUer DP: Effects oftestosterone upon body composition. J AIDS 1996;1:510-511. 101. Gold J, High HA, Li Y, et al: Safety and efficacy of nandrolone decanoate fortreatment of wastingin patients with HIV infection. AIDS 1996;10:745-752. 102. Agin D, Gallagher D, Wang J, et al: Effects of whey protein and resistanceexerciseon body cell mass,musclestrengthand quality of lifein women with HIV. AIDS 2001;15:2431-2440. 103. Bhasin S, Storer TW, Javanbakht M, et al: Testosterone replacement and resistanceexercise in HIV-infected men withweight loss and low testosterone level.JAMA 2000;6:763-770. 104. GrinspoonS, Corcoran C, Parlman K, et al: Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. Ann Intern Med 2000;133:348-355. 105. Strawford A, Barbieri T, Van Loan M, et al: Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss.JAMA 1999;281:1282-1290.
Diabetes Mellitus Daniel L. Hurley, MD, FACE M. Molly McMahon, MD, FACE
CHAPTER OUTLINE Introduction Carbohydrate Metabolism in Health Carbohydrate Metabolism: Effect of Diabetes Mellitus and Illness Diabetes Mellitus and the Gastrointestinal Tract Gastroparesis: Guidelines for Therapy Constipation, Diarrhea, and Fecal Incontinence Nutrition Assessment Adverse Sequelae of Hyperglycemia Hypoglycemia Nutrition Management Glucose Goals Enteral Tube Feeding Tube Feeding and Gastroparesis Long-Term Tube Feeding Parenteral Nutrition Use in Gastroparesis
Patient Monitoring Principles of Glycemic Management
INTRODUCTION Diabetes mellitus is caused by an absolute (type 1; previously called insulin-dependent diabetes mellitus) or a relative (type 2; previously called non-insulindependent diabetes mellitus) lack of insulin. Type 1 diabetes is associated with onset at an early age, a tendency for ketoacidosis, and absolute dependence on insulin. Type 2 diabetes, by far the more common type, is associated with onset in adulthood and insulin resistance. In addition, during severe illness, patients without an antecedent diagnosis of diabetes mellitus may develop stress-induced hyperglycemia. Because of the prevalence of diabetes mellitus and stress-induced hyperglycemia and the comorbidity of diabetes, most hospital clinicians will encounter hyperglycemia in acutely ill
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patients. One third of all persons admitted to an urban general hospital had fasting glucose levels exceeding 126mg/dL or two or more random glucose levels exceeding 200 mg/dL; a third of those with hyperglycemia did not have a prior diagnosis of diabetes.' In this chapter we review the effects of diabetes, illness, and feeding on metabolism, diabetic enteropathy, adverse sequelae of hyperglycemia in the acutely ill patient with and without known diabetes, glucose goals, and the management of tube feeding in hospitalized patients with hyperglycemia.
CARBOHYDRATE METABOLISM IN HEALTH In nondiabetic subjects, the plasma glucose concentration is closely regulated in both the postabsorptive (6 to 14 hours after a meal) and postprandial periods. In the postabsorptive period, plasma glucose is primarily derived from the liver because cellular glucose release requires the action of glucose 6-phosphatase, an enzyme present in significant amounts only in the liver and kidney. Endogenous glucose production results both from glycogenolysis (the breakdown of glucose stored as glycogen) and gluconeogenesis (the formation of glucose from precursors). Euglycemia is maintained because the rate of hepatic glucose production approximates the rate of glucose uptake (glucose utilization) by the liver, brain, and peripheral tissues. These rates average 2 rug/kg/min in the healthy, nondiabetic subject in the postabsorptive period or approximately 200 g/day for the 7Q-kg subject. After meal ingestion (or infusion of dextrose), the increase in plasma glucose leads to an increase in plasma insulin level. The fasting plasma insulin concentration increases from approximately 6 to 10 to 40 to 100).lU/mL postprandially and then returns to basal levels within 3 to 4 hours after eating. Hyperglycemia and hyperinsulinemia are key modulators of glucose turnover rates (rates of glucose production and glucose uptake). Hyperglycemia suppresses hepatic glucose production by decreasing both glycogenolysis and gluconeogenesis and by activating glycogen synthetase (the enzyme stimulating
SECTION V • Disease Specific
glycogen synthesis). Both hyperglycemia (due to mass effect) and hyperinsulinemia stimulate glucose uptake. Postprandial hyperglycemia and hyperinsulinemia convert the liver from an organ that produces glucose to one that takes up glucose by stimulating glucose uptake in peripheral tissues and thereby preventing glucose concentrations from exceeding 150 mg/dL. The rates of glucose production and glucose uptake are restored to preprandial levels as the plasma glucose and insulin levels fall. The decrease in the plasma insulin level permits an increase in hepatic glucose production and a decrease in glucose uptake in insulin-sensitive tissues, namely, liver, muscle, and fat. Lack of suppression of hepatic glucose production in the presence of hyperinsulinemia denotes a resistance to the action of insulin at the liver, i.e., hepatic insulin resistance. Lack of appropriate glucose uptake in the presence of hyperinsulinemia denotes resistance to the action of insulin in peripheral tissues, i.e., peripheral insulin resistance. Both sickness and diabetes are characterized by insulin resistance.
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Patients with diabetes have preprandial and postprandial hyperglycemia from decreased insulin secretion and/or action. The hyperglycemia is due to excessive hepatic glucose production and impaired glucose uptake. Stress-induced hyperglycemia is an important cause of hyperglycemia in critically ill patients. Severe illness is accompanied by a marked increase in the plasma concentrations of glucagon, epinephrine, and cortisol. These counter-regulatory hormones increase hepatic glucose production and decrease glucose uptake," resulting in hyperglycemia. The exaggerated glucose response after a stress-inducing counter-regulatory hormone infusion in healthy diabetic subjects, compared with that in nondiabetic subjects, is one explanation for the deterioration in glucose control in stressed diabetic patients." Cytokines also affect carbohydrate metabolism.
than and no different from those in control sublects.r" One explanation for this finding is impaired visceroception. Peripheral sensory-motor neuropathy is often found in patients with symptomatic gastroparesis. It is generally believed that the cause of gastroparesis is autonomic (sympathetic vagal nerve dysfunction) and enteric (intrinsic) neuropathy.V Common manifestations of diabetic enteropathy include heartburn, dysphagia, nausea, early satiety, postprandial vomiting (especially partially digested food retained from earlier meals), and epigastric pain. Markedly delayed gastric emptying may make the regulation of blood glucose difficult, and hyperglycemia may further delay gastric emptying.s" On the other hand, hypoglycemia may develop in those who take insulin and in whom ingested food is not absorbed because of delayed gastric emptying. 10 Accurate diagnosis of diabetic gastroparesis is essential to avoid attributing the gastrointestinal symptoms to tube feeding alone or to other factors capable of affecting gut motility. A review of the patient's medication list can identify commonly prescribed drugs that may delay gastric emptying. These include anticholinergics, antidepressants, cx2-adrenergic agonists, calcium channel blockers, and opiates. Glucose levels should be closely monitored and managed because gastric emptying may be slowed by hyperglycemia. Knowledge of the fat content of the tube feeding formula is important because enterally provided fat may decrease gut motility. The diagnosis of diabetic gastroparesis should be strongly suspected from the history. Physical examination may reveal gastric dilatation with a "succession splash." Demonstration of a delay in gastric emptying establishes the diagnosis of gastroparesis. Standard barium roentgenographic studies generally demonstrate gastric dilatation and retained solid residue even after a prolonged fast.I I Follow-up films reveal a marked delay of emptying, with more than 50%of contrast material remaining in the stomach after 30 minutes. However, because gastric emptying of liquids may be normal even in the presence of moderately severe symptoms, scintigraphic assessment of emptying of solids has become the preferred test." Endoscopy should be used to exclude organic causes of gastric atony and delayed emptying.
DIABETES MELLITUS AND THE CiASTROINTESTINAL TRACT
CiASTROPARESIS: GUIDELINES FOR THERAPY
Diabetes can affect the entire gastrointestinal tract. Although abnormal esophageal pressure (particularly lower esophageal sphincter pressure) and esophageal dysmotility are reported to occur in the majority of patients with diabetic gastroparesis, these esophageal disturbances are often asymptomatic.' Gastroparesis diabeticorum is a term that denotes gastric atony and delayed gastric emptying in diabetic patients. However, the symptoms of diabetic gastroparesis are related to dysmotility not only of the stomach but also of the small bowel. As many as 30% to 60% of patients with type 1 and type 2 diabetes patients have radiographic evidence of gastroparesis, yet gastrointestinal symptoms have been reported to be both greater
The primary goals of therapy are to control blood glucose levels and to relieve gastrointestinal symptoms. The evaluation of various modalities used to treat gastroparesis is confounded by the intermittent and variable course of symptomatic gastroparesis, poor correlation between the degree of gastric stasis and severity of symptoms, and the effect of hyperglycemia on gastric emptying. These features may explain why some patients have objective measures indicating dysmotility but experience no symptomatic relief after treatment. Treatment of diabetic gastroparesis is necessary when the patient's symptoms are significant and persistent, diabetes control is suboptimal, or nutritional state is compromised. Because gastric emptying is slowed
CARBOHYDRATE METABOLISM: EFFECT OF DIABETES MELLITUS AND ILLNESS
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during hyperglycemia and is reported to be inversely related to the degree of hyperglycemia," aggressive control of blood glucose is indicated. Conventional antiemetic drugs (e.g., prochlorperazine) may provide relief of nausea and vomiting, but their anticholinergic properties may adversely affect gastric emptying. Prokinetic agents are the treatment of choice." Metoclopramide, a central and peripheral antidopaminergic agent, releases acetylcholine from the myenteric plexus and facilitates cholinergic transmission in enteric smooth muscle. Metoclopramide crosses the blood-brain barrier and exerts an antiemetic effect. Mild neurologic side-effects (e.g., anxiety, drowsiness, and lassitude) are reported to occur in up to 49% of patients, IS and dystonic reactions may be seen in 1% of patients. In contrast, domperidone, a peripheral dopamine antagonist lacking cholinergic activity, does not cross the blood-brain barrier and has fewer neurologic side effects. IS.16 Erythromycin increases gut motility through its agonist property with motilin, a gastrointestinal peptide." Bethanechol, a cholinomimetic agent, is rarely used because it has limited efficacy and often causes side effects. Cisapride has beneficial prokinetic effects, but it was removed from the market because of its association with cardiac dysrhythmias. We prefer to use metoclopramide initially because of its proven effectiveness for the relief of gastrointestinal symptoms, availability in oral and intravenous preparations, and lower cost. Intravenous metoclopramide often is required during acute exacerbations of gastroparesis. Prokinetic agents should be administered in a low dose 30 minutes before meals and before a bedtime snack, with the dose increased as tolerated. Although data about the dosing of prokinetic agents during continuous tube feeding are limited, we suggest drug administration every 6 hours. Because absorption of tablets may be compromised by gastroparesis, liquid preparations may be more effective in these patients. Metoclopramide also may be administered by rectal suppository. Only metoclopramide and erythromycin can be administered intravenously. In patients with acute and severe symptoms of gastroparesis who do not show a response to metoclopramide, intravenous erythromycin should be considered.
CONSTIPATION, DIARRHEA, AND FECAL INCONTINENCE Constipation, diarrhea, and fecal incontinence may develop with long-standing diabetes mellitus. Constipation is the most common symptom of diabetic enteropathy, and its prevalence increases with the progression of severe neuropathy.f Constipation often alternates with diarrhea and may simulate irritable bowel syndrome. Diabetic diarrhea is seen in approximately 10% of all diabetic patients and, of these, 40% have fecal incontinence, both of which are more likely in the presence of symptomatic neuropathy. 18 If the history suggests steatorrhea, a 72-hourstool fat collection should be completed. The differential diagnosis of steatorrhea is similar in diabetic and nondiabetic patients. Celiac sprue, pancreatic insufficiency, and bacterial
overgrowth occur more often in diabetic patients, and these conditions can be diagnosed by jejunal biopsy and serologic tests, pancreatic function tests, and cultures of jejunal fluid aspirate, respectively. Infection and medications should be excluded as a cause of diarrhea. Antidiarrheal agents may be used if an infectious cause for the diarrhea has been excluded. Commonly used medications that can cause diarrhea include those with high sorbitol content (poorly absorbed carbohydrate added to certain elixirs for its solvent and sweetener properties), high magnesium content, and/or high osmolality. A history of frequent, small, semiformed stools may be a clue to the presence of fecal incontinence. This is associated with decreased basal internal anal sphincter pressure (autonomic innervation of smooth muscle). 19 Objective tests of anorectal function include manometry and neurophysiologic evaluation of the pelvic floor. If pelvic function is normal, colonic transit time can be assessed by noninvasive radiopaque marker studies.
NUTRITION ASSESSMENT Indications for nutritional support are similar in hospitalized diabetic and nondiabetic patients. Studies have shown that the majority of patients have surprisingly normal energy expenditure, usually between 100% and 120% of predicted caloric needs.P Overfeeding should be avoided in diabetic patients because delivery of excessive calories can cause hyperglycemia. If the patient is overweight (e.g., body mass index between 25 and 30), basal caloric needs should be provided according to the Harris-Benedict equation. If the patient is obese (e.g., body mass index >30), 75% of the Harris-Benedict estimate of caloric requirements should be provided. It is our practice to provide approximately 1.0 g of protein/kg of body weight to mildly stressed patients and 1.5 g of protein/kg of body weight to moderately and severely stressed patients, assuming normal hepatic and renal function. For obese patients with normal hepatic and renal function, we provide 1.5 g of protein/kg of estimated "ideal" weight. Data about nutrition requirements in stressed, obese patients are limited.
ADVERSE SEQUELAE OF HYPERGLYCEMIA Clinicians should attempt to identify causes of unexplained hyperglycemia. During hospitalization, hyperglycemia may adversely affect fluid balance (through glycosuria and dehydration), immune function,21-24 and outcome.P-" In in vitro studies, abnormal white cell and complement functions with hyperglycemia that improved with glucose control were reported. Observational studies indicated that hyperglycemia is also a risk factor for adverse outcomes during acute illness in nondiabetic patients. Two meta-analyses of observational studies quantified the impact of hyperglycemia on the prognosis of patients without diabetes after myocardial infarction and stroke. 27,28 In patients immediately
SECTION V • Disease Specific
after myocardial infarction, glucose values in excess of 110 to 144 mg/dL were associated with a threefold increase in mortality (odds ratio 3.9, 95% confidence interval 2.9-5.4) and a higher risk of heart failure." In patients with ischemic stroke, glucose values in excess of 108 to 144 mg/dL were associated with a threefold increase in mortality (odds ratio 3.1, 95% confidence interval 2.5-3.8) and appear related to the degree of permanent disability after the stroke." Similarly, observational studies in patients with diabetes revealed an increased risk of adverse outcomes.F-" Randomized trials in critically ill patients document an association between hyperglycemia and adverse outcomes. The Veterans Administration Cooperative Study was designed to test the hypothesis that perioperative parenteral nutrition would prevent serious complications after major surgery." Patients receiving parenteral nutrition had fewer noninfectious complications, but infections were twice as common as in control patients. This higher infection rate was associated with provision of excess calories and severe hyperglycemia. A serum glucose concentration greater than 300 mg/dL occurred in 20% of patients receiving parenteral nutrition and in 1% of the control group. Indeed, more than one half of the patients receiving parenteral nutrition had hyperglycemia. A meta-analysis of perioperative nutrition conducted 10 years ago revealed a 61 % greater risk of infection in patients receiving parenteral nutrition compared with enterally fed patients, but this finding between groups was confounded by the difference in serum glucose within the first 5 postoperative days (180 mg/dL vs. 150 mg/dl.)." In the last decade, studies of patients receiving similar caloric provision (while avoiding excess calories) via either enteral or parenteral nutrition have reported narrower differences in glucose levels and similar infection rates between groups. In a recently published randomized trial of enteral and parenteral nutrition, parenterally fed patients with an average maximum serum glucose level of 160 mg/dL had 42% more infections than did patients in the enterally fed group with an average maximum serum glucose level of 144 rng/dl," Control of hyperglycemia during acute illness has been associated with improved outcomes. In an observational study, the implementation of an intravenous infusion of insulin after coronary artery bypass grafting to maintain glucose levels between 150 and 200 mg/day decreased the risk of sternal wound infections by 58%.32 Malmberg'" conducted a randomized trial of intensive insulin therapy in diabetic patients after myocardial infarction (from admission to 3 months after discharge). In this study, known as the D1GAMI trial, the l-year mortality was 29% lower in patients receiving intensive insulin therapy compared with the patients in the standard treatment group." Van den Berghe et aJ26 conducted a randomized trial of intensive glycemic control (glycemicgoal 80 to 110 mg/dL) compared with usual care in a surgical intensive care unit. The patient group with an average blood glucose concentration of 103 mg/dL experienced 44% lower mortality than patients with an average blood glucose concentration of 153 mg/dl.," Researchers have not elucidated whether these health
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benefits are due to improved glycemic control, the correction of relative insulin deficiency, or both.
HYPOGLYCEMIA Hypoglycemia can cause adrenergic or neuroglycopenic symptoms that are difficult to identify in sedated patients or patients dependent on mechanical ventilation. The most common adrenergic symptoms are sweating, palpitations, anxiety, tachycardia, and hunger. Neuroglycopenic symptoms include headache, visual changes, seizures, or confusion. In addition, patients with long-standing diabetes may develop hypoglycemic unawareness and lose the ability to recognize the warning symptoms of hypoglycemia. Therefore, avoidance or minimization of hypoglycemia (i.e., plasma glucose = 60 mg/dL) is crucial. An attempt should be made to identify the factor(s) responsible for hypoglycemia. These include discontinuation of tube feeding, resolution of stress, discontinuation or decreased dose of corticosteroids or sympathomimetic agents, renal dysfunction, acute hepatitis, septic shock, and diabetic gastroparesis. If no explanation is found, the daily dosage of the insulin active at the time of hypoglycemia should be reduced by approximately 10%. If hypoglycemia recurs, a more aggressive decrease in insulin doses should be made. This will be addressed more specifically in the patient monitoring section of the chapter.
NUTRITION MANAGEMENT Glucose Goals The proposed glucose goal range is 80 to 110 mg/dl, for critically ill patients in intensive care units." In medically stable patients who are treated with subcutaneously administered insulin regimens, we aim for a glucose goal between 100 and 150 mg/dL because safe achievement of tighter glucose goal ranges using subcutaneously administered insulin programs is difficult. In addition, outcome studies comparing degrees of glucose goal ranges have not yet been reported in this subset of patients.
Enteral Tube Feeding The enteral route should be used to provide nutrition in patients with a functioning gastrointestinal tract. During hospitalization, avoidance of overfeeding and hyperglycemia are probably more important than is the use of a specific enteral formula. Outcome studies are needed to definitively address this subject. The dietary fiber recommendations for diabetic patients are the same as for the general hospitalized population.
Tube Feeding and Gastroparesis A unique situation is the diabetic patient with gastroparesis who requires supplemental or total nutrition
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43 • Diabetes Mellitus
support by tube feeding. The majority of these patients tolerate jejunal tube feeding when iso-osmolar feedings are started at a low rate (e.g., 20 mUhr) and advanced slowly (20 to 30 mUhr increment every 8 to 12 hr). The method of nutrient delivery depends on the location of the tip of the feeding tube. If gastric feedings have been selected, continuous administration or gravity (intermittent) administration is an option. Continuous feeding is preferred in critically ill patients, whereas gravity administration is preferred in patients with stable conditions because the hormonal profile more closely approximates the postprandial hormonal profile in healthy diabetic subjects. Although there may be theoretical advantages of nocturnal tube feeding (i.e., decreased insulin levels during the nutrition-free period in nondiabetic patients), there are also potential disadvantages. During nocturnal feeding, the caloric provision is both compressed and continuous, causing a sustained, nonphysiologic hyperinsulinemia, which may have adverse sequelae. If jejunal feedings are used, continuous feeding is required. The use of a decompression (or venting) nasogastric tube may provide symptomatic relief in patients with gastroparesis.
Long-Term Tube Feeding Long-term tube feeding should be considered in diabetic patients with gastroparesis who, despite adequate medical therapy, are hospitalized often for symptoms of gastroparesis or who cannot maintain weight or hydration. Before placement of a permanent enteral feeding tube, a trial of nasoenteric feeding is important to confirm that the patient can tolerate tube feeding at a rate of at least 40 mUhr. If gastric feeding cannot be tolerated, jejunal feeding must be selected. Tubes can be successfully placed endoscopically, radiologically, or surgically. Although prospective studies are limited, retrospective studies report greater tube dysfunction after percutaneous endoscopic gastrostomy with jejunal extension because of proximal migration of the jejunal extension tube and coiling in the stomach. However, patients with significant gastroparesis and intractable nausea and vomiting require a decompression gastrostomy.P'" This can be accomplished in one of two ways. One method is to place a gastrostomy tube to use for decompression; this can be converted to a skin level device to be less cumbersome when not in use with a jejunostomy for feeding access. The second method is through a transgastric jejunal tube using the single tube style with a partition creating two lumens, one for gastric decompression and the other for jejunal feeding. With this style of tube, complications associated with a coaxial style of tube are avoided.
Parenteral Nutrition Use in Gastroparesis Parenteral nutrition should be reserved for patients with severe small bowel dysmotility in whom a reasonable trial of nasojejunal tube feeding has failed.
PATIENT MONITORING Principles of Glycemic Management Achieving glucose control in patients with hyperglycemia receiving tube feeding is a challenging but crucial component to nutrition management. Guidelines for frequency of glucose determinations are provided in Table 43-1. Feeding tube administration of oral diabetic agents may be used for medically stable patients with well-eontrolled type 2 diabetes and normal renal and hepatic function. Otherwise, in medically stable diabetic patients, tube feeding calories are typically matched with subcutaneous insulin administration (fable 43-2). Short-acting (regular) or rapid-acting (aspart or lispro) insulin supplementation often is required in addition to intermediate-acting (NPH or lente) insulin. We developed a standardized form for the subcutaneous insulin algorithm (fable 43-3). We rely on short-acting insulin administration until tube feeding tolerance has been established. This approach minimizes the risk of hypoglycemia that could result from the prolonged action of NPHor lente insulin after unexpected discontinuation of tube feeding. When the continuous tube feeding rate has reached 30 to 40 mUhr, the use of intermediate-acting insulin should be safe. We initially provide one half of the patient's preadmission total morning insulin dose as intermediate-acting insulin. In general, the tube feeding infusion rate should not be increased until adequate glycemic control has been achieved. As the rate of tube feeding is increased, the intermediate-acting insulin dose may need to be increased. Twice-daily subcutaneous administration of intermediate-acting insulin may be required for glycemic control if the tube feedings are continuous. If tube feeding is infused by gravity administration, the glucose level should be checked immediately before the feeding is initiated and no sooner than 4 hours after the end of the prior feeding. It is generally not helpful to check glucose levels during or immediately
..
Guidelines for Frequency of Glucose Testing*
Frequency
Clinical Situations
Daily (morning)
Stable oral diabetic agent program with average glucose levels in goal range Once daily or twice daily NPH or Lente program with average glucoses in goal range Initiation of tube feeding and during progression to goal feeding rate Split/mixed program such as once to twice daily NPH/Lente and Regular insulin program or multiple-dose Insulin such as once daily Ultralente/Glarglne and Regular insulin program Intravenous Insulin infusion program
Twice daily (0700, 1600) Four times daily (0700. 1100. 1600,2100)
Every hour to every second hour
*Referto text for glucose monitoring guidelines during administration of tube feeding.
SECTION V • Disease Specific
503
_ _ Insulin Preparation Pharmacokinetics and Pharmacodynamics
Insulin Rapid-acting Lispro Aspart Short-acting Regular
Route
Onset
Peak
Effective Duration
SC SC
5-15 min 5-15 min
30-90 min 30-90 min
5 hr 5 hr
SC
30-60 min
2-3 hr 0.5 hr
5-8 hr
IV Intermediate-acting NPH Lenle Long-acting Ultralente Glargine
3.5 hr
SC SC
2-4 hr 2-4 hr
4-10 hr 4-10 hr
10-16 hr 10-16 hr
SC SC
6-10 hr 2-4 hr
10-16 hr No peak
18-24 hr 20-24 hr
IV, intravenous; SC,subcutaneous.
after the gravity feeding unless hypoglycemia is suspected. Although some patients receiving gravity tube feedings can be managed with intermediate-duration insulin alone, others will need combined treatment with intermediate-acting and short-acting insulin. A common management error occurs when clinicians rely on the short-acting insulin algorithm exclusively for glucose control. Once the patient's condition is medically stable, the preferred management is to review the amount of short-acting insulin required over the preceding 24-hour period and then adjust the intermediateacting and short-acting insulin programs appropriately. Although there are theoretical reasons for use of longacting insulin programs in stable patients, such as a more constant basal insulin profile, studies reporting results in hospitalized patients are limited. The dramatic results of improved glucose control demonstrated in the Diabetes Control and Complications Trial have prompted the increased use of multiple-dose insulin therapy (e.g., once daily long-acting insulin and premeal short-acting insulin) in ambulatory diabetic patients. In general, the dose of long-acting (e.g., ultralente or glargine) insulin (see Table 43-2) should initially be continued at the preadmission dose, and dose adjustments made in the short-acting insulin if necessary. In patients in whom glucose control is unsatisfactory, a graded insulin intravenous infusion should be started (Table 43-4). Successful use of this therapy requires appropriate adjustment of the insulin infusion rate.
_
• . ,
Algorithm for Subcutaneous Administration of Regular Insulin
Plasma Glucose (mg/dL)
150-200 201-250 251-300 301-350 351-400 >400
Subcutaneous Insulin Dose (IJ)*
1-2 2-4 3-6 4-8
5-10 6-12
*Subcutaneous administration of Regular insulin should not be given more often than every 2 hours. The algorithm may need to be modified for certain patients. Start with the lower range of insulin doses.
Studies testing which insulin infusion rate safely achieves the desired glucose goal ranges are limited. If the desired glucose range is not achieved within 2 hours at the prior infusion rate, we recommend increasing the insulin infusion rate by 50% to 100% increments. When adequate glycemic control has been achieved with low rates of intravenous insulin, subcutaneous insulin programs should be used and the intravenous insulin infusion should be continued for several hours after the first subcutaneously administered insulin dose to prevent rebound hyperglycemia. Although the technology to achieve tight glycemic control in the critical care setting is widely available, implementing a safe and effective program may present logistical challenges. One safety concern of aggressive treatment to improve glucose control is the potential increase in the risk of hypoglycemia. A standardized approach to the treatment of hypoglycemia is needed (Table 43-5) because prolonged hypoglycemia can cause irreversible neurologic damage, and prompt restoration of glucose levels to normal usually completely reverses signs and symptoms of
• . , • Craded Intravenous Insulin Infusion: . . Initial Rate·
Plasma Glucose (mg/dL)
>400 351-400 301-350 250-300 200-249 150-199 120-149 100-119 70-99 <70
Insulin Infusion Rate (lJ/hr) 8 6
IV Infusion Rate for a I unIt/mL Admixture (mLjhr) 8 6
4
4
3
3
2.5
2.5
2 1.5
2 1.5 I
1
o o
o
o
*This infusion is NOT intended for patients with diabetic ketoacidosis. Check glucose levels hourly until values have stabilized in range for 4 hours. Testing frequency may be decreased to every 2 hours. Frequency should be increased after infusion rate changes. Studies testing which infusion safely achieves desired glucose goal ranges are limited. If the glucose goal range is not achieved within 2 hours, we increase the insulin infusion rate by 50% to 100% increments.
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43 • Diabetes Mellitus
_ _ Treatment of Hypoglycemia (Blood Clucose Level s60 mg/dL) I. If a patient has symptoms or signs compatible with hypoglycemia, administer treatment without waiting to confirm a low glucose value. Patients with documented hypoglycemia who are asymptomatic should also receive prompt treatment. A. Oral administration of glucose is preferred if the patient is able to swallow safely. The patient should ingest approximately 15 g of dextrose. An enteral tube can be used to provide dextrose. Examples of 15 g of dextrose include: 2 sugar packets/cubes, 15 g of glucose tablets/gel or 1/2 cup (4 oz.) of fruit juice B. If the patient is not able to take oral feeding safely, is taking nothing by mouth (NPO) for any reason, or has severe hypoglycemia, we treat as follows: 1. If intravenous access is available, 50% dextrose solution CD 50%) should be administered intravenously, using an initial dose of 12.5 g of dextrose. 2. If there is no intravenous access, administer 1 mg of glucagon by subcutaneous or Intramuscular injection. II. Glycemic monitoring after treatment A. Recheck the plasma glucose determination in 15 minutes. If the glucose value is S80 mg/dl., repeat the treatment outlined above and recheck the glucose value in 15 minutes. Repeat further treatment and glucose checks at IS-minute intervals until the glucose is >80 mg/dl.,
hypoglycemia. If the patient has signs or symptoms suggestive of hypoglycemia, the clinician should provide treatment without waiting to check the blood glucose level. Hyperglycemia can affect biochemical test interpretation. Hyperglycemia may cause pseudohyponatremia. An increase in the plasma glucose level raises the plasma osmolality (because glucose penetrates cells slowly), causes water to move from the cells to the extracellular volume, and lowers the plasma sodium concentration by dilution. In general, every 62 mgldL increment in the plasma glucose level draws enough water out of cells to reduce the plasma sodium concentration 1 mEq/L. Potassium levels also should be interpreted in light of the glucose value. Hyperkalemia, if accompanied by hyperglycemia, is often effectively treated by supplemental insulin. A sudden increase in plasma insulin (e.g., after refeeding or exogenous insulin administration) may decrease renal sodium excretion and result in salt and water retention. Hyperinsulinemia also may decrease the plasma levels of potassium, phosphorus, and magnesium if their supplementation is inadequate." Baseline studies should include glycated hemoglobin concentration to establish the degree of recent glucose control and help with dismissal diabetes planning. Patients who were receiving oral diabetic agents on admission and had a satisfactoryglycated hemoglobin concentration generally may be dismissed with use of an oral diabetic agent, even if insulin was required during hospitalization. REFERENCES I. Umpierrez GE, Isaacs SD, Bazargan N, et al: Hyperglycemia: An independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87:978-982. 2. Shamoon M, Hendler R, Sherwin R:Synergistic interactions among anti-insulin hormones in the pathogenesis of stress hyperglycemia in humans. J Clin Endocrinol Metab 1981;52:1235-1241. 3. Shamoon M, Hendler R, Sherwin R: Altered responsiveness to cortisol, epinephrine, and glucagon in insulin-infused juvenile-onset diabetes. Diabetes 1980;29:284-291. 4. Borgstrom PS, Olsson R, Sundkvist G, et al: Pharyngeal and oesophageal function in patients with diabetes mellitus and swallowing complaints. Br J RadioI1988;61:817--821. 5. Camilleri M: Advances in diabetic gastroparesis. Rev Gastroenterol Disord 2002;2:47-56.
6. Stacher G: Diabetes mellitus and the stomach. Diabetologia 2001;44:1080-1093. 7. De Block CEM, Leeuw IH, Pelckmans PA, et al: Delayed gastric emptying and gastric autoimmunity in type 1 diabetes. Diabetes Care 2002;25:912-917. 8. Hebbard GS, Sun WM, Dent J, et al: Hyperglycemia affects proximal gastric motor and sensory function in normal subjects. Eur J Gastroenterol Hepatol 1996;8:211-217. 9. Fraser R, Horowitz M, Maddox AF, et al: Hyperglycemia slows gastric emptying in type I diabetes mellitus. Diabetologia 1990;30: 675-680. 10. Wooten RL, Meriwether 1W: Diabetic gastric atony: A clinical study. JAMA 1961;176:1082-1087. 11. Camilleri M, Malagelada JR: Abnormal intestinal motility in diabetics with the gastroparesis syndrome. Eur J Clin Invest 1984;14: 420-427. 12. Hornbuckle K, Barnett JL:The diagnosis and work-up of the patient with gastroparesis. J Clin GastroenteroI2000;30:117-124. 13. Wahren J, Felig P, Ahlborg G, et a1: Glucose metabolism during leg exercise in man. J Clin Invest 1971;50:2715-2725. 14. Rabine JC, Barnett JL: Management of the patient with gastroparesis. J Clin GastroenteroI2oo1;32:11-18. 15. Patterson D, Abell T, Rothstein R, et al: A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol 1999;94:1230-1234. 16. Barone JA: Domperidone: A peripherally acting dopamine-2 receptor antagonist. Ann Pharmacother 1999;33:429-440. 17. Janssens J, Peeters TL,Vantrappen G, et al: Improvement of gastric emptying in diabetic gastroparesis by erythromycin: Preliminary studies. N Engl J Med 1990;322:1028-1031. 18. Ogbonnaya KI, Arem R: Diabetic diarrhea: Pathophysiology, diagnosis, and management. Arch Intern Med 1990;150:262-267. 19. Schiller LR, Santa Ana CA, Schmulen AC, et al: Pathogenesis of fecal incontinence in diabetes mellitus: Evidence for internal anal sphincter dysfunction. N Engl J Med 1982;307:1666-1671. 20. McMahon MM, Farnell MB, Murray MJ: Nutritional support of critically ill patients. Mayo Clin Proc 1993;68:911-920. 21. McMahon MM, Bistrian BR: Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995;9:1-9. 22. McCowen KC, Malhotra A, Bistrian BR: Stress-induced hyperglycemia. Crit Care Clin 2001;17:107-124. 23. Montori VM, Bistrian BR, McMahon M: Hyperglycemia in acutely ill patients. JAMA 2002;288:2167-2169. 24. Hostetter MK: Handicaps to host defense: Effects of hyperglycemia on C3 and Candida albicans. Diabetes 1990;39:271-275. 25. Malmberg K: Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997;314:1512-1515. 26. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the surgical intensive care unit. N Engl J Med 2001;345: 1359-1367.
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27. Capes SE, Hunt D, Malmberg K, et al: Stress hyperglycemia and
32. Furnary AP, Zerr KJ, Grunkemeier GL, et al: Continuous intra-
increased risk of death after myocardial infarction in patients with and without diabetes: A systematic overview. Lancet 2000;355:
venous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352-360; discussion 6Q-62. 33. Fan AC, Baron TH, Rumalla A, et al: Comparison of direct percutaneous endoscopic jejunostomy and PEG with jejunal extension. Gastrointest Endosc 2002;56:89Q-894. 34. ASGE Technology Assessment Committee: Technology status evaluation: Endoscopic enteral nutritional access devices. Gastrointest Endosc 2002;56:796-802. 35. DeFronzo R, Cooke C, Andres R, et at: The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest 1985;55:845-855.
773-778. 28. Capes SE, Hunt D, Malmberg K, et al: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: A systematic overview. Stroke 2001 ;32:2426-2432. 29. Veterans Affairs Total Parenteral Nutrition Cooperative Study Group: Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1993;325:525-532. 30. Moore FA, Feliciano DV, Andrassy RJ, et al: Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis. Ann Surg 1992;216:172-183. 31. Kudsk KA, Laulederkind A, Hanna MK: Most infectious complications in parenterally fed trauma patients are not due to elevated blood glucose levels. JPENJ Parenter Enteral Nutr 2001;25:174-179.
II Cancer: Head and Neck Nancy Evans-Stoner, MSN, RN Cesar Ruiz, MS, CSLP Olga Antonopoulos, MA, RD
CHAPTER OUTLINE Introduction The Mechanics of Swallowing Overview of Normal Phases of Swallowing Impact of Head and Neck Cancer on Swallowing Impact of Head and Neck Cancer Treatment on Swallowing Nutrition Assessment Defining Nutritient Needs Nutrition Management Patient Monitoring Summary
INTRODUCTION Neoplasms of the head and neck are primarily squamous cell carcinomas that occur on the surface of the mucosal lining of the oral cavity, oropharynx, nasopharynx larynx, maxillary sinus, salivary glands, and thyroid gland. Approximately43,000new cases of head and neck cancer are diagnosed in the United States each year. The risk of malnutrition in these patients is well recognized, not only from the disease and its treatments, but also from associated behaviors such as excessive smoking and alcohol abuse. Reports indicate that as many as 60% of patients with newly diagnosed head and neck cancer have poor nutritional status at the time of diagnosis.' To provide a comprehensive approach to the nutritional management of these patients the clinician must have a thorough understanding of the swallowing mechanism and the effects of surgical resection, chemotherapy, and radiation.
THE MECHANICS OF SWALLOWING Functional swallowing is defined as the ability to take foods from the mouth through the pharynx and into the stomach with adequate control.l Patients with head and neck cancers experience changes in the swallowing
structures due to the tumor itself, the type of resection, the type of reconstruction, and tissue changes from radiation and/or chemotherapy treatment. Their dysphagia symptoms vary with the extent of surgery and treatment implernented.v'
Overview of Normal Phases of Swallowing Oral Phase In normal swallowing the individual is able to secure all boluses by creating an anterior seal with the lips and tongue and a posterior seal with the soft palate and the base of the tongue (Fig. 44-1). The bolus is then formed with the use of lateral tongue movements (during chewing). When the bolus has been formed, the individual uses an anterior to posterior sweeping motion of the tongue against the hard palate to transfer the bolus into the pharynx (Fig. 44-2). The transfer of the bolus should take about 1 second.
Pharyngeal Phase When the bolus reaches the posterior tongue at the level of the base of the tongue, the swallow is initiated (Fig. 44-3). During a normal pharyngeal swallow there should be no delay in the initiation. This portion of the swallow process is involuntary. The larynx elevates, allowing the epiglottis to invert and seal against the arytenoids. Laryngeal elevation also elicits cricopharyngeal opening of the entry into the esophagus. Epiglottic inversion is the initial means of protection of the airway followed by true and false vocal fold adduction (Fig. 44-4). As the airway is sealed, the pharynx propels the bolus into the esophagus via a sequential superior to inferior peristaltic movement. The passage of the bolus through the pharynx takes approximately 1 to 2 seconds.
Esophageal Phase Asthe bolus leaves the pharyngeal phase and enters the esophagus, it is the responsibility of the esophagus to
509
510
44. Cancer: Head and Neck
FIGURE 44-1. Oral phase I. The green portion represents the bolus. Observe the tip of the tongue as it seals anteriorly and the base of the tongue as it makes contact with the soft palate to seal posteriorly.
FIGURE 44-3. Pharyngeal phase 1. The tongue has pushed the bolus posteriorly, the soft palate remains against the posterior pharyngeal wall, and the epiglottis is beginning to invert.
FIGURE 44-2. Observe how the green bolus has been pushed posteriorly as the tongue sweeps against the hard palate. The soft palate is now making contact with the posterior pharyngeal wall to prevent nasal regurgitation.
FIGURE 44-4. Pharyngeal phase 2. The bolus has passed the oral phase and has entered the pharynx. The epiglottis is now completely inverted to protect the airway, the soft palate is still making contact posteriorly, and the cricopharyngeus sphincter is beginning to open.
SECTION VI • Cancer
511
may be further compromised when sensory input is affected as well. Tumors affecting cranial nerves V, VII, and XII will have a greater impact on the oral phase of swallowing. Biomechanical changes may be present due to the size and bulk of the tumor within the mouth.'
Pharyngeal Cancer
FIGURE 44-5. Esophageal phase. Observe how the bolus has entered the esophagus, and it is being pushed downward by the pharyngeal and esophageal peristaltic movements. Note how the tongue, soft palate, and epiglottis have returned to their resting positions.
propel the bolus all the way down to the stomach. This is again accomplished via a sequential superior to inferior peristaltic movement. At this time the oral and pharyngeal structures return to their resting positions (Fig. 44-5).
Impact of Head and Neck Cancer on Swallowing Oral Cancer Oral carcinomas can affect the function of the lips, tongue, cheeks, soft palate, hard palate, and jaw.3,5 Impairment of these structures can result in trismus, which is defined as the inability to open the mouth due to lack of jaw range of motion and results in difficulty chewing. If the tumor affects lingual movements, then the ability to form the bolus and to transfer it posteriorly may be affected. Oral stasis (food staying in the mouth), food pocketing, and premature spillage over the base of the tongue are all associated with poor lingual control. Nasal regurgitation may also be present when the closure of the velopharyngeal port is compromised by the tumor. The lips are necessary to create an anterior seal during swallowing. Poor lip closure associated with tumors can compromise lip function and result in anterior leakage and drooling from the affected side. The patient's overall swallowing performance
Pharyngeal carcinomas will affect the peristaltic movement required to clear boluses through the pharynx. The impact of a tumor may be manifested as blockage of the bolus, resulting in pharyngeal stasis or residue in the valleculae and/or piriform sinuses. This residue may overflow into the larynx, resulting in aspiration into the lungs. Some patients may experience a globus sensation, that is, the feeling of food catching in the pharynx despite evidence of food having cleared through the pharynx. Other patients may experience odynophagia or pain during swallowing. Globus sensation and odynophagia have a negative impact on food intake despite adequate sensorimotor input to the pharyngeal structures. Patients with pharyngeal dysphagia caused by a pharyngeal tumor may begin changing and reducing their dietary habits by eating only semisoft or even pureed foods. These changes in the quantity and consistency of food can often result in weight loss due to poor oral intake."
Laryngeal Cancer Laryngeal carcinomas compromise airway protection. Any tumor that prevents epiglottic inversion and vocal fold adduction and sensation will compromise the patient's swallowing ability." Subglottic tumors may bulge against the piriform sinuses to cause blockage, allowing back flow, laryngeal penetration, and aspiration after the swallow. Glottic tumors can interfere with adequate vocal fold adduction during swallowing, as well as vocal fold paralysis, permitting boluses to enter the larynx during the swallow. Supraglottic carcinomas are usually associated with poor epiglottic inversion and vallecular bulging. These presentations result in laryngeal penetration and aspiration before and during the swallow. The aspirated material may cause the patient to cough; however, sensation may be compromised, resulting in silent aspiration. The patient may have recurrent pneumonia due to intermittent or persistent aspiration into the lungs.
Esophageal Cancer Many of the pharyngeal dysphagia symptoms experienced by patients with head and neck cancer are associated with esophageal cancer. Malignant tumors in the esophagus may cause obstruction and dysmotility preventing and/or compromising the passage of boluses into the esophagus,"
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44 • Cancer: Head and Neck
Impact of Head and Neck Cancer Treatment on Swallowing Surgery and Reconstruction The goal of surgical intervention to treat tumors is primarily to gain control of possible spread. Surgeons also strive to preserve as much function as possible so the patient can maintain speech and swallowing skills. Swallowing deficits depend on the extent of the surgery and the mode of reconstruction.v" Primary closure of the affected area refers to removal of the tumor and suturing of the area without using any type of flap. This method is usually used when the tumor is small and superficial. The impact on swallowing is usually minimal. Free flap reconstruction is also used to repair the affected site." This method refers to the use of tissue from another part of the body that is harvested with its own blood vessels that are later microscopically attached to blood vessels from the surgical site. Muscle flaps, which remain attached to their own blood supply, are also used to reconstruct defects. Flap reconstructions of any type serve well to repair the defect but lack the sensation and motility needed for swallowing. II Patients need to rely on remaining normal structures to learn to move the bolus through the oral, pharyngeal, and esophageal phases of swallowing.
Radiation and Chemoradiation Radiation treatment is used to treat head and neck cancers at various stages of the disease. It may be delivered preoperatively, postoperatively, and in combination with chemotherapy at any of the stages. Radiation treatment changes tissue pliability, decreases blood supply, and results in xerostomia (lack of saliva production).12,13 These changes are not reversible and the tissue changes may worsen over time. Radiation causes varying degrees of stomatitis (mouth ulcers) and mucositis (inflammation of the mucosa lining of the pharynx, larynx and/or esophagus), resulting in odynophagia, which has a significant impact on all phases of swallowing.14-16 Xerostomia interferes with lubrication and mixture of boluses as they are formed in the mouth and transferred through the pharynx." The food boluses tend to stick to the mucosa, making it hard for patients to transfer the boluses effectively. Xerostomia may also compromise dental health. 6. 18 Saliva helps to naturally control the growth of Candida organisms on the mucosa. A lack of saliva can cause candidiasis, an excess of candidal accumulation on the oral mucosa. Symptoms of oral candidiasis include odynophagia and disruptions in normal taste. The scarring resulting from radiation treatment can cause biomechanical changes that can compromise the pharyngeal phase of swallowing. 12,19 Pharyngeal peristalsis, epiglottic inversion, laryngeal elevation, and airway protection require adequate range of motion from the muscle group involved. When radiation changes affect
these muscle tissues, the result is poor ability to clear the boluses from the pharynx and persistent laryngeal penetration and aspiration." Chemoradiation has become an integral part of head and neck cancer treatment. Its therapeutic goal is to improve locoregional control of tumors. However, the delivery of both chemotherapy and radiotherapy in a coordinated fashion is associated with significantly more toxicity, which contributes to tissue damage. Chemoradiation will impair immune function to a greater degree and may increase the risk of pneumonia from aspirated materiapO,21
NUTRITION ASSESSMENT Nutritional status is known to profoundly affect treatment morbidity and overall prognosis in patients with head and neck cancer. More than one half of patients with head and neck cancer are malnourished. Their nutritional status is often compromised even before the diagnosis of cancer is made and treatment is initiated.P Patients may exhibit nutritional problems at the time of diagnosis and are often malnourished because of poor dietary habits, excessive alcohol consumption, excessive smoking, local tumor effects, tumor-induced cachexia, and effects of various therapies." During and after therapy, poor oral intake is compounded by shortterm and long-term sequelae of radiation therapy or surgery. Reactions associated with radiation therapy to the head and neck usually occur 10 to 17 days into treatment but may begin as early as the first week of treatment. Acute side effects include mucositis, xerostomia, ageusia, hypogeusia, odynophagia, dysphagia, and stomatitis. Later side effects that may occur include radiation-induced osteonecrosis of the mandible, ulceration of the mucosa, trismus, fibrosis, soft tissue necrosis, radiation-induced caries, endocrine dysfunction, and laryngeal edema. The side effects of therapies such as chemotherapy and radiotherapy not only have an impact on the patient's ability to continue treatment but can also lead to a severe decline in nutritional status. Poor nutritional status can delay or limit the clinician's ability to deliver adjuvant therapy as well as decrease the patient's overall quality of life.24 The patient with cancer of the head and neck has a particularly high risk for malnutrition. These patients should all be routinely screened when entering the health care system to determine their level of nutritional risk. Those with existing malnutrition or at risk for developing malnutrition should be identified and undergo a comprehensive nutritional evaluation to institute early intervention. Patients with early-stage cancer of the head and neck often have vague symptoms and minimal physical findings. The signs and symptoms and the impact on nutritional status will vary with the stage of the cancer and the location of the primary site. A comprehensive patient history must include a detailed review of the patient's dietary intake. It is common for the patient to
SECTION VI • Cancer
report inability to tolerate consumption of solid food. Dietary modifications that result from chewing and/or swallowing difficulties can decrease both the quantity and quality of food intake. Common symptoms of early cancer of the oral cavity include pain, changes in the fit of dentures, and oral ulcers that do not heal. Hoarseness and sore throat may also be symptoms of early laryngeal cancer. Late-stagesof head and neck cancers have detectable signs and symptoms such as airway obstruction, dysphagia, odynophagia, aspiration on swallowing, decreased mobility of the tongue, dry mouth, foreign body sensation, otalgias, and possible formation of fistulas." The conditions of the patient's mouth that may be visible include leukoplakia, erythroplakia, or mixed erythroleukoplakia. Early-stage cancerous lesions may be detected as well. The patient with more advanced disease may be seen with weight loss, muscle and temporal wasting, and deterioration of functional performance status. Weight measurement should include actual body weight for height, weight change, and rate of weight change. Actual weight should be recorded along with usual weight before the onset of illness. The rate of weight loss is significant, because a recent involuntary weight loss of more than 10% may be an indicator of impending malnutrition.P Hydration and volume status can interfere with accurate interpretation of weight parameters and should be carefully evaluated. Weight loss is known to have a predictive value for the occurrence of major postoperative complications after extensive surgery." Evaluation of standard blood protein level measures in relation to nutritional status must be approached cautiously in the patient with cancer. The serum albumin level, ordinarily a sensitive index of the visceral protein compartment of the body and independent of poor food intake, may be decreased due to a hypercatabolic response to acute infection, surgical intervention, chemotherapy or radiotherapy." Serum protein levels less than 65 gil and low levels of albumin, prealbumin, and transferrin have been associated with increased mortality in patients with head and neck cancer." Protein deficiency is common in patients with head and neck cancers and is usually the result of inadequate caloric and protein intake due to local tumor effects, combined with chronic effects of tobacco and alcohol abuse. Total lymphocyte count and immunologic skin testing, indicators of immune status, also may be abnormal in these patients because of hematopoietic toxicity, tumor burden, or corticosteroid therapy; however, these are rarely used to evaluate nutritional status in the clinical setting." In addition, patients with malignant neoplasms of the head and neck may have nutritional problems because their history often includes excessive smoking, dietary indiscretions, and alcohol abuse. Extensive resections of the head and neck region often result in short- or long-term impairments to the mechanics of chewing and swallowing.'" A speech therapist should evaluate the patient's ability to consume an oral diet, particularly after surgical intervention. This assessment
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will help define both the need for and duration of enteral nutrition.
DEFINING NUTRIENT NEEDS Providing adequate caloric needs is essential for head and neck cancer patients." The Harris-Benedict equation may be used to estimate basal energy expenditure and determine calorie requirements; however, the following estimates may be more efficient: • For obese patients who require weight reduction, 20 to 25 kcal/kg • For nonambulatory or sedentary adults who require weight maintenance, 25 to 30 kcal/kg • For those who need to gain weight or who are clearly anabolic, 30 to 35 kcal/kg • For severely stressed patients, 35 kcal/kg adjusted upward as indicated" Most patients with head and neck cancer are in negative nitrogen balance and will remain so. It is important to provide enough protein to meet protein synthesis needs and reduce protein degradation. The following guidelines may be used to determine protein requirements for the individual patient: • Hepatic or renal compromise: 0.5 to 0.8 g/kg • Recommended Dietary Allowance reference protein: 0.8 g/kg • Normal maintenance level: 0.8 to 1.0 g/kg • Safe intake for nonstressed cancer patients: 1.0 to 1.5 g/kg • For increased protein demands: 1.5 to 2.5 g/kg Hydration status affects weight, which is used to determine nutritional status. Enterally fed patients can become dehydrated if fluid is inadequate. Large surgical wounds or excessive secretions from a tracheostomy can contribute to increased fluid loss. Fluid needs range from 30 to 35 mUkg depending on the patient's age and degree of insensible losses. Most standard enteral formu[as contain about 80% free water. Calorie-dense products contain slightly less free water; therefore, patients should be given adequate fluids when concentrated formulas are selected. Zinc and vitamin C supplementation may be beneficial for wound healing. If a history of alcohol abuse is present, thiamin and folate should be supplemented as we[[,32
NUTRITION MANAGEMENT The indication for enteral feeding is an inability to take in sufficient calories to maintain good nutrition. Table 44-1 outlines common indications for enteral nutrition in this patient group. The duration of enteral therapy can range from 1 to 2 weeks (immediate postoperative period) to months (during adjuvant chemotherapy and radiation) to years (permanent swallowing impairment). The type of feeding tube selected is determined by the anticipated duration of enteral therapy. Short-term nasogastric feeding tubes are appropriate with less
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44 • Cancer: Head and Neck
• . ,. Common Indications for Enteral . . Nutrition Severe aspiration risk Extensive and/or complicated surgical resection of the head and neck area Inability to swallow for a prolonged period of time Pharyngeal strictures and fistulas Fibrosis or neurologic damage to the pharynx resulting from cancer, radiation, or surgery" Anticipated rigorous preoperative chemotherapy/radiotherapy
extensive surgical resection where initiation of an oral diet is expected within 1 to 2 weeks. These patients should work closely with a speech therapist to evaluate and assist in the transition to an oral diet. Permanent enteral access devices such as the percutaneous endoscopic gastrostomy (pEG) tube are used extensively in patients with head and neck cancer. The PEG tube can be placed before chemotherapy or radiotherapy is initiated and may not be used immediately for enteral feeding. This proactive approach allows patients to rely on oral intake (ifadequate) until the effects of radiation begin to impair swallowing function or they undergo surgical tumor resection. A PEG tube is the preferred device rather than a nasogastric tube for prolonged enteral feeding. Although complications related to PEG tube placement are rare, in one recent study more persistent dysphagia, an increased need for pharyngoesophageal dilatation, and prolonged tube placement were seen in patients with a PEG compared with those with a nasogastric tube." The authors speculated that shorter tube dependence for patients with a nasogastric tube is related to more aggressive swallowing rehabilitation. In addition, prolonged PEG tube placement may cause atrophy of the muscles involved in swallowing and result in an increased incidence of pharyngeal stenosis. Morestudy is needed in this area to support such observations. Occasionally an open gastrostomy tube is placed if an endoscope cannot be advanced because of tumor burden, strictures, or obstruction. A postpyloric feeding tube (pEG-jejunostomy or open jejunostomy tube) is sometimes indicated ifthe patient has recurrent episodes of tube feeding-related aspiration or severe gastroesophageal reflux.A gastric feeding button or skin-level devices have also been used successfully for patients who have permanent swallowing dysfunction necessitating long-term home enteral feeding and who desire a more aesthetic access device. Tube feedings are instituted when bowel function returns, usually on the first or second postoperative day." The patient with head and neck cancer will generally tolerate a standard polymeric formula administered at 1.0 to 2 callmL. For patients with severe hypercatabolism and extensive wounds a higher protein formula is indicated. For patients who have difficulty tolerating a higher volume of feeding, a calorically dense formula can be used. The delivery method is dictated by the location of the tip of the feeding tube and the patient's tolerance of feeding. Enteral feeding into the small bowel must be delivered via a continuous drip to prevent the development of
osmotic diarrhea, initiated at a slow rate of 20 to 40 mUhr and titrated up to the goal rate. Delivery of nutrients into the stomach can be either intermittent or continuous. There is no conclusive evidence to indicate whether patients with head and neck cancer have a reduced incidence of aspiration with continuous versus intermittent delivery of nutrients into the stomach. Therefore, a sensible approach is to start with intermittent gastric feedings and move to postpyloric feedings if there are complications. A secondary reason to attempt intermittent gastric feeding is that the use of a pump and extended delivery hours is avoided. When the tube tip is in the stomach, insurance reimbursement for enteral feeding pumps for a patient in the home setting may be problematic. Intermittent feeding is initiated with water or formula at a volume between 100and 120 mL every 4 to 6 hours and advanced to the goal as tolerated. Intermittent feedings are given several times a day over at least 30 to 60 minutes. Gastric residual volumes should be checked before each feeding until the patient's intake reaches the goal volume. Residual volumes greater than 150 to 200 mL are significant and warrant holding tube feeding after evaluation of bowel function, use of pain medications or other drugs that can delay gastric emptying, and modification of the fat and fiber content of the formula. If the patient is unable to tolerate intermittent feeding, continuous drip feeding can be instituted." Continuous feedings are initiated at approximately 20 to 40 mUhr and advanced as tolerated to the goal in 10- to 2Q-mL increments every 8 to 24 hours." Residual volumes should be checked every 4 hours until the goal rate is achieved.
PATIENT MONITORING The patient should be monitored by the nutrition support clinician to assess tolerance to enteral nutrition; this assessment includes patient complaints of nausea, vomiting, or diarrhea. Gastric residual volumes, weight, oral and enteral intake, and output also need to be monitored. Biochemical data including serum protein measures and electrolytes must be followed and adjusted on the basis of the patient's clinical status. Generally gastric feeding can be advanced to the goal within 48-72 hours. The most common complications that prevent a patient from achieving the nutritional goal include nausea, vomiting, and diarrhea. Many patients with head and neck cancer will require home enteral feeding. Most will have a long-term feeding tube such as a PEG tube. The nutrition support clinician must collaborate with the physician, speech therapist, and discharge planner to assist in a smooth transition to home care. Table 44-2 presents key points to address when the patient who is receiving enteral feeding is discharged from the hospital.
SUMMARY Enteral nutrition is a significant part of the plan of care for most patients with cancer of the head and neck.
SECTION VI • Cancer
• . .. Discharging a Patient Who Is Receiving . . Enteral Feeding Collaborate with the discharge planner Identify insurance coverage for the enteral feeding Evaluate patient's and caregiver's ability to perform procedures related to home enteral feeding Initiate patient education Select a home care provider for equipment Set up home nursing services to continue teaching plan and monitor tolerance to enteral feeding Outline plan for home monitoring-office visits, laboratory work, tube checks Provide patient with contact numbers to report problems with tube feeding regimen or enteral access device
Patients are at risk for malnutrition at any stage of their disease and at any point during their treatment. Adequate nutritional status is key to maximizing the patient's ability to successfully complete the rigorous therapies that are required to treat cancer of the head and neck. A proactive approach must include incorporation of routine nutrition assessment and intervention into pathways developed for the care of the patient with head and neck cancer. REFERENCES I. Reilly JJ: Does nutrition management benefit the head and neck cancer patient? Oncology 1990;4: 105-116. 2. Logemann J: Evaluation and Treatment of Swallowing Disorders. San Diego, College Hill, 1983. 3. Gaziano J: Evaluation and management of oropharyngeal dysphagia in head and neck cancer. Cancer Control 2002;9:400-409. 4. Pauloski B, Rademaker A, Logemann J, et al: Pretreatment swallowing function in patients with head and neck cancer. Head Neck 2000;22:474-482. 5. Pauloski B, Rademaker A, Logemann J, et al: Swallow function and perception of dysphagia in patients with head and neck cancer. Head Neck 2002;24:555-565. 6. Minasian A, Dwyer J: Nutritional implications of dental and swallowing issues in head and neck cancer. Oncology 1998;12:1155-1162. 7. Rosen A, Rhee T, Kaufman R: Prediction of aspiration in patients with newly diagnosed untreated advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 2001;127:975-979. 8. Adler D, Baron T: 2001 Endoscopic palliation of malignant dysphagia. Mayo Clinic Proc 2001;76:1277-1278. 9. Kreuzer S, Schima W, Schober E, et al: Complications after laryngeal surgery: videofluoroscopic evaluation of 120 patients. Clin RadioI2000;55:775-781. 10. Furia C, Carrara de Angelis E, Martins N, et al: Video fluoroscopic evaluation after glossectomy. Arch Otolaryngol Head Neck Surg 2000;126:378-383. I I. Haughey B,Taylor S, Fuller D: Fasciocutaneous flap reconstruction of the tongue and floor of mouth: outcomes and techniques. Arch Otolaryngol Head Neck Surg 2002;128:1388-1395. 12. Mok P, Seshadri R, Siow J, LimS: Swallowing problems in post irradiated NPCpatients. Singapore Med J 2001;42:312-316. 13. Davies A, Broadley K, Bighton D: Xerostomia in patients with advanced cancer. J Pain Symptom Manage 2001;22:820-825.
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14. Rose-Ped A, Bellm L, Epstein J, et al: Complications of radiotherapy for head and neck cancers. The patient's perspective. Cancer Nurses 2002;25:468-469. 15. Lapeyre M, Charra-Brunaud C, Kaminsky M, et al: Management of mucositis following radiotherapy for head and neck cancers. Cancer Radiother 2001;5(suppl 1):121-130. 16. Mossman K: Frequent short term oral complications of head and neck radiotherapy. Ear Nose Throat J 1994;73:316-320. 17. Logemann J, Smith C, Pauloski B, et al: Effects of xerostomia on perception and performance on swallow function. Head Neck 2001;23:317-321. 18. Andrews N, Griffiths C: Dental complications of head and neck radiotherapy: Part I. Aust Dent J 2001;46:88-94. 19. Smith R, Kotz T, Beitler J, Wadler S: Long term swallowing problems after organ preservation therapy with concomitant radiation therapy and intravenous hydroxyurea: Initial results. Arch Otolaryngol Head Neck Surg 2000;126:384-389. 20. Eisbruch A, Lyden T, Bradford C, et al: 2002 Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head and neck cancer. lnt J Radiat Oncol Bioi Phys 2002;53:23-28. 21. Argiris A: Update in chemotherapy for head and neck cancer. Curr Opin OncoI2002;14:323-329. 22. Laviano A, Meguid MM: Nutritional issues in cancer management. Nutrition 1996;12:358-376. 23. Daley JM, Reynolds J, Thorn A, et al: Immune and metabolic effects of arginine in the surgical patient. Ann Surg 1988;208:512-521. 24. Wang CC: Radiation Therapy for the Head and Neck Neoplasms. Indications, Techniques and Results, 2nd ed. Chicago, Yearbook Medical Publishers, 1990. 25. Vokes EE, Weischelbaum RR, Lippman SM, et al. Review article. Head and neck cancer. N Engl J Med 1993;328:184-192. 26. Hunter AMB: Nutrition management of patients with neoplastic disease of the head and neck treated with radiation therapy. Nutr Clin Pract 1996;11:157-162. 27. Van Bokhorst-de van der Schueren MAE, Van Leeuwen PAM, Sauerwein HP, et al: Assessment of malnutrition parameters in head and neck cancer and their relation to postoperative complications. Head Neck 1997;19:419-425. 28. Phillips A, Shaper AG, Whincup PH: Association between serum albumin and mortality from cardiovascular disease, cancer and other causes. Lancet 1989;2:1434-1436. 29. Zeman FJ, Ney DM: Nutritional care in the critically ill patient. In Applications in Medical Nutrition Therapy, 2nd ed, p 304. Upper Saddle River, NJ, Merrill Prentice Hall, 1996. 30. Williams EF, Meguid MM: Nutritional concepts and considerations in head and neck surgery. Head Neck 1989;11:393-399. 31. Martie C: Calorie, protein, fluid and micronutrient requirements. In McCallum PD, Polisena CG (eds): The Clinical Guide to Oncology Nutrition, pp 45-52. Chicago, American Dietetic Association, 2000. 32. Bloch AS: Nutrition support for general systemic disordersCancer. In Mantarese LE, Gottschich MM (eds): Contemporary Nutrition Support Practice-A Clinical Guide, 2nd ed, p 498. St Louis, WB Saunders, 2003. 33. Hunter JG, Laurentino L, Shellito PC: Percutaneous endoscopic gastrostomy in head and neck cancer patients. Ann Surg 1988;20:42-46. 34. Mekhail TM,Adelstein DJ, Rybicki LA, et al: Enteral nutrition during the treatment of head and neck carcinoma. Cancer 2001;91: 1785-1790. 35. Starkey JF, Jefferson PA, Kirby DE: Taking care of percutaneous endoscopic gastrostomy. Am J Nurs 1988;88:42-45. 36. Sigler BA: Nursing care of patients with laryngeal carcinoma. Semin Oncol Nurs 1989;5:160-165. 37. Nyulasi IB, Metz G: Methods of introducing nasoenteric feeding. Med J Aust 1984;141:496-498.
Esophageal/Gastric/Pancreati c Cancer Juan Pablo Arnoletti, MD Satoshi Aiko, MD, PhD
CHAPTER OUTLINE Malnutrition and Upper Gastrointestinal Tract Malignancies Theoretical Advantages of Enteral Nutrition Route of Administration Preoperative Enteral Nutrition Early Postoperative Enteral Nutrition Specific Considerations Esophageal and Gastric Cancer Pancreatic Cancer
Conclusions
MALNUTRITION AND UPPER GASTROINTESTINAL TRACT MALIGNANCIES Patients with malignant tumors of the esophagus, stomach, and pancreas often are significantly malnourished. The causes for cancer cachexia are multifactorial. Patients with these malignancies usually have decreased oral intake and certainly display the cytokine-induced abnormalities in the intermediate metabolism of carbohydrate, protein, and fat that characterize patients with cancer.l-' Dysphagia, obstructive jaundice, and chronic bleeding also contribute to nutritional depletion in this particular subgroup of patients. Enteral feedings playa significant, yet still controversial, role in the management of patients with esophageal, gastric, and pancreatic cancers, mainly in the perioperative setting. At the same time, feeding tubes are often placed in patients with unresectable or metastatic disease. These procedures are done with palliative intent in an effort to maintain enteral access and, in some patients, to relieve symptoms of gastric outlet obstruction. In this chapter we will focus on enteral nutrition in the perioperative setting among patients with malignant tumors of the esophagus, stomach, and pancreas at a 516
resectable stage, who otherwise are candidates for curative resection. Rather than performing an exhaustive analysis of the available literature, we will concentrate on some of the clinically significant aspects of enteral nutrition in the patient with cancer of the upper digestive tract.
THEORETICAL ADVANTAGES OF ENTERAL NUTRITION As described earlier in this textbook, there are several theoretical advantages to enteral feedings, especially when compared with total parenteral nutrition (fPN) and when metabolic end points are taken into consideration. Early enteral nutrition given to patients after major abdominal surgery has been reported to result in significant attenuation in gut mucosal permeability, faster recovery of bowel function, significant improvement in protein metabolism, and an important reduction in infectious compllcations.t" Also, enteral feedings have been associated with prevention of intestinal mucosal atrophy, decreased bacterial translocation, improved gut oxygenation, and reduced patient costs.l? There is no consensus, however, on the benefits of enteral nutrition in cancer patients when "hard" clinical end points are considered such as length of hospital stay, postoperative morbidity, and survival. In the past decade a multitude of reports describing the impact of enteral nutrition among patients with upper digestive tract cancers have been published. Interpretation and comparison of those studies are extremely difficult because they are highly heterogeneous with variable design and outcome measures. Based on the beneficial metabolic effects of enteral nutrition, reports from several clinical series indicated decreased incidence of infectious complications and reduced length of hospital stay when patients with upper gastrointestinal tract malignancies received perioperative enteral nutrition.P'" As we will see in this chapter, results of several other well-designed studies suggested that despite a possible reduction in incidence of septic complications, there is no difference in the incidence of major postoperative complications, length of
SECTION VI • Cancer
hospital stay, and hospital mortality when postoperative enteral nutrition is compared with TPN to intravenous hydration alone.P:" Recent excellent reviews are available in the literature for a thorough examination of the published clinical series on this subject. 16,17
ROUTE OF ADMINISTRATION Nasojejunal tubes or jejunostomy tubes are usually placed in patients with upper digestive tract cancers when enteral access becomes necessary in the perioperative setting. Dysfunction of the stomach and colon usually prevents oral or gastric feeding for 2 to 5 days postoperatively. In addition, surgical resections of upper digestive tract cancers often include different types of gastrectomy or reconstruction with a gastric conduit, all of which preclude placement of enteral access through the stomach, However, as several authors have shown, intestinal motility and absorptive capacity are not inhibited in the immediate postoperative period. 4,18,19 Aiko and associates'? confirmed that nutritional fluid given enterally is completely absorbed, even immediately after highly invasive esophageal surgery. It has also been suggested that constant infusion is better tolerated than intermittent infusion and causes fewer side effects such as diarrhea and abdominal pain." Aspiration pneumonia can easily develop after esophageal surgery because the motility of the denervated stomach is seriously diminished, and dissection of the perineural lymph nodes occasionally causes temporal palsy of the recurrent nerve. Therefore, continuous jejunostomy feedings may be the safest method of enteral feeding for patients after upper gastrointestinal surgery. Nasojejunal tubes are sometimes placed after gastrectomy, and they are an acceptable route for short-term «30 days) enteral access.F Jejunostomy tubes may be placed via open or laparoscopic procedures, and they are often used in patients with esophageal, gastric, and pancreatic cancers. Laparoscopic jejunostomy is less invasive than standard surgery and, when indicated, can be safely and effectively performed in conjunction with tumor staging procedures in patients with upper digestive tract neoplasms.P
PREOPERATIVE ENTERAL NUTRITION Patients with resectable gastrointestinal tumors often are severely malnourished (weight loss more than 10% in the prior 6 months and/or albumin level <3.5 mg/dL). The role of preoperative TPN, often combined with postoperative nutritional support, in the management of patients with esophageal, gastric, and pancreatic cancer, has been addressed in several randomized clinical series. 24- 26 Those reports focus on administration of preoperative TPN, and their analysis is beyond the scope of this chapter. As we will see later in this chapter, several studies using various combinations of preoperative and postoperative enteral nutritional support have been
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conducted recently. However, there are only two small studies in which the role of preoperative enteral nutrition alone has been addressed, and these researchers reported a decrease in infectious complications among patients with cancer who received preoperative enteral nutrition compared with those who received TPN or no nutritional support. 27,28 These results suggested a beneficial role for preoperative enteral nutrition when administered for more than 10 days and in adequate volumes to severely malnourished patients with digestive tract cancers. With the advent of neoadjuvant treatment strategies, enteral access is important in the management of patients with locally advanced cancers of the upper digestive tract to make delivery of preoperative therapy feasible. There are currently no studies that have specifically addressed the role of preoperative enteral nutrition in the context of neoadjuvant treatment for gastrointestinal malignancies. In brief, there may be an advantage to providing preoperative enteral nutrition to severely malnourished patients with upper gastrointestinal cancers (particularly locally advanced esophageal and gastric cancers). Results have not been consistent so far, and the definitive answer can only be provided by adequately designed randomized clinical trials.
EARLY POSTOPERATIVE ENTERAL NUTRITION Earlyenteral nutrition given to patients after major abdominal surgery has been reported to result in a significant attenuation of gut mucosal permeability, faster recovery of bowel function, a significant improvement in protein metabolism, and an important reduction in the incidence of infectious complications.Pf-" Early postoperative enteral feeding is a controversial aspect in the nutrition of patients with upper digestive tract cancers. Analysis of the available studies is difficult because many of them combined preoperative and postoperative nutritional support, with variable total calorie intake and different kinds of formulas, including the addition of immune-modulating nutrients." Furthermore, not all studies offer "intention-totreat" analysis and are thus flawed by possible exclusion of patients with adverse outcomes.l-" Braga and colleagues have been some of the most enthusiastic supporters of early enteral nutrition after upper digestive tract surgery for cancer. 3D-35 Their studies include combinations of preoperative and postoperative enteral nutrition protocols, usually immune-enhancing, compared with TPN or to intravenous hydration alone. These authors have repeatedly reported that early postoperative enteral nutrition significantly reduces the complication rate and duration of hospital stay compared with parenteral nutrition for patients with tumors of the upper digestive tract. However, as other authors have pointed out, the patient populations they analyzed probably overlapped between their different studies, and this may detract from the validity of their results. 17 Several other authors have also concluded that early postoperative enteral feedings (especially with
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45 • Esophageal/Gastric/Pancreatic Cancer
immune-enhancing formulations) are associated with reduced incidence of infectious complications and lower treatment costs after gastrointestinal surgery.IO·36,37 Aiko and associates suggested that immediate enteral nutrition may have beneficial effects on immune competence among patients undergoing esophagectomy.P Results of a meta-analysis of randomized, controlled clinical trials comparing enteral nutritional support supplemented with key nutrients versus standard enteral nutrition favored the former with a consistent trend toward reduction in the incidence of infectious complications and length of hospital stay among patients with gastrointestinal cancer. I I The key components of the various combinations included in the studies that were part of the meta-analysis were L-arginine, L-glutamine, branched-chain amino acids, essential fatty acids, and RNA. On the other hand, in several well-designed trials a clear benefit of early postoperative enteral nutrition was not demonstrated. Heslin and co-workers" randomly assigned 196 patients with upper gastrointestinal malignancies to a treatment group who received an immune-enhancing formula via jejunostomy or to a control group who received intravenous hydration alone. There were no significant differences in the number of infectious complications and length of hospital stay between the two groups. Enteral feeding via a nasojejunal tube provided no measurable benefit compared with intravenous hydration only for patients undergoing routine esophagectomy." Furthermore, results from another randomized clinical trial of patients undergoing major gastrointestinal surgery in which postoperative TPN was compared with enteral nutrition did not show a clinical benefit for the enteral route.P In a prospective multicenter randomized trial, Pacelli and associates 15 also failed to demonstrate that enteral feeding after major abdominal surgery reduces postoperative complications and mortality compared with parenteral nutrition. The same authors pointed out that early enteral nutrition may not be the nutritional treatment of choice after major surgery for gastrointestinal cancer." The cited studies also point to the fact that a large subgroup of patients (up to 20%) do not readily tolerate early enteral feedings and that there is a small (2%), but concerning, incidence of serious jejunostomy-related complications, including small bowel necrosis.P'" In summary, favorable results in several studies suggest that early postoperative enteral nutrition may benefit malnourished patients with upper digestive tract cancers, especially with the use of immune-enhanced formulas. These studies, however, may have design flaws, and results do not clearly demonstrate such benefit when clinical end points are taken into consideration. An objective analysis of the currently available evidence does not favor the routine use of early postoperative enteral nutrition over TPN or in some instances, intravenous hydration alone, among patients with esophageal, gastric, and pancreatic cancer. This is in agreement with what several other authors have recently stated and can only be confirmed or denied by rigorously designed clinical trials. 41-43 Enteral immunonutrition after curative cancer operations is an attractive concept, but parameters such as timing, duration, exact
composition, and impact on oncologic outcome remain to be addressed by such studies.
SPECIFIC CONSIDERATIONS
Esophageal and Gastric Cancer Patients with locally advanced esophageal and gastric cancer may be selected for placement of preoperative enteral access when they are severely malnourished and when feedings are administered for at least 10 days. These patients usually have severe dysphagia, and enteral feedings may provide nutritional support on an outpatient basis. This approach may be associated with decreased incidence of infectious complications and lower costs compared with TPN,but its true clinical benefit remains to be clarified. A jejunostomy tube can often be placed laparoscopically, in conjunction with staging procedures. Surgical resection can then be performed electively, when the patient's nutritional status has improved. Alternatively the patient may participate in neoadjuvant treatment protocols, preferably by enrolling on a clinical trial. In the vast majority of patients who undergo esophagectomy or total gastrectomy jejunostomy tubes are placed at the time of surgery. This is done because oral feedings are not resumed for at least 1 week postoperatively, and it may take several additional weeks or months before adequate caloric intake can be reached. Also, both those surgical procedures can be associated with significant morbidity that may delay oral feedings even further. In patients who undergo partial gastrectomy jejunostomy tubes or nasojejunal tubes should be placed selectively at the time of surgery, depending on their overall nutritional status and the surgeons assessment of risk for postoperative complications.
Pancreatic Cancer Postoperative enteral nutrition may be associated with increased incidence of delayed gastric emptying after pylorus-preserving pancreaticoduodenectorny." In a previous study, cyclic enteral nutrition was recommended for patients undergoing pancreaticoduodenectomy because it was shown to decrease the interval to resumption of an oral diet and reduce the length of hospital stay." High levels of cholecystokinin, which are known to cause delayed gastric emptying, have been implicated in this mechanism."
CONCLUSIONS Based on analysis of currently available evidence, our conclusions about the role of enteral nutrition in patients who have upper gastrointestinal tract cancer at a curable stage are the following: • Preoperative enteral nutrition may be advantageous in severely malnourished patients, when administered for at least 10 days.
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• No evidence is available to support the routine use of enteral feedings rather than TPN, when indicated in the postoperative period. • The sole advantage of placing enteral access and selecting the enteral route rather than postoperative TPN is that it may allow for outpatient enteral feedings when complications delay resumption of an oral diet. • Early enteral nutrition is associated with a small incidence of serious jejunostomy-related complications, including bowel necrosis, and has no proven clinical benefit. • The type of formula used, either preoperatively or postoperatively, should be patient-specific and, despite encouraging reports, evidence is lacking to support the routine use of immune-enhanced preparations. • All decisions should be made on an individual basis, depending on the surgeons assessment of the patients nutritional status, type of underlying malignancy, and risk of perioperative complications. REFERENCES 1. Smith JS, Souba WW: Nutritional support. In DeVita VT, HellmanS, Rosenberg SA (eds): Cancer Principlesand Practice of Oncology, 6th ed. Philadelphia, Lippincott, Williams & Wilkins, 2001, pp 3012-3022. 2. Nelson KA: The cancer anorexia-cachexia syndrome.SeminOncol 2000;27:64-68. 3. Carr CS, Ling KDE, BoulosP, et al: Randomised trial of safetyand efficacy of immediate postoperative enteral feeding in patients undergoinggastrointestinal resection. BMJ 1996;312:869-871. 4. Velez JP, Lince LF, Restrepo JI: Early enteral nutrition in gastrointestinal surgery: A pilotstudy. Nutrition 1997;13:442-445. 5. Harrison LE, Hochwald SN, Heslin MJ, et al: Early postoperative enteral nutrition improves peripheral protein kinetics in upper gastrointestinal cancer patients undergoing complete resection: a randomizedtrial.JPEN J Parenter EnteralNutr 1997;21:202-207. 6. Moore FA, Moore EE: The benefits of enteric feeding. Adv Surg 1996;30:141-154. 7. Mainous M, Xu DZ, Lu Q, et al: Oral-TPN-induced bacterial translocation and impaired immune defenses are reversed by refeeding. Surgery 1991;110:277-283. 8. Suchner U: Enteralversus parenteral nutrition: Effects on gastrointestinal function and metabolism. Nutrition 1998;14:76--81. 9. Braga M, Gianotti L, Gentilini 0, et al: Early postoperative enteral nutrition improves gut oxygenation and reduces costs compared with parenteral nutrition. Crit Care Med2001;29:242-248. 10. Senkal M, Zumtobel V, Bauer KH, et al: Outcome and costeffectiveness of perioperative enteral immunonutrition in patients undergoingelective upper gastrointestinal tract surgery. ArchSurg 1999; 134:1309-1316. 11. Heys SO, Walker LG, Smith I, et al: Enteral nutrition supplementation with key nutrients in patients with critical illness and cancer. AnnSurg 1999;229:467-477. 12. Bozzetti F, Braga M, Gianotti L, et al: Postoperative enteral versus parenteral nutrition in malnourished patients with gastrointestinal cancer: A randomized multicentre trial. Lancet 2001;358: 1487-1492. 13. Reynolds JV, Kanwar S, Welsh FK, et al: Does the route of feeding modify gut barrier function and clinical outcome in patients after major upper gastrointestinal surgery? JPEN J Parenter Enteral Nutr 1997;21:196-201. 14. Heslin MJ, Latkany L, Leung 0, et al: A prospective, randomized trialofearlyenteral feeding after resectionof upper gastrointestinal malignancy. AnnSurg 1997;226:567-580. 15. Pacelli F, Bossola M, Papa V, et al: Enteral vs parenteral nutrition after majorabdominal surgery. ArchSurg2001;136:933-936. 16. Heslin MJ, BrennanMF: Advancesin periopeativenutrition: cancer. World J Surg2000;24:1477-1485.
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17. McCowen K, Bistrian BR: Immunonutrition: problematic or problem solving? Am J ClinNutr2003;77:764-770. 18. Sager S, Harland P, Shield R: Early postoperative feeding with elemental diet. BMJ 1979;1:293-295. 19. Bower RH, Talamini MA, Sax HC, et al: Postoperative enteral vs parenteral nutrition.ArchSurg 1986;121:1040-1045. 20. AikoS, Yoshizumi Y, Sugiura Y, et al: Beneficial effectsof immediate enteral nutrition after esophageal cancer surgery. Surg Today 2001;31:971-978. 21. Kirby OF, DeLegge MH, Fleming CR: American gastroenterological association technical review on tube feeding for enteral nutrition. Gastroenterology 1995;108:1282-1301. 22. Sand J, Luostarinen M, Matikainen M: Enteralor parenteral feeding after total gastrectomy: prospective randomized pilot study. Eur J Surg 1997;163:761-766. 23. Ellis LM, Evans DB, Martin 0, et al: Laparoscopic feeding jejunostomy tube in oncology patients. SurgOncol 1992;1:245-249. 24. Muller JM, Brenner U, DienstC, et al: Preoperative parenteral feeding in patients with gastrointestinal carcinoma. Lancet 1982; 1:68-71. 25. The Veterans Affairs Total Parenteral Nutrition CooperativeStudy Group: Perioperative total parenteral nutrition in surgical patients. NEngl J Med 1991;325:525--532. 26. Brennan MF, PistersPW, Posner M, et al: Aprospectiverandomized trialof total parenteral nutritionafter majorpancreatic resection for malignancy. Ann Surg 1994;220:436-441. 27. Shukla HS, Rao RR, Banu N, et al: Enteral hyperalimentation in malnourished surgical patients. Indian J Med Res 1984;80: 339-346. 28. Meijerink WJ, von Meyenfeldt MF, Rouflart MM, et al: Efficacy of perioperative nutritional support [letter]. Lancet 1992;340: 187-188. 29. Beier-Ho1gersen R, Boesby S: Influence of postoperative enteral nutrition on postoperative infections. Gut 1996;39:833-835. 30. BragaM, Vignali A,GianottiL, et al: Immune and nutritional effects of early enteral nutrition after major abdominal operations. Eur J Surg 1996;162:105--112. 31. Gianotti L,BragaM, Vignali A, et al: Effect of route of deliveryand formulation of postoperative nutritionalsupport in patients undergoing major operations for malignant neoplasms. Arch Surg 1997;132:1222-1229. 32. DiCarloV,Gianotti L, BalzanoG,et al: Complicationsof pancreatic surgery and the role of perioperative nutrition. Dig Surg 1999;16: 320-326. 33. BragaM, Gianotti L, Radaelli G, et al: Perioperative immunonutrition in patients undergoing cancer surgery: Results of a randomized double-blind phase 3 trial. ArchSurg 1999;134:428-433. 34. Gianotti L, Braga M, Gentilini 0, et al: Artificial nutrition after pancreaticoduodenectomy. Pancreas 2000;21 :344-351. 35. Braga M, Gianotti L, Nespoli L, et al: Nutritional approach in malnourished surgical patients:A prospective randomized study. Arch Surg2002;137:174-180. 36. Daly JM, Lieberman MD, Goldfine J, et al: Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: Immunologic, metabolic, and clinical outcome. Surgery 1992;112:56-67. 37. Daly JM, Weintraub FN, Shou J, et al: Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Ann Surg 1995;221:327-338. 38. Page RD, 00 AY, Russell GN, et al: Intravenous hydration versus naso-jejunal enteral feeding after esophagectomy: A randomised study. Eur J CardiothoracSurg 2002;22:666-672. 39. PacelliF, BossolaM, Papa V, et al: Postoperativeenteral versusparenteral nutrition [letter]. Lancet 2002;359:1697-1698. 40. Braga M, Gianotti L, Gentilini 0, et al: Feeding the gut early after digestive surgery: Results of a nine-year experience. Clin Nutr 2002;21 :59-65. 41. Lipman TO: Grains or veins; is enteral nutrition really better than parenteral nutrition? A look at the evidence. JPEN J Parenter EnteralNutr 1998;22:167-182. 42. Jeejeebhoy KN: Total parenteral nutrition: potion or poison? Am J ClinNutr2001;74:160-163. 43. Bistrian BR: Route of feeding in critically ill patients [letter]. Crit Care Med 2002;30:489-490.
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44. Martignoni ME, Friess H, Sell F, et al: Enteral nutrition prolongs delayed gastric emptying in patients after Whipple resection. Am J Surg 2000;180:18-23. 45. van Berge Henegouwen MI, Akkermans LMA, van Gulik TM, et al: Prospective randomized trial on the effect of cyclic versus continuous enteral nutrition on postoperative gastric function after
pylorus-preserving pancreatoduodenectomy. Ann Surg 1997;226:
677-687. 46. Kleibeuker JH, Beekhuis H, Jansen JB, et al: Cholecystokinin is a physiological and hormonal mediator of fat-induced inhibition of gastric emptying in man. Eur J Clin Invest 1988;18:173-177.
Intestinal Transplantation Lori Kowalski, MS, RD, CNSD Anita Nucci, PhD, RD Jorge Reyes, MD
CHAPTER OUTLINE Introduction Indications for Intestinal Transplantation Nutritional Implications of Intestinal Failure Nutrition Assessment-Before Transplant Anthropometric Assessment Physical Examination Biochemical Tests Macronutrient Requirements Feeding History Nutrition Management Before Transplant Parenteral Nutrition Enteral Nutrition Protein Carbohydrate Fat Fiber Enteral Formulas Nutrition Management After Transplantation Initial Enteral/Parenteral Nutritional Support Advancement of Enteral/Oral Feeding and Weaning of PN Long-Term Nutritional Goals Present Status and Future Goals
INTRODUCTION Transplantation of organs such as the kidney, heart, and liver has been performed successfully in children for almost 40 years. Intestinal transplantation has remained challenging because of technical complications and the inability to immunosuppress the host adequately. This has resulted in infections that are difficult to control and often rejection. The first pediatric intestinal transplants were completed with the use of immunosuppressive agents such as cyclosporine, azathioprine, and corticosteroids'<;
however, these agents were in the long term mostly unsuccessful. Advances in clinical surgery and the emergence of tacrolimus (Prograf, previously FK506, Fujisawa, Deerfield, IL) as the primary immunosuppressive agent in intestinal transplantation has improved survival.' Despite these improved results, the postoperative management of nutritional therapy and medications remains complex, and the long-term outcomes such as adequate growth and improved quality of life are still being explored.
INDICATIONS FOR INTESTINAL TRANSPLANTATION Children with irreversible intestinal failure may be considered as candidates for intestinal transplantation. Patients are deemed to have intestinal failure when fluid, electrolyte, and nutritional status cannot be maintained without parenteral nutrition (PN),4 and this dependence on PN has lead to complications that include catheter infections, sepsis, loss of venous access, cholestatic liver disease, and in some instances liver failure. The causes of intestinal failure are divided into two groups, surgical and functional. Patients with surgical reasons for intestinal failure have intestinal atresias, gastroschisis, mid-gut volvulus, necrotizing enterocolitis, and vascular catastrophes such as trauma or thrombosis. Functional problems include disorders of motility such as chronic pseudo-obstruction, Hirschsprung's disease, or aganglionosis and secretory disorders such as microvillus inclusion disease and protracted diarrhea of unknown etiology. A coordinated, multidisciplinary team approach can help to facilitate the identification and management of transplant candidates. The initial evaluation of potential transplant candidates includes determination of venous access, functional status of the intestine (including motility studies), length of the intestine, degree of liver damage from PN, and the involvement of other organs in the disease. This information helps the team to identify which type of allograft the patient will need. Allograft options include an isolated small intestine, a liver/small
523
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46 • Intestinal Transplantation
intestine, or a multivisceral graft. Optimizing the patient's clinical and nutritional management both before and after the transplant should allow for a transition from parenteral to enteral/oral nutritional support as well as adequate growth, development, and improved quality of life.
NUTRITIONAL IMPLICATIONS OF INTESTINAL FAILURE Maintenance of growth and development may be severely compromised in patients with intestinal failure. Macro- and micronutrient absorption and electrolyte malabsorption depend on the status and function of the intestinal tract. The type and amount of nutritional support used is influenced by the type, length, and condition of the existing bowel; colon length; the presence or absence of the ileocecal valve; intestinal motility; and the function of the liver, pancreas, and gallbladder," The duodenum and jejunum are the primary sites for protein, fat, vitamin, and mineral absorption. Carbohydrate malabsorption from decreased disaccharidase activity may lead to osmotic diarrhea from undigested carbohydrate in jejunal resections. Ileal resection usually allow for better long-term adaptation than jejunal resections. Problems with fluid, electrolyte, and bile salt malabsorption (that leads to watery diarrhea and fat and fat-soluble vitamin malabsorption) are common with large ileal resections. The jejunum may not be able to compensate for fluid and electrolyte shifts and may even leak fluid at the jejunal epithelial junctions. Increased amounts of bile salts in the colon may further exacerbate diarrhea (choleretic diarrhea)." The ileocecal valve functions as both a barrier to bacteria from the colon as well as a "brake" on intestinal transit. Malfunction or absence of this valve may increase the risk of bacterial overgrowth or translocation. This increased bacterial concentration may lead to bile acid deconjugation and mucosal inflammation, thus promoting fat and fat-soluble vitamin malabsorption. The colon, if present, absorbs water and sodium. Bacterial fermentation of unabsorbed carbohydrate and fiber in the colon produces short-ehain fatty acids (primarily acetate, propionate, and butyrate) that are used for energy by the colon. Colonic resection probably has the greatest impact on malabsorption of fluid and electrolytes rather than nutrients. The overall condition of the remaining bowel, including stasis due to fibrosis, surgical narrowing, or poor perfusion, may have more of an effect on absorption than the length or location of a resection. The goal of therapy should be to maximize enteral absorption (to promote motility, gastrointestinal secretions, and trophic hormones) and to minimize PN to avoid or delay PN-associated liver disease. Cholestatic liver disease is more common in children, especially those who are unable to tolerate enteral teeding.I" Other etiologies that have been suggested are a disruption in
the enterohepatic circulation," repeated episodes of catheter sepsis, and bacterial overgrowth from intestinal stasis. Cholecystokinin release, which is a stimulus for emptying of the gallbladder, is decreased without enteral stimulation.'? Bowel atrophy, dysmotility, and stasis may also occur. Both an overabundance (protein, carbohydrates, tryptophan, and f1avonoids) and deficiency (taurine and selenium) of nutrientsl':" have been suggested as causative factors. Excessive manganese supplementation" has also been implicated in exacerbation of cholestasis in children. Patients with liver and intestinal failure have been shown to have significant 1year mortality because of infection, bleeding, and
encephalopathy."
NUTRITION ASSESSMENT-BEFORE TRANSPLANT A thorough nutrition assessment before transplantation is critical to help maximize the patient's nutritional status. An optimum nutritional state is believed to increase the patient's chance of a successful outcome. To achieve this objective the four main nutritional goals can be summarized as follows: 1. Appropriate PN management, including correct substrate use and cycling of PN when possible 2. Maintenance of vitamin and mineral status 3. Oral stimulation 4. Adjustment of enteral feedings
Anthropometric Assessment Anthropometric measurement in children is a valuable tool because it is easily obtained and age-specific standards are available. Growth is plotted and followed for all transplant candidates. This includes current weight, height, weight for height, and occipital head circumference (if younger than 3 years of age). If the patient is older than 2 years of age, body mass index should also be assessed. The growth velocity is evaluated, and adjustments should be made in provision of kilocalories to allow for adequate growth. An amount 10% to 20% above kilocalorie estimates may be necessary to achieve adequate catch-up growth. Measurement of triceps skinfold thickness and midarm circumference may also be followed. It is important to use appropriate instruments, the same observer, and serial measurements to interpret these results.
Physical Examination Along with anthropometric measurement, patients may also be given a quick physical examination. This preliminary look may then lead to more detailed evaluation if necessary. Hair that is sparse or easily breakable may indicate malnutrition. Dryskin is often a sign of vitamin A or folic acid deficiency. Skeletal changes may point to problems with vitamin D or calcium metabolism.
SECTION VII • Transplant
Biochemical Tests Monitoring of laboratory tests helps the clinician to adjust the provision of nutrients and electrolytes in enteral feedings, intravenous replacement fluids, and PN both before and after transplantation. Basic pretransplant biomedical tests should include measurements of electrolytes, total bilirubin, alkaline phosphatase, triglycerides, calcium, phosphorus, magnesium, albumin, hemoglobin, hematocrit, platelets, and prothrombin time and other liver function tests among others (Table 46-1). Levels of vitamins A, D, B12, and E and zinc, copper, manganese, selenium, and carnitine should also be checked.
Macronutrient Requirements Kilocalorie requirements for children receiving oral or enteral nutrition are usually assessed based on the Recommended Dietary Allowances (RDAs) for age plus additional kilocalories for growth and development." Indirect calorimetry remains the best and most accurate way to assess basal metabolic requirements. However, this test is often not practical to perform, or it may produce unreliable results when a patient is receiving mechanical ventilation and multiple air leaks are present. For patients receiving both enteral and parenteral N, kilocalorie requirements are usually estimated to be 5% to 10% less than the RDA (90 to 110 kcal/kg). Kilocalorie
525
requirements in PN-dependent patients may be even lower (60 to 80 kcal/kg). Some centers have shown that PN-dependent children can maintain growth with as little as 70% of the RDA. 16 Overfeeding, especially of PN, may hasten the onset of cholestatic liver disease. Protein requirements are estimated based on the RDA for age. Adjustments are made based on the patient's liver and renal function. The patient's total bilirubin (TB) level is often used as a guide for protein provision (TB >3.0 mg/dL, 1.0 g of protein/kg; TB <3.0 mg/dL, 1.5 g of protein/kg).
Feeding History A complete nutritional assessment should also include a history of enteral feeding tolerance and current eating habits. Often for children with intestinal failure, many different types of infant and enteral formulas have been tried before the best option is chosen. It is important to note the type of enteral feeding and route, as well as the percentage of kilocalories that are contributed to the patient's total kilocalorie intake. Infants and children are also at risk for aversion to oral feeding if they have received PN or enteral feedings for a long period of time." Normal feeding and swallowing development are often missed. For children who can swallow, oral feeding of small amounts of food with varied tastes and textures is encouraged. Maintenance of oral stimulation may help in the post-transplant period when the patient's feeding is being transitioned from enteral to oral.
IlmllIB
Recommended Biochemical Monitoring _ _ Pretransplant
Biochemical indexes Electrolytes Total bilirubin Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) y-Glutamyl trans peptidase (GGT) Alkaline phosphatase Triglycerides Blood urea nitrogen Creatinine Amylase Lipase Carbon dioxide Ionized calcium Glucose Albumin Total protein (may be more indicative of liver synthetic function than of nutritional status) Hemoglobin Hematocrit Platelets Prothrombin time Carnitine
Vitamin and mineral studies Serum vitamin A, E, and BI~ levels Vitamin 0 (25 and 1,25) levels Red blood cell folate level Serum zinc level Serum copper level
NUTRITION MANAGEMENT BEFORE TRANSPLANT Enteral and parenteral nutritional support modifications along with other strategies that are used before transplantation (e.g., anti-motility and prokinetic agents, control of bacterial overgrowth, and surgical therapies such as restoring intestinal continuity and bowel tapering and lengthening) may help to stabilize the patient's clinical status as he or she waits for organ donation.
Parenteral Nutrition Appropriate PN management and the avoidance of overfeeding are critical components of nutritional care in the pretransplant period. Delaying the potential onset of PNinduced cholestatic liver disease is crucial. One of the primary nutrition management techniques used involves cycling PN with a goal of 12 hours on and 12 hours off. This may be difficult in young infants receiving PN, who may suffer from severe hypoglycemia because of the inability to store glycogen and perform glycogenolysis in the liver." Even 2 to 4 hours without PN may be of some benefit to the patient.'? The use of Tropharnine-" as the amino acid source in PN has also been suggested. TrophAmine contains taurine that may help with bile
526
46 • Intestinal Transplantation
acid conjugation. As with other critically ill patients, the nonprotein calorie-to-nitrogen ratio should be kept at 150 to 250:1 when a patient is receiving PN.21 Vitamin, mineral, and trace mineral status must be closely monitored. Blood levels of fat-soluble vitamins, zinc, selenium, copper, manganese, and camitine should be measured at evaluation and then every 3 months until transplant. Because copper and manganese are excreted via the biliary route, they are often omitted in the PN of patients with cholestasis. Manganese toxicity may actually exacerbate cholestasis in children." Copper deficiency has been linked to pancytopenia. Provision of one half dose of standard trace minerals with adequate zinc should satisfy the requirements for these nutrients without toxic effects. Selenium is involved in the body's antioxidant defense system (as a component of glutathione peroxidase) and is routinely not included in the standard trace mineral solution. Supplementation should be 3 Jlg/kg/day for children from birth to 10 years of age and 20 to 60 Jlg/day for adolescents." Camitine status may also be important in patients with intestinal failure. Camitine helps to facilitate ~ oxidation of long-chain fatty acids into the mitochondria. Decreased serum triglyceride levels have been seen in some patients with hypertriglyceridemia after camitine supplementation of PN (starting at 10 mg/kg/day).
Enteral Nutrition Enteral feeding of patients with intestinal failure should always be the goal of nutritional therapy. Contraindications to this route of feeding are gastrointestinal bleeding and excessive stool output, although after these problems are addressed, enteral feeding should be restarted. Enteral nutrition helps to stimulate small bowel adaptation by direct contact with and absorption of nutrients by enterocytes. Mucosal mass is maintained by the presence of nutrients in the small bowel. Nutrients also help stimulate pancreatic and biliary secretions as well as secretions of other trophic hormones and growth factors. There is compelling evidence that enteral feedings are trophic for the small bowel, although the exact interplay between nutrients, hormones, and growth factors continues to be actively studied.
Protein Amino acid, hydrolyzed protein, and whole protein formulas have been used for children with intestinal failure. Protein hydrolysates have been shown to be more easily absorbed than whole proteins." Mucosal hyperplasia was not enhanced by whole proteins in comparison to protein hydrolysates in animal studies." Peptide-based formulas are often well tolerated (part of the protein absorbed in the small intestine is in the form of di- and tripeptides). These formulas have the benefit of a lower osmolality because of the presence of peptides instead of amino acids. This lower osmolality may make peptide products more suitable for patients who have increased
stool output. They may also promote better kilocalorie and protein provision than an amino acid-based formula because there is less need to dilute the solution. Conversely, amino acid-based formula may be better tolerated by children with either eosinophilic inflammation of the stomach and small bowel or gastrcenteritis." Powdered amino acid-based formulas that contain free glutamine have been shown to protect gastrointestinal mucosa and to reduce bacterial translocation.tv" Studies that directly compare protein sources for children with intestinal failure have not been conducted.
Carbohydrate Carbohydrates are usually present in enteral formulas in the form of glucose, sucrose, or glucose polymers. Modular carbohydrate powders (mainly glucose polymers) are often used to increase the caloric density of formula to help increase the patient's overall calorie intake. Bacterial fermentation of malabsorbed carbohydrate and the increased absorption of short-ehain fatty acids (including o-lactate) may lead to diarrhea and metabolic acidosis. Reducing substances and a low stool pH «5.5) may reflect carbohydrate malabsorption. In severe occurrences, a commercial formula with very low amounts of carbohydrate may be useful. Carbohydrate can then be reintroduced as tolerated. In some children, lactose may also need to be avoided when decreased lactase activity is present. An enteral formula containing a combination of glucose or sucrose with glucose polymers that is also lactose free is probably the best choice for children with intestinal failure.
Fat Traditionally, low-fat diets were recommended for patients with short bowel syndrome based on the association of low-fatdiets with a decrease in stool and water output as well as a decrease in steatorrhea." Successful advancement of enteral feedings with high-fat diets (65% of calories as fat) with medium-chain triglycerides (MCTs) as the fat source has been reported." MCTs may be more easily absorbed than long-ehain triglycerides when insufficient amounts of bile acids are present. Long-chain triglycerides do need to be provided (about 10% of total calories) to prevent essential fatty acid deficiency. Long-ehain fats may also stimulate mucosal hyperplasia better than MCTs.29
Fiber The addition of fiber to enteral feedings may help to regulate intestinal transit and to improve stool consistency. Fiber has also been suggested to stimulate the production of colonic bacteria to help carbohydrate metabolism in the colon. If bacterial overgrowth is present, addition of fiber may increase bacterial fermentation that could worsen acidosis. Fiber supplements include
SECTION VII • Transplant
pectin or guar gum products and are usually given at 10 to 15 gIL. Patients with a stool output of >40 mUkg may benefit from the addition of fiber to enteral feedings. Studies of fiber supplementation in this patient group are currently not available.
Enteral Formulas No consensus on the best enteral feeding product for children with intestinal failure currently exists. Either a peptide- or amino acid-based formula high in MCTs with a mixture of glucose and glucose polymers is probably the best choice. A list of the most commonly used commercial products appears in Table 46-2.
NUTRITION MANAGEMENT AFTER TRANSPLANTATION Initial Enteral/Parenteral Nutritional Support In the first 24 to 48 hours after transplantation, patients are usually maintained on intravenous fluids because of electrolyte imbalances and fluid shifts. Adequate perfusion of the new graft and replacement of ileostomy and gastric losses are the primary goals. PN is usually restarted 1 to 2 days after transplantation and administered over 24 hours. Protein and kilocalorie requirements will vary based on the patient's pretransplant nutritional status, ventilatory status, and wound healing and the presence of sepsis. As stated earlier, kilocalorie requirements may be as low as 70% of the RDA in a well-nourished patient or as high as 120% above the RDA in patients with
. . Potentially Usable Commercial Enteral Products Posttransplant Enteral Products
527
malnutrition or an open abdominal wound. Protein is usually provided at 1.5 times the RDA. Posttransplant immunosuppressive therapy can exacerbate or cause problems with hyperglycemia, renal insufficiency, electrolyte and fluid provision, and hyperlipidemia, all of which may necessitate a change in nutritional therapy. Tacrolimus has been shown to cause hyperkalemia and hypomagnesemia." The potassium level must be carefully monitored, and many patients require magnesium replacement. Corticosteroid use can cause hyperglycemia, and insulin therapy may be necessary in the short term to control blood glucose levels. The use of corticosteroids and other immunosuppressive drugs may also place patients at risk for hyperlipidemia. When patients are receiving intravenous lipids, serum triglyceride levels should be checked. Lipids should be stopped at levels greater than 300 mgldL. When serum triglyceride levels return to normal, a cycled lipid infusion or every other day lipid administration may be better tolerated. Frequent adjustments of the nutritional care plan may need to be made owing to sudden changes in the patient's clinical course throughout this period. A surgical jejunostomy is usually created proximally into the transplanted jejunum during surgery. Poor gastric motility and adaptation may persist for months to years after transplantation. When evidence of ileostomy output or bowel function is seen, enteral feedings are started (usually 3 to 14 days after transplantation). Feedings are generally started continuously at small volumes (1 to 5 mUhr) and are then advanced in 2 to 5 mUhr increments on the basis of stomal output and abdominal status. Infant formulas are initially given at 20 calories/oz. Amino acid-based powdered formulas are usually mixed at 24 calories/oz because of their high osmolality. Peptide-based formulas may be started at full strength or 30 calories/oz (l calorie/mL). Acceptable stool output is considered to be less than 40 mUkg/day. Higher stool outputs are treated with fiber supplements or antidiarrheal agents or a decrease in the formula volume. Dilution of the formula may also be necessary along with fluid replacement in the form of intravenous fluids.
Protein
Fat
Carbohydrate
Pregeslimil
Casein hydrolysate Amino acid
Corn syrup Corn starch Dextrose
Advancement of Enteral/Oral Feeding and Weaning of PN
Neocate
Amino acid
MCT 55% Corn Safflower Soy Safflower Coconut Soy
Corn syrup
MCT600/" Soy Canola MCT 359(, Canola Safflower
Maltodextrin Corn starch
After enteral feedings have been well established and the patient's condition is medically stable, PN should be gradually cycled and enteral feedings increased. This may be done in 2- to 4-hour increments with careful monitoring of glucose levels. Older children may be able to tolerate more dramatic changes in PN. Intravenous fluid replacement may need to be continued throughout this period to provide adequate hydration. Oral intake may be initiated during this period (usually 7 to 14days after transplantation) when the child has been weaned from mechanical ventilation. Oral feedings should be low osmolar clear liquids, and the diet should be advanced as tolerated. Many of these patients are adverse to oral feeding from years of dependence on
Peptamen Junior Neocate Junior Pepdite One Plus
Peplinex DT
Hydrolyzed Whey Amino acid
Pork Soy Casein hydrolysate Amino acid
MCT 359(, Canola Safflower MCT 500/" Soy
Corn starch
Corn starch
Maltodextrin Corn starch
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46 • Intestinal Transplantation
PN, and training them to eat requires time and dedication. Diets are generally not restricted to give the patient multiple food choices. Some patients may need to follow a low simple carbohydrate diet to help control osmotic diarrhea. Others may be sensitive to lactosecontaining or high-fat diets. Eventually jejunostomy tube feedings are transitioned to gastrostomy tube feedings to provide additional emptying time and absorption from the stomach to the duodenum. As the patient's oral intake and absorption improves, as measured by nutrient intake evaluations, continuous feedings may be decreased to cycled nighttime feedings. Even a small decrease in the number of hours of infusion may improve oral intake.
Long-Term Nutritional Goals The long-term nutritional goals for pediatric intestinal transplant patients include the following: 1. Discontinuation of PN 2. Management and eventual discontinuation of hydration fluid regimens 3. Cycling of enteral feedings and transition to all oral intake 4. Appropriate growth and development Once PN has been discontinued, oral or enteral vitamin and mineral supplementation is required. Because fat malabsorption may continue to be a problem after transplantation, a water-soluble form of multivitamin is often used. ADEK (Scandipharm, Birmingham, AL) supplies both water-soluble versions of fat-soluble vitamins and water-soluble vitamins, as well as zinc. In addition, many patients require extra zinc supplementation (l to 1.5 times the RDA) if they have large stool outputs. Excessive stool output is managed in the same way as that in earlier stages of post-transplant care. Administration of hydration fluids may need to be continued for many months to help stabilize electrolyte levels. Vitamin and mineral levels should be checked quarterly at first. The frequency of vitamin and mineral monitoring decreases when patients have their stomas closed, enteral feedings are discontinued, and they are able to maintain oral intake as their sole source of nutrition. Food allergies are not uncommon in this group of patients. Symptoms include rash, vomiting, and increased stool output. Milk protein, lactose, wheat, peanut, and egg allergies are the most commonly reported." Other allergies may be determined by using a radioallergosorbent test32 that checks for possible allergic responses to substances in the environment. Some patients also experience persistent fat malabsorption after transplantation. Pancreatic enzyme therapy may be of some benefit in patients with quantitative fecal fat levels greater than 20%.33 Many patients continue to have severe aversion to oral intake. Inpatient feeding rehabilitation programs may be helpful for these patients. Growth and weight gain should be closely monitored. Height and weight should be plotted at each outpatient visit. Kilocalorie requirements are based on growth, activity level, and absorption. Often growth is not good
in the first years after transplantation. Factors that may inhibit growth include episodes of rejection that necessitate corticosteroid usage and viral infections and sepsis that make frequent hospitalizations common. Any of these complications may lead to an adjustment of nutritional therapy to prohibit both weight loss and a decline in nutritional status. The medical and nutritional care of pediatric intestinal transplant patients can be very challenging. An interdisciplinary care center with a team of transplant and pediatric surgeons, gastroenterologists, registered dietitians, nutritional support nurses, and transplant nurse coordinators has many advantages for the transplant patient. These include (1) integration of management by specialists to improve the outcome of the disease process, (2) communication of the treatment plan to the family by the entire team, and (3) continuity of care throughout the whole treatment."
PRESENT STATUS AND FUTURE GOALS In our program, 84 patients have received 89 intestinal transplants between June 1990 and January 2002. Twenty-six received isolated intestine, 54 received combined liver/intestine, and 4 received multivisceral transplants. Forty-five (54%) of these patients are still alive. The actuarial survival rate for this patient population at I, 3, and 5 years was 74%, 59%, and 56%, respectively. The patients with isolated intestinal grafts had better graft and patient survival rates than patients with liver/intestine or multivisceral grafts. The development of new clinical and surgical strategies has increased the feasibility, reliability, and lifesaving potential of intestinal transplant procedures.F" Improvements in pre- and post-transplant care continue to be explored." Areas of interest include techniques to increase linear growth in this population, whether by medication, hormone therapy, or nutritional modification; the effect of elevations of pancreatic enzyme levels on nutritional outcomes; and early enteral feeding after transplantation, with minimal or no PN support. Studies of glutamine in enteral and parenteral solutions, use of probiotics, diet modification, and the best protein source for enteral feedings may also provide valuable information for the optimal care of children with intestinal transplants. REFERENCES 1. Grant D: Intestinal transplantation: Current status. Transplant Proc
1989;21 :2869-2871. 2. Starzl T, Rowe M,Todo S, et a1: Transplantation of multiple abdominal viscera. JAMA 1989;261:1449-1457. 3. Todo S, Tzakis A, Abu-Elrnagd K, et al: Cadaveric small bowel and small bowel-liver transplantation in humans. Transplantation
1992;53:369-376. 4. Nucci A, Barksdale E, Beserock N, et al: Long-term nutritional outcome after pediatric intestinal transplantation. J Pediatr Surg
2002;37:46Q-463. 5. Warner B, Ziegler M: Management of short bowel syndrome in the pediatric population. Pediatr Clin North Am 1993;40:1335-1350.
SECTION VII • Transplant
6. Hofman A, Poley 1: Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection: Response to cholestyramine or replacement of dietary long-chain triglyceride by medium-chain triglyceride. Gastroenterology 1972;62:918-934. 7. Beale E, Nelson R, Bucciarelli R, et al: Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics 1979;64:342-347. 8. Colomb B,Goulet 0, Rambau D, et al: Long term parenteral nutrition in children; liver and gall bladder disease. Transpl Proc 1992;24:1054. 9. Balisteri W, Bove K: Hepatobiliary consequences of parenteral alimentation. Prog Liver Dis 1990;9:567-601. 10. Teitelbaum D, Han-Markey T, Schumacher R: Treatment of parenteral nutrition-associated cholestasis with cholecystokininoctapeptide. J Pediatr Surg 1995;30:1082-1085. II. Manginello F, Javitt N: Parenteral nutrition and neonatal cholestasis. J Pediatr 1981;99:445-449. 12. Das J, Cosentino C. Levy M, et al: Early hepatobiliary dysfunction during total parenteral nutrition: an experimental study. J Pediatr Surg 1993;28:14-18. 13. Fell J, Reynolds A. Meadows N, et al: Manganese toxicity in children receiving long-term parenteral nutrition. Lancet 1996; 345:1218. 14. Bueno J, Ohwada S, Kochosis S, et al: Factors impacting on the survival of children with intestinal failure referred for intestinal transplantation. J Pediatr Surg 1999;34:27-33. 15. National Academy of Sciences: Recommended Dietary Allowances, IOth ed. Washington, DC, National Academy Press, 1989. 16. Iyer K, Iverson A. DeVoll-Zabrocki A. et al: Pediatric intestinal transplantation-Review of current practice. Nutr Clin Prac 2002; 17:350-360. 17. Strohm S, Reyes J, Koehler A: Pediatric Small Bowel Transplantation. In Hasse JM, Blue LS(eds): Comprehensive Guide to Transplant Nutrition, pp 216-225. Chicago, American Dietetic Association, 2002. 18. Meehan J, Georgeson K: Prevention of liver failure in parenteral nutrition-dependent children with short bowel syndrome. J Pediatr Surg 1997;32:473-475. 19. Faubion W, Baker W, lott B, et al: Cyclic TPN for hospitalized pediatric patients. Nutr Suppl Serv 1981;1:24. 20. Guertin F, Roy C, Lepage G, et al: Effect of taurine on total parenteral nutrition-associated cholestasis. JPEN J Parenter Enteral Nutr 1991;15:247-251.
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21. Nutritional Support Committee: In Barksdale EM, Nucci A, Yaworski JA (eds): Parenteral Nutrition Manual, 5th ed., p 7. Pittsburgh, Children's Hospital of Pittsburgh, 2003. 22. Cosnes J, Evard D, Beaugerie J, et al: Prospective randomized trial comparing small peptides vs. whole proteins in patients with a high jejunostomy [abstract]. Gastroenterology 1990;98:AI65. 23. Vanderhoof J, Grandjean C, Burkley K, et al: Effect of casein versus casein hydrolysates on mucosal adaptation following massive bowel resection in infant rats. J Pediatr Gastroenteral Nutr 1984;3:262-267. 24. Vanderhoof J, Kaufman S, Murray N, et al: Evaluation of Neocate in infants with milk protein induced colitis [abstract]. J Pediatr Gastroenteral Nutr 1995;21:3331. 25. Van Der Hulst R, Van Kreel B, Von Meyenfeldt M, et al: Glutamine and the preservation of gut integrity. Lancet 1993;341:1363-1365. 26. Vanderhoof J, Blackwood D, Mahammadpour H, et al: Effects of oral supplementation of glutamine on small intestinal mucosal mass following resection. J Am Coli Nutr 1992;11:223-227. 27. Dudrick S, Latif R, Fosnocht D: Management of the short-bowel syndrome. Surg Clin North Am 1991;71:625-643. 28. Hays T, Saavedra J, Mattis L, et al: The use of high-fat low-earbohydrate diets for advancement of enteral feedings in children with short-bowel syndrome. Top Clin Nutr 1995;10:35-41. 29. Grey V, Garofalo C, Greenberg G, et al: The adaptation of the small intestine after resection in response to free fatty acids. Am J Clin Nutr 1984;40:1235-1242. 30. Fung J, Al1essiani M, Abu-Elmagd K, et al: Adverse effects associated with the use of FK506. Transplant Proc 1991;23: 3105-3108. 31. Koehler A, Yaworski J, Gardner M, et al: Coordinated interdisciplinary management of pediatric intestinal failure: A 2-year review. J Ped Surg 2000;35:380-385. 32. Jacobs D, DeMott W, Strobel S, et al: Chemistry. In Jacobs D, Kaster B, DeMott W, et al (eds): Laboratory Test Handbook, 2nd ed., pp 76-78. Cleveland, Williams & Wilkins, 1990. 33. Strohm S, Koehler A, Mazariegos G, et al: Nutrition management in pediatric small boweltransplanl. Nutr Clin Prac 1999;14:58-63. 34. Grant D: Current results of intestinal transplantation. International Transplant Registry. Lancet 1996;347:1801-1803. 35. Reyes J, McGhee W, Mazariegos G, et al: Thymoglobulin in the management of steroid resistant acute cellular rejection in children. Transplantation 2002;74(4):419.
Chronic Liver Disease and Transplantation Vincent Armenti, MD, PhD Jeanette Hasse, PhD, RD, FADA, CNSD
CHAPTER OUTLINE Introduction Chronic Liver Disease Liver Transplantation Organ Allocation Surgical Procedure Nutrition Assessment Nutritional Status Malnutrition Obesity Nutrition Management of Chronic Liver Disease Nutrition Recommendations Enteral Nutrition Nutrition Management of Liver Transplantation Factors Affecting Post-Transplant Nutrient Requirements Nutrition Recommendations Enteral Nutrition Conclusions
INTRODUCTION Nutritional abnormalities are seen nearly universally in patients with chronic liver disease. Because the liver synthesizes, degrades, activates, and stores several macro- and micronutrients, liver dysfunction almost inevitably causes some degree of malnutrition. Chronic liver disease also influences nutrient intake because anorexia, dysgeusia, early satiety, nausea, vomiting, and diarrhea are common symptoms in people suffering from liver failure. The type of nutrient alterations and degree of malnutrition depend on the liver disease diagnosis, ensuing symptoms of end-stage liver disease (e.g., ascites and variceal bleeding), and effects of medical treatment. Patients undergoing liver transplantation 530
already have a risk for nutritional deficiencies due to nutritional alterations caused by liver failure. Metabolic changes resulting from surgery and immunosuppressive drugs further compromise nutritional status.
CHRONIC LIVER DISEASE There are four main categories of liver disease that may lead to transplantation: parenchymal liver disease, cholestatic liver disease, congenital errors of metabolism, and hepatic tumors. The most common indication for liver transplantation in adults is postnecrotic cirrhosis, the main etiology being chronic viral hepatitis B or C. Another main cause of cirrhosis is alcohol; it is estimated that approximately 10% of the adult population has a history of alcohol abuse. Cryptogenic cirrhosis (in which no defined etiology can be determined) also is seen in a significant percentage of patients with liver failure. Other parenchymal causes include sub fulminant hepatic failure, Budd-Chiari syndrome, and congenital hepatic fibrosis. In the cholestatic category of liver failure are primary biliary cirrhosis, sclerosing cholangitis, secondary biliary cirrhosis, biliary atresia, and familial cholestasis. Errors of metabolism disorders (such as Wilson disease or hemochromatosis) and tumors are other categories for liver transplantation.'
LIVER TRANSPLANTATION
Organ Allocation Classification methods to allocate livers for transplantation have changed over the years. Recently, the United Network for Organ Sharing (UNOS) Liver and Intestinal Committee revamped the allocation policy. They looked at previously published survival models to estimate the survival of patients with end-stage liver disease and develop a new disease severity index for use in allocating liver donor organs. Since February 2002, organ allocation
SECTION VII • Transplant
has been based on the Model for End-Stage Liver Disease (MELD) score. This model is a disease severity index based on serum creatinine and total bilirubin levels and the international normalized ratio for prothrombin time.' Because advanced liver disease is associated with diminished nutritional status, one could theorize that patients with parenchymal and cholestatic liver disease undergoing transplantation today have a higher rate of malnutrition than those who received transplants under the previous organ allocation system in which waiting time rather than degree of illness was a major determinant for organ allocation. In 2002, 5,326 liver transplants were performed in the United States. As of April 20, 2003, 17,068 patients were waiting for a liver transplant.' The disparity between the number of patients needing a transplant and the number of donors available has led to increased mortality among those awaiting transplantation. In 2002, 1,773 patients died while they were on the liver transplant waiting list."
Surgical Procedure When a liver transplant donor is available, a suitable candidate is identified from the waiting list. Patients are called in to the hospital, quickly prepared for surgery, and transported to the operating room for liver transplantation. When the procurement team has seen the liver and determined that it is suitable for transplantation, typically the recipient is prepared for surgery. A cadaver donor is the source of the majority of liver transplants although experience with living donor liver transplantation in which a portion of the liver is removed from a live donor and then transplanted into the recipient is increasing.' Good predictors of how a patient will do in the immediate postoperative recovery phase include the amount of blood that is lost during the procedure and whether liver function begins promptly. In some patients, a delay in function may be seen; a dramatic presentation of poor postoperative function is known as primary graft nonfunction and requires emergency retransplantation. The two options for management of the biliary tree may have nutritional implications. The donor duct may be anastomosed to the recipient duct or to the recipient small bowel via a Rouxen-Y limb, which involves more dissection and could delay return of bowel function, although not usually signlficantly.'
NUTRITION ASSESSMENT Nutrition plays a vital role in the management of patients with chronic liver disease and transplantation. Nutrition therapy begins with a comprehensive assessment. Traditional nutrition assessment parameters are difficult to interpret in patients with chronic liver disease. For example, weight loss can be masked by fluid retention and levels of hepatic transport proteins such as albumin are diminished owing to reduced synthesis by the liver.
531
Dual-energy X-ray absorptiometry is considered the gold standard for determining fat and fat-free mass in transplant patients but is not available for daily clinical practice. Measuring fat-free mass with single-frequency bioelectrical impedance is valid only in transplant recipients without obvious ascites or edema." Therefore, assessment of a transplant candidate is best achieved using a combination of objective and subjective data. Table 47-1 summarizes comprehensive nutrition assessment guidelines.
NUTRITIONAL STATUS
Malnutrition Cirrhosis represents the end stage of chronic liver disease and is often associated with malnutrition." Malnutrition may be related to causes that limit oral intake or complications of liver disease, such as gastrointestinal bleeding, sepsis, ascites, and encephalopathy. Other causes may relate to impairment in digestion and absorption or interference with nutrient metabolism." Metabolic derangements in cirrhosis seem to mimic a state of catabolism, which has been compared with that of sepsis or trauma. Urinary nitrogen losses are increased, and the altered metabolism does not respond normally to feeding. Malnutrition is prevalent in patients awaiting transplantation and may actually accelerate liver deterioration.' Several studies demonstrated that a malnourished state adversely affects transplant outcomes (Table 47-2).9--16 The pattern of malnutrition varies based on type of liver disease and is summarized in Table 47-3.
Obesity As the prevalence of obesity in the United States climbs, so does the prevalence of obesity among individuals with chronic liver disease. Nonalcoholic fatty liver disease is a syndrome with symptoms ranging from steatosis to advanced fibrosis and cirrhosis that affects 10% to 25% of Arnericans.Fr'? Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease characterized by fatty liver, inflammation, necrosis, and fibrosis in the absence of significant alcohol ingestion." NASH affects only 3% of the lean population and nearly 50% of morbidly obese individuals." NASH is commonly associated with metabolic syndrome and its common features of obesity, diabetes mellitus, dyslipidemia, hypertension, and hyperinsulinemia with insulin resistance.il-" Musso and colleagues'? suggested that dietary habits influence NASH by affecting hepatic triglyceride accumulation, antioxidant activity, insulin sensitivity, and postprandial triglyceride metabolism. Current treatment focuses on dietary changes, weight loss, and use of insulinsensitizing drugs. 2o Obesity also was identified in one study to be an independent predictor for hepatocellular carcinoma in patients with alcoholic or cryptogenic
cirrhosis."
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47 • Chronic Liver Disease and Transplantation
Components of a Comprehensive Nutritional Assessment for an Adult Organ Transplant Recipient
Component
Purpose
Specific Elements
Physical assessment
Determine general nutrition condition including fat and muscle stores and fluid retention.
Initial overview: • Is the patient of appropriate weight for stature? • Does patient have noticeable ascites or fluid retention? • Is muscle wasting apparent? • Does the patient require oxygen, a wheelchair, or other asslstive device? • Is the patient jaundiced? • Is the patient alert? Detailed physical examination: • Evaluate degree and distribution of fat and/or muscle loss and fluid retention. • Examine skin for color, texture, ecchymoses, telangiectasias, etc. • Examine nail beds and hair for symptoms of nutrient deficiencies. • Assess the oral cavity for dental problems or signs of vitamin deficiencies. • Obtain medical history of the type, degree, duration, and treatment of organ failure and associated complications. • Evaluate the patient's physical function. • Obtain accurate dietary history to determine adequacy of current dIetary intake. • Note gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, early satiety, etc.) and other factors affecting appetite or Intake. • Evaluate medications for drug-nutrient Interactions. • Question patient thoroughly about use of nutrition supplements, vitamin or minerai supplements, and herbal preparations. • Assess psychosocial and economic conditions to determine patient's ability to comply with prescribed dietary regimen. • Fluid retention may have least measurements effect on upper arm measurements. • Anthropometric measurements have limitations in sensitivity and reliability but may be useful if monitored serially over time. • Reliability is improved if all serial measurements are made by a single observer. • Other functional measurements such as hand grip strength may be helpful as indirect measures 01 protein stores. • Serum protein concentrations are affected by many non-nutritional factors (e.g., fluid status, liver and kidney function, vitamin status). • Urinary tests (e.g., nitrogen balance, creatinine-height index) are also influenced by many non-nutritional factors (e.g., fluid status, liver and kidney function). • Immunocompetence tests (e.g., skin test antigens, total lymphocyte count) are influenced by Immunosuppressive drugs.
Assess the degree and distribution of deficiencies.
History
Determine cause, degree, and duration of nutrient deficiencies.
Anthropometric measurements
Provide objective measurements to evaluate and monitor progress.
Laboratory tests
Provide detailed information; must be used selectively to avoid tests using confounded by non-nutritional factors.
Reprinted from HasseJM: Nutrition assessment and support of organ transplant recipients. JPEN J Parenter Enteral Nutr2001;25:120-131.
Morbid obesity has been considered a relative contraindication for liver transplantation and most transplant selection committees consider severe obesity a risk factor to be considered in view of the patient's overall condition and candidacy. If a patient has severe truncal fat accumulation, transplantation can be technically difficult. In single-center studies evaluating graft function and patient survival after transplantation in obese
patients differences were not detected. 24-27 However, wound infection rates were increased in obese versus nonobese patients as was respiratory failure and increased hospital length of stay.24-27 In a recent study, using multicenter data from the United Network of Organ Sharing database, 1- and 2-year mortality rates were increased in morbidly obese patients as was the frequency of primary graft nonfunction." Severely and morbidly
SECTION VII • Transplant
533
_ _ Effects of Malnutrition on Liver Transplantation Researchers
Methods
Outcomes
Harrison et al''
n = 102
Survival 6 months after transplant was 87% in malnourished group compared with 100% in adequately nourished group. I-year survival was 88% in wellnourished patients and 62% in malnourished patients. 5-year survival was 88% in wellnourished patients and 54% in malnourished patients. Malnourished patients had mortality of 29% to 37% vs. 16% mortality in well-nourished patients. Severely and moderately malnourished patients had T ICUand hospital lengths of stay. There was a trend for T mortality in severely malnourished patients. 1- and 3-year survival rates were lower in severely malnourished vs. better nourished patients. i Handgrip strength and BCAA levels were associated with i ICUstay and infections. No nutritional parameter was associated with mortality. Malnourished patients required more blood products and had longer hospital length of stay compared with better-nourished patients. No significant relationship between nutrition and early morbidity due to insufficient data. Grip strength and midarm muscle area were depressed in patients in Child-Pugh classes Band C.
Malnutrition defined by anthropometries <25th percentile Selberg et al'"
n = 150 High nutrition risk defined as body cell mass <35W, body weight by bioelectrical impedence
Lautz et all'
n = 123 Malnutrition determined by multiple objective tests n = 68 Malnutrition determined by SGA
Pikul et aIl2
Hasse et all:!
n = 1224 Malnutrition determined by SGA
Figueiredo et aIl4
n = 53 Malnutrition determined by SGAand multiple objective tests
Stephenson et aJis
n = 109 Malnutrition determined by SGA
Abbott et al"
n = 80 Malnutrition determined by grip strength, triceps skinfold, and midarm muscle area
BCAA, branched chain amino acid; ICU, intensive care unit; SGA, subjective global assessment; T, increased.
obese patients also had reduced 5-yearsurvival rates due to cardiovascular events."
NUTRITION MANAGEMENT OF CHRONIC LIVER DISEASE Protein-ealorie malnutrition is common in patients with advanced liver disease. Central to the approach to these
-
Alcohol Viral Primary biliary cirrhosis Primary sclerosing cholangitis
Muscle Wasting
of Fat Stores
Nutrition Recommendations Protein and Amino Acid Alterations
Pattern of Malnutrition in Chronic Liver Disease" Loss
patients are the assumptions that accelerated starvation is present and there is a need to address protein imbalance, especially in patients with hepatic encephalopathy. Amino acid metabolism is the metabolic abnormality that has received a significant amount of attention and around which much of the concern for nutrition repletion is focused.
Reduced Synthetic Function
+++ ++ +++
+
++
++ +++
+ +
++
+
+
*+, mild abnormalities; ++, moderate abnormalities; +++, severe abnormalities. Reprinted from McCullough AI: Malnutrition in liver disease. Liver Transplant 2000;6(4suppl 1):S85-S96.
Hepatic encephalopathy is the presentation of a constellation of neuropsychiatric derangements that can range from mild mental status changes to coma. The pathogenesis of encephalopathy is controversial, but the most likely cause is thought to be the inability of the liver to metabolize neurotoxic chemicals, which accumulate in the brain and have some effect on neurotransmitters or the generation of false neurotransmitters in the brain. Events that commonly precipitate encephalopathy include gastrointestinal bleeding, infection, electrolyte imbalance, sedatives, and constipation. It is thought that in a minority of patients, hepatic encephalopathy may be precipitated by protein intake, but in the majority of patients with cirrhosis and even in the presence of
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47 • Chronic Liver Disease and Transplantation
encephalopathy, patients can tolerate mixed proteins. In addition, ammonia levels do not correlate well with the degree of mental impairment. Therefore, protein restriction is generally not indicated. It has been postulated that part of the amino acid imbalance in cirrhosis may be low levels of branched-ehain amino acids (BCAAs) and high levels of aromatic amino acids. Therefore, formulas enriched with BCAAs were developed to address this imbalance, yet no clear proof of the role of this has been published. For patients with compensated cirrhosis and without any complicating ascites or encephalopathy, protein restriction is not indicated and a diet containing approximately 30 to 40 kcal/kg/day and 1.2 to 1.5g of protein/kg/day is generally recommended." Protein requirements may be as high as 1.8 g/kg in malnourished patients.' One approach to protein requirements is to look at trends within a given patient's clinical course. An accurate diet history will help determine these. For example, if a patient with encephalopathy is consuming a highprotein diet up to 2 g of protein/kg/day, improvement may be noted by reducing the protein to 1.2 g of protein/ kg/day, which although not considered a low-protein diet for patients with cirrhosis, may help improve encephalopathy. If a dietary history reveals intake of only 0.5 g of protein/kg/day, this amount should probably not be restricted further, because of the possibility of nutritional depletion. Although there is no absolute correlation between ammonia levels and encephalopathy, if a patient is comatose due to encephalopathy, nutrition support may be delayed while the precipitating cause is determined. Lactulose will be given to titrate to at least two to three bowel movements daily. At the same time, an investigation is initiated to determine the cause of deterioration, which may be sepsis or other Iiverrelated complications. Protein is introduced and increased to 1 to 1.5 of g/kg/day depending on the patient's nutritional status. Patients with significant disabling encephalopathy who do not tolerate standard proteins or have not responded to lactulose or neomycin may be considered candidates for BCM-enriched tormulas." Another dietary factor implicated in encephalopathy is zinc deficiency. Patients with zinc deficiency may have reduced urea synthetic capacity. This is due to decreased hepatic ornithine transcarbamylase activity because zinc is a cofactor in hepatic ornithine transcarbamylase enzyme activity." Zinc deficiency also increases enzymes that increase ammonia production from aspartate. Finally, zinc deficiency may playa role in derangements in brain neurotransmitter metabolism."
Approximately two thirds of patients with cirrhosis have hyperglycemia. Hyperinsulinemia and insulin resistance in peripheral tissues may account for hyperglycemia in patients with cirrhosis." The number of insulin receptors and their binding affinity may be reduced. Insulin resistance could also be due to increased insulin production and reduced hepatic clearance or portosystemic shunting of insulin released from the liver." On the other hand, hypoglycemia may be seen with acute viral hepatitis or fulminant liver failure. Hypoglycemia may be due to diminished glycogen stores, reduced glycogenolytic response to glucagon, decreased gluconeogenesis, and impaired repletion of glycogen." In extreme hypoglycemia, a continuous dextrose infusion must be administered intravenously.
Lipid Alterations In chronic liver disease, hepatic secretion of lipoproteins is reduced as is clearance of chylomicron remnants." Fatty liver can present as macro- or microvesicular fatty deposits. Obesity, kwashiorkor, diabetes mellitus, corticosteroids, and alcohol can cause accumulation of large fat droplets in the liver. Accumulation of small fat droplets can occur with acute fatty liver of pregnancy, Reye syndrome, and valproic acid and tetracycline toxicity." NASH was discussed in an earlier section. Steatorrhea occurs most often in patients with cholestatic liver disease and causes malabsorption of fat and fat-soluble vitamins. These patients should undergo screening for fat-soluble vitamin deficiencies. Mediumchain triglyceride oil may be used to supplement calories. Medium-ehain triglyceride oil does not require bile salts and micelle formation; therefore, it can be absorbed via the portal route.
Vitamin and Mineral Requirements Vitamin supplements should be given when deficiencies are noted. A water-miscible form of fat-soluble vitamins may be required if patients have steatorrhea. Considerations for vitamin and mineral abnormalities are highlighted in Tables 47-4 and 47-5. Osteopenia causes significant morbidity among patients with liver disease, predominantly in those with cholestatic liver disease, such as primary biliary cirrhosis and sclerosing cholangitis, but it may also occur in patients with alcoholic liver disease, hemochromatosis, and corticosteroid-treated autoimmune hepatitis. Adequate calcium and vitamin D supplementation should be considered.
Glucose Alterations In patients with cirrhosis in the unfed state, fat will be burned preferentially for energy rather than glycogen. Therefore, food should not be withheld for long periods, and frequent small feedings and an evening snack are of benefit. In noncritically ill patients with chronic encephalopathy, a bedtime snack with either four or six meals a day may help achieve positive nitrogen balance.
Electrolyte and Fluid Requirements Dietary sodium restriction (",,2,000 mg/day) is a mainstay of treatment for ascites and edema. Fluid restriction (usually 1.0 to 1.5 Uday) is indicated if hyponatremia is present. Overall guidelines for the nutrition management of patients with liver disease are summarized in Table 47-6. 7
..
SECTION VII • Transplant
Potential Vitamin Deficiencies in Patients with Chronic Liver Disease
Vitamin
Potential Causes of Deficiencies
A
Steatorrhea, neomycin, cholestyramine, alcoholism, and inadequate retinol-binding protein production by the liver Alcoholism Alcoholism, cholestyramine Alcoholism Alcoholism Poor diet, steatorrhea, corticosteroids, cholestyramine, and inadequate 25-hydroxylation of cholecalciferol and ergocalciferol in the cirrhotic liver Steatorrhea, antibiotics, cholestyramine Steatorrhea, antibiotics, cholestyramine Alcoholism, antibiotics
B6 BI ,
Niacin Thiamin D
E K
Folate
Adapted from Hasse JM, Blue L'i, Watkins LA: Solid organ transplantation. In Gottschlich MM, Matarese LE, Shronts EP (eds): NutritionSupport Dietetics Core Curriculum, 2nd ed, pp 409-422. SilverSpring, MD, American Society for Parenteral and Enteral Nutrition, 1993.
Enteral Nutrition When oral supplementation is unsuccessful, supplemental tube feedings have been shown to be of benefit.32,33 There are mechanical issues with respect to enteral feeding in this population. Early satiety and gastric dysfunction coupled with esophageal varices may make ' . . •
Potential Mineral and Electrolyte Abnormalities in Patients with Chronic Liver Disease
Mineral/Electrolyte
Potential Abnonnalities and Causes
Calcium
Glucocorticoids increase urinary excretion. Gastrointestinal loss is seen with steatorrhea. Decreased excretion is associated with biliary obstruction or Wilson disease. Chronic bleeding can cause deficiency. Hemochromatosis causes excess iron stores. Diuretics and alcoholism can cause deficiency. Anabolism, alcoholism, and glucocorticoids can cause deficiency. Potassium-wasting diuretics, anabolism, and insulin use can cause hypokalemia. Potassium-sparing diuretics can cause hyperkalemia. Depending on fluid status and blood pressure, sodium restriction may be necessary. Diarrhea, diuretics, alcoholism can cause deficiency.
Copper Iron Magnesium Phosphorus Potassium
Sodium Zinc
Adapted from Hasse JM: Solid organ transplantation. In Matarese LE, Gottschlich MM (eds): Contemporary Nutrition Support Practice: A Clinical Guide, 2nd ed, pp 560-573. Philadelphia, WB Saunders, 2003.
535
nasoenteral tube placement precarious. If, after upper endoscopic examinations, significant varices are found, if sclerotherapy has been used, or if the patient has a history of concomitant ulcer disease, there can be reluctance to placing a feeding tube. The gastrointestinal service should be consulted to be sure of the safety of tube placement. Ascites may be significant and have secondary effects on bowel function and should be addressed with a combination of diuretic therapy and paracentesis when necessary. Placement of long-term feeding tubes such as gastrostomy or jejunostomy tubes is problematic, because these patients are poor operative candidates and complications of even minor procedures are significant, especially with regard to wound healing and worsening overall disease course. In addition, placement of these tubes are contraindicated if a patient has ascites.
Enteral Nutrition Formula Selection Standard intact protein formulas are usually adequate for patients with end-stage liver disease. A concentrated formula may be helpful if hyponatremia is a problem. Patients with hyperkalemia and hyperphosphatemia (possibly due to hepatorenal syndrome) may benefit from renal formulas. BCAA formulas may be indicated when patients continue to have recurrent hepatic encephalopathy with standard formulas.
NUTRITION MANAGEMENT OF LIVER TRANSPLANTATION Factors Affecting Post-Transplant Nutrient Requirements In patients who have undergone liver transplantation, complex factors interact to alter nutrient requirements and influence decisions about the nutrition support route. Pretransplant nutritional status and medical condition, transplant graft function, the function of other organs, the presence of infection or other post-transplant complications, and medication regimen affect not only metabolic requirements, but also digestion and metabolism of nutrients (Table 44-7). In addition, immunosuppressive medications, although an indispensable part of transplantation, create many undesirable side effects. Table 44-8 provides details about these medications, including their actions, side effects, and nutritional implications.
Nutrition Recommendations All of the factors discussed earlier should be considered when an individual patient's nutrient needs are determined. Although general nutritional recommendations can be given, measuring each individual's requirements if possible is best when accuracy is necessary.
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47 • Chronic Liver Disease and Transplantation
_ _ Overall Guidelines for the Nutritional Management of Patients with Liver Disease 1. Assume protein-calorie malnutrition is present in all patients. 2. Assume an inadequate dietary intake, even In hospitalized patients. 3. Qualitative stool fat should be performed intermittently, especially in patients with alcoholic or cholestatic cirrhosis. If malabsorption is present, determine the cause and treat. 4. Treatment with either neomycin or lactulose for hepatic encephalopathy may exacerbate malabsorption and should be considered in nutritional management. 5. Treat ascites aggressively to decrease energy expenditure. 6. Diuretic therapy is preferred over large-volume paracentesis for the management of ascites to minimize protein loss. 7. Balance the need for sodium restriction with nutritional considerations and diet palatability. 8. Nutrition assessment is useful in all types of patients with cirrhosis. a. A composite score (emphasizing anthropometry and creatinine-height index) combined with overall clinical judgment should be used. b. The clinician should remember that all methods for nutrition assessment in cirrhosis are influenced or potentially influenced by the presence of liver disease alone as well as abnormalities associated with liver disease, such as renal failure, alcohol ingestion, and expansion of the extracellular water compartment. 9. Determine energy expenditure requirements with indirect calorimetry (if possible) in hospitalized patients or patients on the list for liver transplantation. If energy expenditure requirements are estimated from prediction equations, energy need is calculated based on ideal weight rather than on actual weight if extracellular water (ascites/edema) is present. 10. Multiple (5 to 6) small feedings with a carbohydrate-rich evening snack, which consists of approximately 10% to 15% of caloric needs, should be given. The need for breakfast feeding must also be stressed to the patient. 11. For calories, complex rather than simple carbohydrates should be used. Lipids should supply 20% to 40% of caloric needs. 12. Nutritional requirements may vary according to the specific type of patients and/or clinical situation. a. Severely malnourished or decompensated patients with cirrhosis should be administered oral or enteral supplements. b. Long-term nutritional supplements may be necessary to provide recommended protein and caloric supplements. c. Patients with severe alcoholic hepatitis should be given supplemental standard protein, 1.0 g/kg, through an enteral or peripheral parenteral route. d. Perioperative nutritional therapy should be administered to patients with cirrhosis with significant malnutrition, as defined by weight loss of more than 10% or for anthropometry or creatinine-height index less than 5% of predicted values. e. After liver transplantation, patients need higher amounts of protein and energy. Pediatric patients undergoing liver transplantation may benefit from branched-chain amino acids. 13. Patients with cirrhosis should never be treated prophylactically with protein restriction to prevent hepatic encephalopathy. a. Standard protein or amino acid mixtures should be supplied to meet the measured estimated nitrogen needs. b. Protein restriction should be implemented only if protein intolerance manifested by encephalopathy occurs In the absence of precipitating factors. c. Protein restriction less than the required amounts should not be continued for more than 3 to 4 days. d. Branched-chain amino acids should be administered only if the required amount of standard feedings cannot be tolerated without precipitating hepatic encephalopathy. 14. Monitor for hypoglycemia and treat aggressively with concentrated glucose solutions, which may also decrease serum ammonia levels. 15. Enteral feeding is the preferred route of feeding for patients with Insufficient oral intake. Enteral feeding tubes may be used even if nonbleeding varices are present. Reprinted from Mccullough AI: Malnutrition in liverdisease. Liver Transplant 2000;6(4, suppl 1):585-596.
Calories Generally, consumption of 30 to 35 kcal/kg (1.3 x basal energy expenditure) is recommended for immediate postoperative or critically ill transplant recipients. These estimates are based on studies that measured resting energy expenditure from 2 to 28 days after transplantationP':" When patients have complicated medical conditions, measuring calorie needs with indirect calorimetry is invaluable. If malabsorption is present (such as external biliarydrainage causing fat malabsorption), caloric intake should be increased to account for losses. The nutrition practitioner must also consider nutrition goals when making caloric recommendations. For example, the higher end of the suggested range is appropriate if a patient needs to gain weight. Likewise, for weight maintenance or loss, the lower end of the range is recommended.
Carbohydrate Hyperglycemia occurs almost universally in the immediate postoperative phase due to effects of
immunosuppressive medications, metabolic response to injury, and neurohormonal and cytokine-mediated stimuli." Patients undergoing liver transplantation for cirrhosis due to hepatitis C have an increased rate of post-transplant diabetes mellitus compared with patients with other diagnoses." Most patients require treatment with short-acting insulin prescribed according to a sliding scale. Depending on the time period and criteria to define diabetes mellitus, 5% to 68% of patients develop this condition after transplantation.Pr" The incidence of diabetes declines over time after transplantation. The cause of postreperfusion hyperglycemia is glycogenolysis in the new graft." When immunosuppressive agents are administered, corticosteroids cause insulin resistance and may also reduce insulin receptors and affinity, impair muscle uptake of glucose, impair suppression of endogenous insulin production, or activate free fatty acids and glucose." Insulin secretion may be suppressed by cyclosporine and tacrolirnus.P In addition, calcineurin inhibitors can increase insulin resistance.v It is important to note that transplant centers
SECTION VII • Transplant
•
Conditions after Liver Transplantation That Influence Nutrient Requirements and Nutrition Support Route
Condition
Considerations
Pretransplant malnutrition
Malnourished patients are more likely to be deconditioned and at increased risk of infection than well-nourished patients. A patient's ability to eat adequately after transplantation partially reflects pretransplant oral intake. If patient is critically ill before transplant. he or she is less likely to eat well after transplant than a medically stable patient living at home before transplantation. Suboptimal graft function (or need for retransplant) can alter nutrient requirements and dictate need for nutrition support. Organ dysfunction may alter nutrient requirements or delivery. For example, renal failure may necessitate restriction of fluid. phosphorus, or potassium; renal replacement therapy may alter requirements further. Respiratory failure requiring mechanical ventilation necessitates initiation of nutrition support. Sepsis alters metabolic rate and nitrogen excretion. Any post-transplant complication has the potential to affect oral intake or nutrient requirements. For example. reoperations or GI bleeding may require a period of NPO status. A postoperative ileus may require initiation of parenteral nutrition. Wound infection or dehiscence requires aggressive nutrition therapy to ensure healing.
Pretransplant medical condition Transplant graft function Dysfunction of other organs
Infection or other posttransplant complications
GI, gastrointestinal; NPO, nothing by mouth.
are conducting trials of different combinations of immunosuppressive medications and lowering doses of or eliminating the use of calcineurin inhibitors or corticosteroids. The reduction or absence of either is expected to reduce the incidence of hyperglycemia.
Lipid Lipid is a preferred fuel substrate immediately after liver transplantation and shifts to glucose after approximately 6 hours.48,49 Typically, nutrition support regimens will provide approximately 30% of nonprotein calories as lipid. The preferred type of lipid fuel for transplant patients has not been determined. Theoretically, n-3 fatty acids would decrease synthesis of proinflammatory eicosanoids." Supplementation of n-3 fattyacids (as fish oil) in kidney transplant recipients reduced blood pressure, serum triglyceride levels. and platelet aggregation.5O-52 In addition. renal graft function improved and the nephrotoxic effects of cyclosporine were reduced with fish oil. Alexander'" reported reduced systolic blood pressure and rejection episodes (in cyclosporine-treated
537
patients) when kidney transplant recipients ingested 30 g of canola oil and 9 g of arginine daily.53 These trials and results have not been reproduced in liver transplant recipients. However, at least one study found that fish oil (12 g/day) improved renal hemodynamics compared with com oil in liver transplant recipients receiving maintenance doses of cyclosporine.f Again, one cannot assume that results will be uniform with other types of transplants or immunosuppressive drug regimens.
Protein Generally postoperative recommendations for protein are 1.5 to 2.0 g/kg. This recommendation is based on urine urea nitrogen excretion results from five studies in liver transplant recipients 2 to 28 days after transplantation.34-37,55 Urine urea nitrogen excretion ranged from 3 to 25 g/day, highlighting the variability of protein needs based on nutritional status, time after transplant, posttransplant condition, and effect of corticosteroids. Again, the corticosteroid dose will determine the degree of catabolism. In low- or no-steroid regimens, protein requirements are expected to be lower compared with those in conditions (such as rejection) when corticosteroids are given at increased amounts. In a recent study, altered amino acid profiles associated with end-stage liver disease were partially corrected with transplantation. Tietge and associates'" evaluated plasma amino acid levels in patients with cirrhosis and in those who underwent liver transplantation. Aromatic amino acid and methionine levels were elevated in patients with cirrhosis and normalized after liver transplantation. BCM levels remained depressed for more than 6 months after liver transplantation. There was a correlation between increased BCM levels and increased levels of circulating catecholamines (epinephrine, norepinephrine, and dopamine) and insulin. The authors speculated that adrenergic tone elevations and hypersecretion of insulin in the post-transplant period may result in persistent BCM metabolism in muscle"
Vitamins There are few studies evaluating micronutrient needs after transplantation. Ukleja and co-workers" found reduced levels of serum retinol and hepatic vitamin A levels in patients with cirrhosis who underwent transplantation. However, serum and hepatic levels did not correlate. On the other hand, serum levels of vitamin E correlate with hepatic vitamin E levels in patients with cirrhosis, suggesting that a serum vitamin E level is an appropriate marker for supplementatlon." General guidelines suggest supplementation of vitamins to meet Dietary Reference Intake (DRI) levels. Additional supplementation in the immediate posttransplant period could be given based on general assumptions. For example, vitamins A, B6• B12. niacin, thiamine, and folate may be deficient in patients with alcoholic liver disease." Likewise, fat-soluble vitamins can be low in patients with cholestatic liver disease.
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47 • Chronic Liver Disease and Transplantation
_ _ Immunosuppressant Drugs, Nutritional Side Effects, and Interventions Drugs
Activity
Nutritional Side Effects
Suggested Nutrition Therapy
Anti-lymphocyte serum (ATGAM, Thymoglobulin)
Binds with lymphocytes, resulting in phagocytosis Inhibits and destroys lymphocytes Inhibits purine nucleotide synthesis, blocking T- and B-Iymphocyte proliferation
Fever and chills
Provide nutrient-dense foods patient will eat. Ensure patient is receiving adequate protein. Try antiemetic medications; if vomiting does not subside, consider tube feeding or PN. Review drugs and substitute for those that may be causing diarrhea; make sure that patient is receiving adequate fluid to replace losses. Provide foods that will not irritate the throat. Offer a variety of foods with different tastes. Make sure folate intake is adequate. Initiate nutrition support if pancreatitis is severe.
Azathioprine (lmuran)
Increased risk of infection, profound leukopenia Nausea, vomiting
Diarrhea
Sore throat/mucositis Altered taste acuity Macrocytic anemia Pancreatitis Basiliximab (Simulect)
Corticosteroids (methylprednisolone, prednisone, prednisolone, Solu-Medrol, Solu-Cortef)
Acts against the interleukln-2R-a chain (CD25) on activated T-Iymphocytes, and inhibits interleukin-2mediated activation of lymphocytes Anti-inflammatory properties Inhibits cell-mediated-and, to a lesser degree, humoral-immunity Inhibits lymphocyte proliferation Inhibits Iymphokine production
None reported
Hyperglycemia
Sodium retention Ulcers Osteoporosis
Hyperphagia Impaired wound healing and increased infection risk Hypertension Pancreatitis Cyclosporine (Neoral, Sandimmune)
Inhibits cell-mediated immunity; inhibits T-cell proliferation Suppresses interleukin-2 production Prevents )'-interferon release
Hyperkalemia Hypomagnesemia Hypertension Hyperglycemia
Hyperlipidemia
Dacliximab (Zenapax)
Inhibits interleukin-2-dependent human T-Iymphocyte activation
Monitor blood sugar and the need for long-term diabetes diet and hypoglycemic agents. Avoid high-sodium foods. Avoid foods that irritate stomach. Ensure adequate calcium and vitamin D intake; consider need for calcitriol, fluoride, or estrogen. Behavior modification to prevent overeating. Ensure adequate protein intake; consider need for vitamins A, C, or zinc. Avoid high-sodium foods; maintain healthy weight. Initiate nutrition support if pancreatitis is severe. Restrict high-potassium foods. Supplement with highmagnesium foods or supplements. Avoid high-sodium foods; maintain healthy weight. Monitor blood glucose level and need for long-term diabetes diet and hypoglycemic agents. Limit fat intake to <30% calories during long-term phase; maintain healthy weight.
None reported
Continued
SECTION VII • Transplant
IIImIfII
539
Immunosuppressant Drugs, Nutritional Side Effects, and Interventlons-eont'd
Drugs
Activity
Nutritional Side Effects
Suggested Nutrition Therapy
Muromonab-CD3 (OKT3)
Blocks T3 antigen recognition and T-cell effector function Causes T cell lysis
Nausea, vomiting
Try antiemetic medications; if vomiting does not subside, consider tube feeding or PN. Review drugs and substitute for those that may be causing diarrhea; make sure that patient is receiving adequate fluid to replace losses. Offer frequent meals of nutrient-dense foods. Limit fat intake to <30% calories during long-term phase; maintain healthy weight. Monitor for adequate nutrient intake.
Diarrhea
Anorexia Sirolimus (rapamycin, Rapamune)
Tacrolimus (prograf, FK5(6)
Blocks the response of T- and B-cell activation by cytokines, which prevents cell-cycle progression and proliferation
Suppresses T cellmediated immunity and interleukin-2 production
Hyperlipidemia
Gastrointestinal disorders (constipation, diarrhea, nausea/ vomiting, dyspepsia) Nausea, vomiting
Hyperkalemia Hyperglycemia
Abdominal distress
Mycophenolate rnoletll (CellCept)
Inhibits DNA synthesis and mixed lymphocyte production Inhibits antibody formation
Diarrhea
Try antiemetic medications; if vomiting does not subside, consider tube feeding or PN. Avoid high-potassium foods. Monitor blood glucose level and need for long-term diabetes diet and hypoglycemic agents. Monitor oral intake; consider alternate methods of nutrition support if intake is suboptimal. Review drugs and substitute for those that may be causing diarrhea; make sure that patient is receiving adequate fluid to replace losses.
ATGAM, anlithymocyte )"globulin; EN, enteral nutrition; PN, parenteral nutrition. Reprinted from Hasse JM: Solid organ transplantation. In Matarese LE, Gottschlich MM (eds): Contemporary Nutrition Support Practice: A Clinical Guide, 2nd ed, pp 560-573. Philadelphia, WB Saunders, 2003.
Vitamin D levels may be low owing to the inability of a diseased liver to activate vitamin D.
Minerals As with vitamins, minerals should be supplemented to levels that meet the DRI guidelines. Specific considerations are outlined in Table 47-9.
Hyponatremia is usually associated with impaired ability of the kidneys to excrete free water": therefore, treatment usually includes fluid restriction. Potassium requirements depend on renal function and kidney losses. Hypokalemia can be caused by potassium-wasting diuretics, corticosteroids, gastrointestinal losses, and magnesium deficiency." Hyperkalemia can occur with renal insufficiency or use of potassium-sparing diuretics or blood products."
Fluid and Electrolytes Fluid and electrolyte requirements vary depending on medical condition and medications. For example, fluid requirements are increased with high urine output, dehydration, diarrhea, and excessive drain losses. Fluid should be restricted when patients are volume overloaded and have pulmonary edema, anasarca, or oliguria.
Enteral Nutrition Indications and Benefits Figure 47-1 presents a decision tree for provision of nutrition support to organ transplant recipients.
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47 • Chronic Liver Disease and Transplantation • ..
•
•
Postoperative Mineral Supplementation Considerations for Liver Transplant Recipients
Nutrient
Consideration
Iron
Do not supplement if patient had hemochromatosis or hemosiderosis. Supplementation may help In presence of blood loss or anemia. Do not supplement if patient had Wilson disease. Withhold copper supplementation in presence of long-term biliary obstruction. Withhold manganese supplementation in presence of long-term biliary obstruction. Supplement if low. Restrict if elevated (such as renal insufficiency). May need phosphate binders if patient develops renal failure and hyperphosphatemia. Supplement if low; calclneurin Inhibitors cause magnesium wasting, and some patients need chronic supplementation. Withhold if levels are high (e.g., renal failure). Post-transplant hypocalcemia can be due to use of citrated blood products; ionized calcium levels will remain low until citrate metabolism in the liver returns. Chronically, calcium supplementation may be needed for optimal bone health. Occasionally, hypercalcemia develops In acutely ill patients and low-calcium formulas may be preferred.
Copper
Manganese Phosphorus
Magnesium
Calcium
Provision of enteral nutrition (EN) to patients after transplantation can be preemptive or reactive. Benefits of preemptive EN (whereby all patients receive postoperative EN) include possible reduction in stress response, early achievement of adequate nutrition, decreased nitrogen deficit, and reduced infection rates." Because the surgical team has access to the stomach and duodenum during the procedure, it is possible to negotiate feeding tube placement by anesthesia via the nose down to the stomach into a postpyloric position and possibly past the ligament of Treitz unless there is some predisposing prior surgical reason why this cannot be done. This gives the advantage of early posttransplant feeding. In several studies tolerance and nutrient adequacy with immediate post-transplant EN have been reported. 37•6Q-63 More technical complications (tube obstruction, infection, and small bowel obstruction) were reported when EN was given via jejunostomy tubes" versus nasoenteral tubes. 37,62 Wicks and colleagues" demonstrated equal results with enteral and parenteral nutrition. Hasse and associates" demonstrated superior results (reduced nitrogen loss and viral infection rates) when EN was compared with intravenous fluid. Rayes and co-workers" further showed that the combination of enteral formula and probiotics influenced post-transplant outcome. In their study, enteral nutrition with a fiber-eontaining formula plus a
probiotic (Lactobacillus plantarum 299) reduced infection rates compared with a fiber-eontaining formula without a probiotic or standard EN when given for 12 days postoperatively.P One may never assume that similar results will be achieved if the duration of EN or immunosuppression or antimicrobial regimens are different than those reported. More trials are needed to confirm benefits under alternate situations. If EN is initiated at any time after transplantation, a nasoenteral tube is best for short-term therapy. After surgery or if a patient has delayed gastric emptying or a high risk of aspiration, a tube placed past the ligament of Treitz is preferred over a nasogastric tube. Gastrostomy or jejunostomy tubes are more suited for long-term EN therapy when ascites or open abdominal wounds are not present.
Enteral Nutrition Formula Selection Apart from the study by Rayes and co-workers." researchers have not compared different EN formulas in liver transplant recipients. The effects of immuneenhancing diets are unknown-would immune function be stimulated enough to precipitate rejection or would it help deter infection? Until studied in a prospective, randomized, controlled study, recommendations for immune-enhancing diets cannot be made. Other general guidelines for EN formula selection are outlined in Table 47-10. Standard advancement and precaution protocols should be adequate for EN protocols for transplant recipients. However, each transplant center may want to evaluate allowable hang times for open-system EN devices because of the severe ramifications of EN contamination in immunocompromised patients.
Monitoring Enteral Nutrition in Liver Transplant Recipients When a liver transplant recipient is receiving EN, medical condition, nutrient intake, nutritional status, and EN tolerance should be monitored routinely. As discussed earlier, medical condition alters nutrient needs and choice of the nutrition support route. Nutrient intake should be monitored via intake and output records, as well as calorie counts when patients are eating. Evaluating other sources, such as medications and intravenous fluids, for hydration and nutrients (dextrose and lipid) is also important. As discussed in an earlier section, nutritional status is difficult to ascertain using objective parameters. Monitoring for changes is also difficult because many objective parameters are invalid, unreliable, or insensitive for detecting changes because of variable organ function and fluid changes. Signs of wound healing, ambulation, and overall recovery may be the most important clinical aspects to monitor. As with any patient receiving EN, tolerance must be monitored by evaluating the site to ensure that
SECTION VII • Transplant
541
FIGURE 47-1. Nutrition support algorithm for organ transplant recipients. TPN, total parenteral nutrition. (Reprinted from Hasse JM, Roberts S: Transplantation. In Rombeau JL, Rolandelli RH (eds): Parenteral Nutrition, 3rd ed, pp 529-561. Philadelphia, WB Saunders, 2001.)
the tube has not migrated and no local irritation is present; watching for signs of gastrointestinal intolerance such as nausea, vomiting, abdominal distension, constipation, or diarrhea; and monitoring for signs of aspiration and reducing the risk by keeping the head of the bed
elevated and placing a tube post-pylorically if aspiration is a significant risk or if delayed gastric emptying is found. Laboratory tests and vital signsare monitored often for signs of infection and rejection. Likewise, alterations in electrolyte status should be noted and treated.
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47 • Chronic Liver Disease and Transplantation
•
Considerations for 58lectlon of Enteral Nutrition Formulas for Liver Transplant Recipients
Condition
Fonnula Consideration
Normal postoperative course Fluid overload
Use polymeric, high-nitrogen formula
Renal insufficiency
Diarrhea or constipation Pancreatitis Maldigestlon
May benefit from a concentrated formula May benefit from formula restricted In fluid and/or phosphorus and potassium May benefit from fiber-enriched formula; provide sufficient fluid May benefit from low-fat formula May benefit from partially hydrolyzed formula
Adapted from Hasse JM: Adult liver transplantation. In Hasse JM, Blue LS (eds): Comprehensive Guide to Transplant Nutrition, pp 58-59. Chicago, American Dietetic Association, 2002.
CONCLUSIONS Patients with chronic liver disease and those who undergo liver transplantation have complex nutritional problems. Because malnutrition is common in this patient group, EN may often be used. Nutrient requirements must be individualized and altered according to patients' conditions and treatments. REFERENCES 1. Marino IR, Doyle HR, Starzl TE: Orthotopic liver transplantation. In Hess W, Berci G (eds): Textbook of Bilio-Pancreatic Diseases, vol III, pp 1779-1807. Padua, Italy, Piccin, 1997. 2. Wiesner RH, McDiarmid SV, Kamath PS, et al: MELD and PELD: Application of survival models to liver allocation. Liver Transplant 2001;7:567-580. 3. U.s. transplantation data. Available at http://unos.org. 4. Sudan DL: Current status of partial liver transplantation in adults from cadaveric and living donors. In Maddrey WC, Schiff ER, Sorrell MF (eds): Transplantation of the Liver, 3rd ed, pp 65--78. Philadelphia, Lippincott Williams & Wilkins, 2001. 5. Kato T, Levi D, Nery J, et al: Operative procedures. In Maddrey WC, Schiff ER, Sorrell MF (eds): Transplantation of the Liver, 3rd ed, pp 47-64. Philadelphia, Lippincott Williams & Wilkins. 2001. 6. Kyle UG, Genton L,Mentha G,et al: Reliable bioelectrical impedance analysis estimate of fat-free mass in liver, lung, and heart transplant patients. JPENJ Parenter Enteral Nutr 2001;25:45--51. 7. McCullough AJ: Malnutrition in liver disease. Liver Transplant 2000;6(4 SuppI1):S85--S96. 8. Teran JC, McCullough AJ: Nutrition in liver diseases. Sci Pract Nutr Support 2001;26:537-552. 9. Harrison J, McKiernan J, Neuberger JM: A prospective study on the effect of recipient nutritional status on outcome in liver transplantation. Transplant IntI997;10:369-374. 10. Selberg 0, Bottcher J, Tusch G, et al: Identification of high- and low-risk patients before liver transplantation: A prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology 1997;25:652-657. 11. Lautz HU, Selberg 0, Korber J, et al: Protein-calorie malnutrition in liver cirrhosis. Clin Invest 1992;70:478-486. 12. Pikul J, Sharpe MD, Lowndes R, et al: Degree of preoperative malnutrition is predictive of postoperative morbidity and mortality in liver transplant recipients. Transplantation 1994;57:469-472. 13. Hasse JM, Gonwa TA, Jennings LW, et al: Malnutrition affects liver transplant outcomes [abstract]. Transplantation 1998;66:S53.
14. Figueiredo F, Dickson ER, Pasha T, et al: Impact of nutritional status on outcomes after liver transplantation. Transplantation 2000;70: 1347-1352. 15. Stephenson GR, Moretti EW, El-Moalem H, et al: Malnutrition in liver transplant patients. Transplantation 2001;72:666-670. 16. Abbott WJ, Thomson A, Steadman C, et al: Child-Pugh class, nutritional indicators, and early liver transplant outcomes. HepatoGastroenterology 2001;48:823-827. 17. Falck-Ytter Y, Younossi ZM, Marchesini G, et al: Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001;21:17-26. 18. Clark JM, Brancati FL, Diehl AM: Nonalcoholic fatty liver disease. Gastroenterology 2002;122:1649-1657. 19. Angulo P: Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221-1231. 20. Musso G, Gambino R, De Michieli F, et al: Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003;37:909-916. 21. Marchesini G, Bugianesi E, Forlani G, et al: Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37: 917-923. 22. Pagano G, Pacini G, Musso G, et al: Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: Further evidence for an etiologic association. Hepatology 2002;35:367-372. 23. Nair S, Mason A, Eason J, et al: Is obesity and independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 2002; 36:150-155. 24. Testa G, Hasse JM, Jennings LW, et al: Morbid obesity is not an independent risk factor for liver transplantation [abstract]. Transplantation 1998;66:S53. 25. Braunfeld MYV, Chan S, Pregler J, et al: Liver transplantation in the morbidly obese. J Clin Anesth 1996;8:585--590. 26. Sawyer RG, Pelletier SJ, Pruett TL: Increased early morbidity and mortality with acceptable long-term function in severely obese patients undergoing liver transplantation. Clin Transplant 1999; 13(1 Pt 2):126-130. 27. Nair S, Cohen DB,Cohen C, et al: Postoperative morbidity, mortality, costs, and long-term survival in severely obese patients undergoing orthotopic liver transplantation. Am J Gastroenterol 2001;96: 842-845. 28. Nair S, Verma S, Thuluvath PJ: Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105-109. 29. Hasse JM, Weseman B, Fuhrman MP, et al: Nutrition therapy for end-stage liver disease: A practical approach. Support Line 1997;19(4):8-15. 30. Mullen KD, Weber FL: Role of nutrition in hepatic encephalopathy. Semin Liver Dis 1991;11:292-304. 31. Weisiger RA: Hepatic metabolism in liver disease. In Goldman L, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed, pp 768-770. Philadelphia, WB Saunders, 2000. 32. Keams PJ, Young H, Carcia G, et al: Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102:200-205. 33. Cabre E, Gonzalez-Huix G, Abad-Lacruz A, et al: Effect 01 total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. A randomized controlled trial. Gastroenterology 1990;98:715--720. 34. Delafosse B, Faure JL, Bouffard Y, et al: Liver transplantationEnergy expenditure, nitrogen loss, and substrate oxidation rate in the first two postoperative days. Transplant Proc 1989:21:2453-2454. 35. Shanbhogue RLK, Bistrian BR, Jenkins RL, et al: Increased protein catabolism without hypermetabolism after human orthotopic liver transplantation. Surgery 1987;101:146-149. 36. Plevak DJ, DiCecco SR, Wiesner RH, et al: Nutritional support for liver transplantation: Identifying caloric and protein requirements. Mayo Clin Proc 1994;69:225--230. 37. Hasse JM, Blue LS, Liepa GU, et al: Early enteral nutrition support in patients undergoing liver transplantation. JPEN J Parenter Enteral Nutr 1995;19:437-443. 38. Driscoll DF, Palombo JD, Bistrian BR: Nutritional and metabolic considerations of the adult liver transplant candidate and organ donor. Nutrition 1995;11:255--263.
SECTION VII • Transplant 39. Baid S,Cosimi AB, Larrell ML, et al: Posllransplant diabetes mellitus in liver transplant recipients: Risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation 2001 ;72:1066-1072. 40. AssanR, Large E,Samuel F, et al: Prevalence of diabetes mellitus in liver transplant patients [abstract]. J Hepatol 1993;18:570. 41. Wahlstrom J, Cooper G, Gores C, et al: Survival after liver transplantation in diabetics. Transplant Proc 1991;23:1565-1566. 42. Jindal RM,Sidner RA, Hughes D, et al: Metabolic problems in recipients of liver transplants. Clin Transplant 1996;10:213-217. 43. Jindal RM: Posttransplant diabetes mellitus-A review. Transplantation 1994;58: 1289-1298. 44. Navasa M, Bustamante J, Marroni C, et al: Diabetes mellitus after liver transplantation: Prevalence and predictive factors. J Hepatol 1996;25:64-71. 45. Tabasco-Minguillan J, Mieles L, Carroll P, et al: Insulin requirements after liver transplantation and FK-506 immunosuppression. Transplantation 1993;56:862-867. 46. Winkler M, Brinkmann C, Jost U, et al: Long-term side effects of cyclosporine-based immunosuppression in patients after liver transplantation. Transplant Proc 1994;26:2679-2682. 47. Merritt WT: Metabolism and liver transplantation: Review of perioperative issues. Liver Transplant 2000;6(4 Suppl 1):S76-584. 48. Osaki N, Ringe B, Gubernatis G, et al: Changesin energy substrates in relation to arterial ketone body ratio after human orthotopic liver transplantation. Surgery 1993; 113:403-409. 49. Takada Y, Ozawa K, Yamaoka Y, et al: Arterial ketone body ratio and glucose administration as an energy substrate in relation to changes in ketone body concentration after live-related liver transplantation in children. Transplantation 1993;55:1314-1319. 50. Homan van der Heide JJ, Bilo HJG, Donker AJM, et al: Dietary supplementation with fish oil modifies renal reserve filtration capacity in postoperative, cyclosporin A-treated renal transplant recipients. Transplantlnt 1990;3: 171-175. 51. Homan van der Heide JJ, Bilo HJG, Donker AJM, et al: The effects of dietary supplementation with fish oil on renal function and the course of early postoperative rejection episodes in
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cyclosporine-treated renal transplant recipients. Transplantation 1992;54:257-263. 52. Sweny P, Wheeler DC, Lui SF, et al: Dietary fish oil supplements preserve renal function in renal transplant recipients with chronic vascular rejection. Nephrol Dial Transplant 1989;4: 1070-1075. 53. Alexander JW: Pharrnaconutrients in transplantation. Presented at A.S.P.E.N. Research Workshop Nutrition Support in Transplantation, Nashville, TN, January 23, 2000. 54. Badalamenti S, Salerno F, Lorenzano E, et al: Renal effects of dietary supplementation with fish oil in cyclosporine-treated liver transplant recipients. Hepatology 1995:22:1695-1671. 55. O'Keefe SJ, Williams R, Caine RY: "Catabolic" loss of body protein after human liver transplantation. BMJ 1980;280: 1107-1108. 56. Tietge UJF, Bahr JM, Manns MP, et al: Plasma amino acids in cirrhosis and after liver transplantation: Influence of liver function, hepatic hemodynamics and circulating hormones. Clin Transplant 2002;16:9-17. 57. Ukleja A, Scolapio JS,McConnell JP,et al: Nutritional assessment of serum and hepatic vitamin A levels in patients with cirrhosis. JPEN J Parenter Enteral Nutr 2002;26:184-188. 58. Ukleja A, Scolapio JS, McConnell JP, et al: Serum and hepatic vitamin E assessment in cirrhotics before transplantation. JPEN J Parenter Enteral Nutr 2003;27:71-73. 59. Hasse JM: Nutrition assessment and support of organ transplant recipients. JPENJ Parenter Enteral Nutr 2001 ;25:120-131. 60. Mehta PL, Alaka KJ, Filo RS, et al: Nutrition support following liver transplantation: A comparison of jejunal versus parenteral routes. Clin Transplant 1995;344:837-840. 61. Pescovitz MD, Mehta PL, Leapman SB, et al: Tube jejunostomy in liver transplant recipients. Surgery 1995;117:642-647. 62. Wicks C, Somasundaram S, Buarnason I, et al: Comparison of enteral feeding and total parenteral nutrition after liver transplantation. Lancet 1994;344:837-840. 63. Rayes N, Seehofer D, Hansen S, et al: Early enteral supply of Lactobacillus and fiber versus selective bowel decontamination: A controlled trial in liver transplant recipients. Transplantation 2002;74:123-128.
Hematopoietic Stem Cell Transplantation Polly Lenssen, MS, RD
CHAPTER OUTLINE Introduction Basics of Hematopoietic Stem Cell Transplantation and Implications for Nutrition Support Conditioning Therapy and Infection Risk Graft-versus-Host Disease-A Serious Complication Graft-versus-Leukemia Effect-The Therapeutic Advantage of Allogeneic Transplantation Pathophysiology of Mucosal Injury and Gastrointestinal Failure-"Barriers" or "Opportunities·· for Enteral Nutrition? Conditioning Regimen-Related Toxicities Gastrointestinal Graft-versus-Host Disease Nutrition Role in Modulation of Toxicities Efficacy of Enteral Feeding Dislodgment of Tubes Delayed Gastric Emptying Diarrhea Infections and Gastric Leakage Inadequacy of Intake Cost Formulas Patient Tolerance and Acceptance Guidelines for Initiation. Monitoring. and Management of Complications Candidates Tube Placement and Care Formulas Schedules Nutrient Needs Goals of Therapy
INTRODUCTION The principal method of nutritional support during hematopoietic stem cell transplantation (HSCT) has been total parenteral nutrition (TPN) rather than enteral nutrition over the last 30 years. The reasons for this are 544
twofold: first, because the doses of chemotherapy and radiation considered necessary to destroy the patient's own immune system and tumor cells in patients with malignancy are highly toxic to the oral mucosa and gastrointestinal (GI) tract; and second, because every patient has had central venous access already established for other supportive therapies. The Hickman catheter was created specifically for the patient undergoing HSCT in the early 1970s,1 and the double-lumen catheter was designed by the early 1980s because of the need to infuse adequate amounts of TPN.2 Very few transplant centers even attempted tube feeding in the 19805 owing to the formidable list of GI complications (Table 48-1), and those that did provided TPN as a "rescue" treatment or to supplement enteral feedlng.v' Over the decades, HSCT has evolved into a diverse treatment approach for many types of hematologic, immune, and genetic disorders (Table 48-2). Less intensive treatment regimens are now available for patients who would not otherwise tolerate the conventional, high-dose approach. Likewise, technology and knowledge in enteral nutrition have evolved such that now there is a firm place for tube feeding in patients undergoing HSCT. In this chapter, Iwill describe the HSCT process, review the published studies in enteral feeding, and discuss the unique considerations of enteral feeding in this population.
BASICS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION AND IMPLICATIONS FOR NUTRITION SUPPORT The process of HSCT involves three steps (Table 48-3): (1) preparing or "conditioning" the patient for the graft by delivering immunosuppressive and myelosuppressive therapy; (2) "grafting" or transplanting stem cells via an infusion of healthy stem cells collected from the bone marrow, peripheral blood, or placental cord blood of either the patient (autologous graft) or a donor (allogeneic graft); and (3) in allogeneic HSCT, administering therapies to prevent and manage the serious complications of graft-versus-host disease (GVHD).
545
SECTION VII • Transplant
•
Cil Symptoms Presenting Challenges to Enteral Feeding in Hematopoietic Stem Cell Transplantation
Symptom
Differential Diagnosis
Nausea & vomiting
Chemotherapy, radiation Medications: antibiotics, cyclosporine GVHD Liver disease (GVHD, viral infection) Infections Pancreatitis Gastroparesis Chemotherapy, radiation GVHD Viral infections Antibiotics Pseudomembranous colitis
Diarrhea
Dysphagia
Abdominal pain
Ileus
Autologous
Allogeneic
Malignancies
(Clostridium difficile)
Bleeding
-
Diseases Treated by Hematopoietic Stem cell Transplantation
Ulcers (gastric, duodenal, small bowel, or colon) GVHD Chemotherapy, radiation Viral or fungal infection Reflux esophagitis GVHD GVHD Infections (c. difficile, cytomegalovirus, H. pylori) Liver disease (infection, VOD, abscess) Pancreatitis Duodenal or gastric ulcer Biliary sludge or gallbladder stones Typhlitis Opiate analgesics Sepsis GVHD Infections Pancreatitis Pneumonia
GVHD, graft-versus-host disease; VOD veno-occlusive disease of the liver.
Conditioning Therapy and Infection Risk In conventional HSCT, the patient's immune system and tumor cells are ablated by chemotherapy, often combined with total body irradiation (rBI), During the prolonged period of immunodeficiency that follows a myeloablative conditioning regimen, the patient has an extreme risk for infections, initially bacterial and fungal, and later viral. The period of absolute neutropenia is relatively short, from as few as 7 to 10 days when peripheral blood is the source of stem cells, 14 to 21 days when bone marrow is used, and up to 1 month or longer when placental cord blood is infused. However, the complete range of T-cell and B-eell immunity does not fullydevelop for 1year and often longer in patients receiving allografts. The use of TPN during neutropenia has been associated with an increased risk of infection in several randomized trials in patients undergoing HSCT in which TPN was compared with intravenous fluid support.V Because no deaths were associated with TPN-related bacteremia and TPN improved long-term survival in the largest of these trials.' an increased risk of infection has not appreciably
Lymphoma-Non-Hodgkin, Hodgkin disease Hodgkin disease Leukemias-acute and chronic Myelodysplastlc syndromes Multiple myeloma Neuroblastoma Breast cancer Germ cell tumors Ovarian cancer Small cell lung cancer Central nervous system tumors
X
X X
X
X X X X X X X X X
X X
Bone marrow failure or disorders Aplastic anemia Fanconl anemia Sickle cell anemia Thalassemia
X X X X
Congenital immune deficiencies" Metabolic disorders
X
Gaucher disease Osteopetrosis Mucopolysaccharidose1 Metachromatic leukodystrophy Adrenoleukodystrophy
X X X X X
Rare dlsell8e8: Paroxysmal nocturnal hemoglobinuria, Blackfan Diamond anemia, Shwachman-Dlamond syndrome
X
Experimental Indications: Rheumatologic disorders (scleroderma, systemic lupus erythematosus) Neurologic disorders (multiple sclerosis) Hematologic disorders (autoimmune hemolytic anemia, autoimmune neutropenia)
X
*Severe combined immune deficiencies, T-celldeficiencies, X-linked proliferative syndrome, Wiskott-Aldrich syndrome, phagocytic cell diseases, Fas deficiency. 'Hurler syndrome, Hunter syndrome, Maroteaux-Lamy syndrome, Sanfilippo A and B disease. From Atkinson K (ed): Clinical Bone Marrow and Blood Stem Cell Transplantation. Boston, Cambridge University Press, 2000.
altered patterns of TPN use nor served as an urgent reason to overcome barriers to tube feeding in the early post-transplant period.
Graft-versus-Host DiseaseA Serious Complication The most significant complication of allografting is GVHD, in which the grafted donor T cells mediate cytotoxic, often life-threatening damage to host (patient) target organs. Ferrara and Antin? describe GVHD as an "exaggerated, undesirable manifestation of a normal
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48 • Hematopoietic Stem Cell Transplantation
_ _ The Process and Nutrition-Related Consequences of Hematopoietic Stem Cell Transplantation (HSCT) Steps In HSeT
Autologous HSCT
Allogeneic HSCT
I. Conditioning therapy
Myeloablative Goal: Eradicate tumor; in allografting suppress host immunity
Reduced Intensity Goal: Partially suppress host immune system; provide some anti-tumor activity Mild-to-moderate toxicities-Grade I to II (see Table 48-4)
Moderate-to-severe toxicities-Grade II to 111 oral and I to 111 gastrointestinal (see Table 48-4); other major organs often affected (hepatic VOD, kidney, lung, heart) 2. Infusion of stem cells
Non-myeloa bla five Goal: Partially suppress host immune system Minimal toxicities
Goal: New stem cells rescue from lethal doses of conditioning therapy Goal: Donor cells eradicate residual tumor (GVL or GVT) "Pseudo" acute GVHD Stomach: nausea, vomiting, anorexia Skin and liver: mild and usually not associated with nutritional side effects
3. Post-grafting immunosuppression
Acute and chronic GVHD Oral: stomatitis, xerostomia, taste changes Intestine: diarrhea, cramping, malabsorption, ileus, GI bleeding Liver: anorexia, malabsorption Esophagus: strictures, dysphagia Lung: hypermetabolism, poor exercise tolerance Skin: hypermetabolism, ulceration and protein losses Musculoskeletal system: muscle weakness, contractures, decreased mobility Goal: control GVHD and establish long term graft-host tolerance
Corticosteroids: Occasionally needed for "pseudo" acute GVHD
Cyclosporine: Anorexia, renal dysfunction, severe magnesium wasting, hyperlipidemia Tacrolimus: Renal dysfunction, magnesium wasting, glucose intolerance Corticosteroids: Extreme muscle wasting and debilitation, glucose intolerance, hyperlipidemia, osteoporosis, growth failure Mycophenolate moietil: anorexia, nausea, diarhea Sirolimus: Hyperlipidemia Many other experimental modalities use d in treatment
til, gastrointestinal; UVHD, graft-versus-host disease; GVL, graft-versus-leukemia effect; GVT, graft-versus-tumor effect; VOD, veno-occlusive disease.
inflammatory mechanism in which donor lymphocytes encounter foreign antigens in a milieu that fosters inflammation." GVHD occurs in 30% to 40% of related donor transplants and 70% to 90% of unrelated donor transplants, with the frequency being increased in patients who are older, have transplants from female donors, or have greater histocompatibility differences (HLA typing) with their donors. In the acute disease that emerges in the first 3 months after HSCT, the skin, liver, and gut are the primary organs involved, whereas in chronic GVHD that occurs 3 months to 1year or longer after HSCT, additional organs such as the musculoskeletal system and mouth are targeted (see Table 48-3). These time frames are beginning to shift with some of the newer, lessintense conditioning regimens, with the onset of acute disease being delayed up to 3 months post-transplant. Treatment often requires use of multiple immunosuppressive agents and years of therapy for chronic GVHD. Weight loss, debilitation, anorexia, and GI symptoms are common findings in GVHD, and nutritional support is often indicated in both acute and chronic GVHD. One survey of 93 patients with chronic GVHD evaluated at a median of 2.4 years after transplantation indicated a 43% prevalence of malnutrition, 29% moderate (body mass index
18.5 to 21.9 kg/rn") and 14% severe (body mass index <18.5 kg/rrr') malnutrition, and weight loss ranging as high as 35% body weight." GVHD is intrinsically linked to infection. The immune dysregulation that accompanies GVHD and the immunosuppressive therapies used for treatment lead to frequent occurrence of infections. In turn, any infection can activate or cause a "flare" of GVHD. The use of TPN during GVHD and its potential relationship to infection risk in GVHD have not been investigated as they have in the early post-transplant period. However, with the exception of intestinal GVHD, there are fewer physical barriers to implementation of enteral feeding during GVHD, and the concern about infection with TPN may motivate the oncology team to establish an enteral feeding plan with the patient.
Ciraft-versus-Leukemia Effect-The Therapeutic Advantage of Allogeneic Transplantation The "silver lining" of GVHD is its induction of a complex surveillance system against residual malignant cells that
SECTION VII • Transplant
is now recognized as being as important in eradicating the cancer as supralethal doses of chemotherapy and radiation. The graft-versus-leukemia (GVL) effect or graftversus-tumor effect in solid tumors significantly lowers disease relapse rates in patients receiving allografts compared with those receiving autografts. The balance between the GVL effect and GVHD is a delicate one, with the risk of mortality from GVHD being counterbalanced againstthe risk of mortality from diseaserelapse. The scientific unraveling of the GVL phenomenon has led to the development of reduced intensity and nonmyeloablative conditioning regimens that exploit the anticancer capabilities of the graft and decrease treatment-related toxicities and rnortality.v'? GVHD, however, remains a major clinical problem (see Table 48-3). A basic understanding of the immunology of HSCT as well as an appreciation of the rapid pace of evolution of this clinical area is essential for the nutrition support clinician. Nutrition support strategies need to be evaluated in the context of the impact they have not only on short-term end-points, such as infection rates or gut toxicities, but also on the major causes of mortality, such as GVHD in allografting and relapse in autografting, The clinician, furthermore, needs to recognize that many factors influence the course and outcome of HSCT, including the underlying disorder, preexisting medical status, patient age, donor histocompatibility, source of stem cells, conditioning regimen, type of GVHD prophylaxis,
547
GVHD treatment modalities, and any post-transplant "consolidation" treatments (e.g., local radiation to solid tumors or immunotherapy in acute leukemia). In this heterogeneousenvironment, there is no one single approach to nutritional support of the patient undergoing HSCT.
PATHOPHYSIOLOGY OF MUCOSAL INJURY AND GASTROINTESTINAL FAILURE-"BARRIERS" OR "OPPORTUNITIES" FOR ENTERAL NUTRITION?
Conditioning Regimen-Related Toxicities The mucosal and GI toxicities related to conditioning regimens generally parallel the intensity of the regimen. Champlin and associates'? depicted the evolution of conditioning regimens in allogeneic HSCT: intensity increases for myelosuppression are based on the aggressiveness of the malignancy and for immunosuppression are based on the genetic disparity between donor and patient. 10 In Figure 48-1, the magnitude of GI toxicity is overlaid on this model. Cancers more sensitive to the GVL effect and appropriate for a nonmyeloablative approach are more indolent, such as chronic leukemias and low-grade
Aggressiveness of malignancy FIGURE 48-1. The effect of different conditioning regimens on gut toxicity in allogeneic HSCT. Bu, busulfan (at 8 or 16 mg/kg); Cy, cyclophosphamide; Flud, f1udarabine; Flag, f1udarabine + cytosine arabinonucleoside; GI, gastrointestinal; Mel, melphalan (at 140 or 180 mg/m 2) ; TBI, total body irradiation. (From Champlin R, Khouri I, Anderlini P, et al: Nonmyeloablative preparative regimens for allogeneic hematopoietic transplantation. Oncology 2003; 17:94-100.)
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48 • Hematopoietic Stem Cell Transplantation
lymphomas, whereas more rapidly proliferating acute leukemias respond best to myeloablative therapy. Likewise, more intense therapy is needed when there is greater genetic incompatibility, as with unrelated donors or donors mismatched at the major histocompatibility antigens (HLA mismatched). The majority of patients still receive myeloablative regimens, whereas truly nonmyeloablative approaches are currently reserved to treat patients who are older, have medical conditions that contraindicate high-dose chemoradiotherapy, or have nonmalignant, life-threatening diseases for which no alternative therapy exists, such as genetic or immune deficiency and stem cell disorders.l-" Even with the use of intensive conditioning regimens, however, the profile of mucosal and GI toxicity varies among individual agents (Table 48-4). In dose escalation trials the GI tract has been discovered to be the dose-limiting organ for TBI and for several commonly used agents, including busulfan, melphalan, thiotepa, and etoposide.P Many investigators have adopted the Bearman system 14 or a similar grading system to describe and compare complications among regimens (see Table 48-4 for Bearman grades for stomatitis and GI toxicity). Toxicity grading provides a framework for determining which conditioning regimens offer opportunities for enteral nutrition. In myeloablative regimens, mucosal injury of the mouth is characterized by pain, edema, erythema, lesions, pseudomembrane formation, excessive mucous production, reduced saliva production, and bleeding. IS With severe oral toxicity, the patient may require high doses of anti-inflammatory agents or ventilation for airway protection. Patients have characterized oral mucositis as the single most debilitating side effect of HSCT.16 The severity of oral mucositis is increased in patients treated with TBJl7 or methotrexate as prophylaxis against GVHD.18 Placement of a feeding tube during the presence of active symptoms, when oral intake is at its nadir or nil, seems formidable to many transplant clinicians, and placement before symptom onset has been a goal in many of the enteral feeding studies. It is more difficult to
IImrIID
characterize the injury in the gut, and the symptoms of diarrhea, abdominal pain, and poor oral intake typically are the surrogates for toxicity. Four phases of mucosal injury have been described." The first phase is the inflammatory phase, in which intestinal damage manifest by villous blunting, apoptosis, and brush border loss correlates with cytokine and tumor necrosis factor-a levels. The second phase is the epithelial phase when an arrest of the cell cycle and inhibition of repair lead to mucosal atrophy, thinning, and necrosis. The third phase is the ulcerative bacteriologic phase, culminating about 14 days after the start of conditioning therapy. The disruption of the mucosal barrier is believed to be the portal of infection for 25% to 75% of bacteremias.!" Decreases in salivary and intestinal immunoglobulins contribute to the breakdown in host defense." Finally, the fourth (healing) phase begins with neutrophil engraftment. Oral mucositis resolves within 2 to 3 weeks, whereas gut function does not return to normal for several more weeks. During the initial inflammatory phase, an increase in intestinal permeability occurs before the onset of any clinical symptoms." The immediate and early spike in permeability after the start of conditioning is believed to initiate the injury phase of cytotoxic therapy and predispose the patient to GVHD. In experimental models the severity of GVHD has been amplified as the intensity of the conditioning regimen increases, presumably by the translocation of endotoxin or lipopolysaccharide, a known constituent of normal bowel flora and potent stimulator of inflammatory cytokine production.P The use of pharmacologic agents, such as interleukin-ll and keratinocyte growth factor, to shield the GItract from the mucosal injury of conditioning, prevents intestinal GVHD and reduces GVHD mortality rates in preclinical models." Other agents under investigation as gut protectants are pentoxifylline, sucralfate, amifostine, transforming growth factor-B, and glutarnine-'; a discussion on glutamine is found in the next section. Some investigators have suggested that early intervention with enteral nutrition in this initial, presymptomatic phase might be
Oral and Gastrointestinal Toxicity Grade. Related to Conditioning Regimen. CBearman Grades)
Stomatitis
Gastrointestinal toxicity
Grade I
Grade II
Grade III
Agents Implicated
Pain or ulceration not requiring a continuous IV narcotic
Pain or ulceration requiring a continuous IV narcotic
Moderate: busulfan,
Watery stools >500 mL but <2000 mL every day not related to infection
Watery stools >2000 mL every day; macroscopic hemorrhagic stools
Severe ulceration or mucositis requiring intubation or resulting In aspiration pneumonia Ileus requiring nasogastric suction or surgery or hemorrhagic enterocolitis affecting cardiovascular status and requiring transfusion
mitoxantrone, paclitaxel, TBI, thiotepa Severe: etoposide, melphalan Mild: carboplatin, cyclophosphamide, cytosine arabinoside Moderate: carmustine, cisplatin, etoposide, melphalan, TBI
IV, intravenous; TBI, total body irradiation. From Bensinger WI, Buckner CD: Preparative regimens. In Thomas ED,Blume KG, Forman SJ (eds): Hematopoietic Stem Cell Transplantation, 2nd ed, pp 123-134. Malden, MA: Blackwell Science, 1999;Bearman SI, Appelbaum FR, Buckner CD,et al: Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin OncoI1988;6:1562-1568; and Bearman SI:Toxicity of drugs used in stem cell transplantation regimens. In Atkinson K (ed): Clinical Bone Marrow and Blood Stem Cell Transplantation, p 829. Boston, Cambridge University Press, 2000.
SECTION VII • Transplant
another means to maintain mucosal integrity, diminish the inflammatoryresponse, and ameliorate injury." In the second phase, intestinal permeability peaks, and clinical toxicities become apparent. Johansson and colleagues" serially measured intestinal permeability as assessed by 5lCr-ethylenediamine tetraacetic acid absorption in 25 patients treated with a varietyof myeloablative conditioning regimens, approximately one half of which contained TBI.2! They found that permeability peaked between days 4 and 7 after transplantation and that diarrhea and vomiting, but not oral toxicity (defined as ulcers or inability to eat), correlated with increased permeability. The same investigators studied intestinal permeability in a reduced intensity regimen (fludarabine and antithymocyte globulin with either cyclophosphamide or busulfan) and found no increase." Furthermore, average days of elevated C-reactive protein (0.3 vs. 5.3) and days of TPN (1.4 vs. 18.3) were significantly less for the patients receiving reduced intensity therapy compared with those for patients receiving myeloablative therapy (fBI and cyclophosphamide); only two patients receiving the reduced intensity conditioning regimenexperienced nausea, vomiting, oral pain, or diarrhea. Other investigators have documented a significant reduction in the need for TPN as a reflection of the blunting of mucosal injurywith lower intensityand nonmyeloablative regimens,25,26 confirming the model of GI toxicitydescribed in Figure48-1.
Gas troi ntesti nal Graft-vers u s-Hes t Disease The pathophysiologic effects of GVHD of the GI tract are complex. As indicated in the previous section, the initial phase begins with conditioning regimen-related damage to the gut, the translocation of inflammatorystimuli such as endotoxin, and subsequent cytokine-mediated damage, promoting a vicious cycle of further inflammation and damage. Other mechanisms, however, appear to contribute to the pathogenesis. In experimental murine models, when GVHD is induced in the absence of chemoradiotherapy, early alteration of the integrity of tight junctions in the gut occurs in association with interferon-y production, increased crypt cell mitotic activity, crypt lengthening, and intraepithelial lymphocyte proliferation.22 Furthermore, in patients who undergo HSCT after nonmyeloablative conditioningand are spared damage to the mucosal barrier and unleashing of the inflammatory response, cytokinestorm, the onset of gut GVHD appears delayed, but GVHD is not prevented. Mielcarek and colleagues" compared the onset of GVHD and morbidities of key target organs in 44 recipients after HSCT with nonmyeloablative conditioning and 52 recipients after HSCT with myeloablative conditioning. Onsetof GVHD occurred significantly later at 3 months after HSCT in recipients of nonmyeloablative regimens compared to 0.95 months in recipients of myeloablative regimens. Gut morbidity peaked in the first month post-transplant in patients receiving intensive therapy, whereas gut morbidity was significantly delayed and peaked between 6 and 12 months post-HSCT in patients receiving the low-dose regimens."
549
The initial proliferative phase is followed by destructive and atrophic phases, characterized by villous blunting, lamina propria inflammation,crypt destruction, crypt stem cell loss, and mucosal atrophy. Histopathologic findings in humans reveal patchy disease, from necrosis of individual intestinal crypt cells to total mucosal denudation.27,28 Prevention of GVHD in addition to the standard use of immunosuppression (see Table 48-3) has included strategies such as decontamination of the gut to reduce the numbers of Gram-negative organisms and endotoxin translocation and, in experimental models, inhibition of systemic lipopolysaccharide by neutralizing proteins." Thesestrategieshave been only partially successfulat best. Furthermore, therapies designed to neutralize inflammatory cytokines must be monitored for possible interference with the GVL effect, because only the GVL effectcan eradicate "the 'last' hematopoietic cell of host origin."!' Diarrhea in GVHD results from multiple mechanisms, including excessive osmotic water and carbohydrate loss due to enterocyte damage and disaccharidase deficiency, an increase in the proportion of immature enterocytes with subsequent enzyme deficiency and impaired water transport, and protein and water exudation though a very leaky epithelium. In the colon, damage to enterocytes also impairs water resorption." GI GVHD is staged according to the volume of diarrhea using the definitions by Glucksberg and associates'" and more recently the International Bone Marrow Transplant Registry" (Table 48-5). In the most severe form of acute intestinal GVHD, the volume of diarrhea is large (>2.5 to 3.0 Uday) and corresponds to the extent of mucosal damage." The diarrheal fluid is typically green and watery and contains mucus, protein, cellular debris, and occult blood. Protein content is high, as evidenced by hypoalbuminemia and elevated fecal o-antitrypsin." The occurrence of severe GI bleeding in patients with GVHD appears to have decreased significantly over the years, but when it occurs the mortality rate exceeds 40%.32 The use of antidiarrheal agents is generally contraindicated in GVHD because of the risk of ileus and abdominal
_
• . ':
Glucksberg Stage
CrIteria for Grading Gastrointestinal Gnft·versus·Host Disease IBMTR Severity Index Stage
o I
1-2
2 3 4
3 4
Volume of Diarrhea (mL/day)
<500 >500-1000 >1000-1500 >1500 Severe abdominal pain with or without ileus
IBMTR, International Bone Marrow Transplant Registry. FromGlucksberg H,Storb R, FeferA, et al: Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974;18:295-304; and Rowlings PA, Przepiorka D, Klein JP, et al: IBMTR Severity Index for grading acute graft-versus-disease: Retrospective comparison with Glucksberg grade. BrJ Haematol 1997;97(4-11):855-864.
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48 • Hematopoietic Stem Cell Transplantation
distention, although some centers use octreotide acetate. Octreotide (500 ug intravenously three times a day) appears to be most effective when it is used with systemic steroids (2 mg/kg/day) immediately upon the confirmation of a diagnosis of GVHD by histopathologic flndings.P To minimize the risk of ileus, the use of octreotide should be discontinued as soon as diarrhea resolves or, if diarrhea persists, it should be administered for a maximum of 7 days. No centers have reported successful enteral feeding strategies during severe GIGVHD. A milder clinical variant of GI GVHD has been described in patients with a wide variety of upper gut symptoms, including anorexia, dyspepsia, food intolerance, nausea, and vomiting. Only an endoscopic biopsy of the stomach can establish a diagnosis and distinguish GVHD from delayed recovery from conditioning regimeninfection-, and medication-induced symptoms." The disease typically responds well to steroids given systemically or in a nonabsorbable topical form, and nutritional support is often not needed." In patients with more prolonged anorexia, enteral nutrition is an appropriate intervention, especially if the acute disease evolves into chronic disease with recurring episodes. Chronic GI GVHD has been considered to be rare and has not received a lot of attention. Lee and colleagues," however, found that intestinal involvement, defined as the presence of chronic diarrhea, affected 30% of unrelated donor and 20% of HLA-matched sibling transplant recipients with chronic GVHD and was a poor prognostic sign. In another case series describing the histopathologic course of chronic GI GVHD, the incidence was 7.3% of 232 children receiving transplants." Villous atrophy, crypt abscesses, apoptosis, and inflammatory infiltration of the lamina propria with cytotoxic T lymphocytes were generally moderate and focal and did not correlate well with the severity of diarrhea or nausea and vomiting. Of these children, 35% were unable to eat at all and required TPN or tube feeding; however, the authors did not provide the proportions of children who could be fed enterally versus parenterally. In one small series of patients receiving HSCT after nonmyeloablative conditioning, in which onset of GVHD is delayed and chronic disease may be more accurately classified as "late-onset acute" GVHD, one half required TPN at a mean of 79 days post-transplant (range 9 to 292 days) because of significant GI complications that were contraindications to tube feeding."
Nutrition Role in Modulation of Toxicities There is keen interest in the potential role of enteral feeding for modulating the inflammatory response and its interrelated corollaries-regimen-related toxicity, infection, and GVHD-but to date no published studies have adequately addressed these outcomes. One early study did find a protective role of volitional oral protein intake on the incidence of GVHD,39 allaying any concerns that protein macromolecules in the peritransplant period were
antigenic and should be minimized. Several researchers have attempted to ascertain a relationship with lipids and modification of GVHD by suppressing production of inflammatory cytokines via prostaglandin E2-mediated pathways. Two of these studies involved intravenous lipids. One large study (n =512) showed no difference in prevalence of or time to develop grade II to IV acute GVHD between low and moderate doses of lipid," and another small study (n = 66) showed that the lethality of GVHD decreased in patients randomly assigned to receive 80% lipid or lipid-free TPN,41 Fat modulation by the enteral route has been reported in only one published study." In this study, 1.8 g/day of oral eicosapentaenoic acid was given as a supplement from day 21 to day 180 after transplantation; the seven patients in the eicosapentaenoic acid group experienced grade II to III GVHD and all survived, whereas in the control group (n =9), six patients experienced grade II to IVGVHD and five of these died. In nutrition research designed to modulate incidence, onset, target organ expression, and severity of GVHD, the enteral route is favored over the parenteral route because of the ability to more easily manipulate fat composition and provide other "imrnunonutrients." The use of oral and intravenous glutamine to reduce mucosal toxicity has been investigated in patients undergoing HSCT; results for the primary reported clinical end points of infection and mucositis have been mixed. In a Cochrane review of available trials in humans, intravenous glutamine was associated with decreased incidence of blood infections." However, careful analysis of the data reveals that the Cochrane review counted colonization cultures from stool and other sites as blood infections; the results of these studies44,45 are perhaps not as strong as suggested and caution with the use of glutamine is warranted. Indeed, in a recent clinical trial using alanyl-glutamine dipeptide, a commercially available and more stable form of glutamine, significantly more relapses were seen in patients undergoing autologous HSCT who were randomly assigned to receive glutamine supplementation." raising concern about the effect of glutamine supplementation on long-term survival in patients with cancer. Glutamine enhances the synthesis of the intracellular antioxidant glutathione, such that pharmacologic doses given peritransplant could protect the tumor. To examine the key end-points of relapse and survival, PowellTuck and co-workers" suggested that a glutamine study in HSCT would require more than 160 patients, far more than the number in any study to date. The use of intravenous glutamine has not influenced mucosal toxicity as measured by severity of mucositis or reduction in days of TPN44,45 nor has the use of oral glutamine in four published trials.48-51 Jebb and colleagues" provided a dose of 16 g/day from day 1 after HSCT until mucositis resolved or hospital discharge in recipients of autologous transplants (n = 24) randomly assigned in matched pairs according to the chemotherapy regimen. They found no benefit for glutamine with objective or subjective assessment of mucositis or days of TPN. Anderson and co-workers" delivered a smaller dose
SECTION VII • Transplant
551
of glutamine (4 g/rn") but as a concentrated suspension from admission until day 28 after HSCT. Although glutamine appeared to lower significantly narcotic use for mucositis pain in recipients of autologous transplants, it had the opposite effect in recipients of related donor grafts and no effect in recipients of unrelated donor grafts. These investigators postulated that mucositis was worsened by glutamine in the allogeneic transplant setting owing to coadministration with methotrexate given to prevent GVHD; in experimental models glutamine delays renal clearance of methotrexate and thereby could enhance toxicity.S Additional findings included no difference in TPN use nor in the incidence and type of bacterial and fungal infections." In two other studies using oral glutamine at a dose of 30 g/day,50,51 results for mucositis, positive blood cultures, days of TPN, and diarrhea (median days and total volume) were similar among glutamine- and placebo-treated patients undergoing both autografting and allografting. Whether delivery of glutamine distal to the esophagus in the stomach or small intestine in tube feeding alters clinical findings has yet to be reported, although glutamine-based formulas are being used.53,54 As with parenteral glutamine, the safe use of the oral or enteral form for long-term outcome (relapse-free survival) has not been demonstrated. Coghlin Dickson and Investigators" found that actuarial estimates of 2-year survival and relapse rates were similar between oral glutamine- and placebo-treated patients; however, the study population was too small when other variables affecting survival and relapse, including transplant type and diseases with different prognoses, were accounted for. The effect of either intravenous or oral glutamine on GVHD is also an unanswered question. Although glutamine is the primary fuel for lymphocytes." there is insufficient evidence that it supports lymphocyte function and lowers the incidence of infectious complications after transplantation or conversely that it activates lymphocyte and stimulates GVHD. In the study of Anderson and co-workers'? of oral glutamine suspension, lymphocyte stimulation of oral GVHD, the pain of which mimics conditioning-related mucositis, was suggested as a reason why patients receiving glutamine supplementation needed more pain medications. Ziegler and colleagues.f on the other hand, reported higher total numbers of lymphocytes, CD3+, CD4+, and CD8+ T lymphocytes, without an increase in the rate of GVHD in glutamine-treated patients compared with control subjects.
Gastroparesis may be a factor contributing to nausea and vomiting and its occurrence has caused at least one group of researchers to not attempt full enteral feedings.' In a study investigating the factors associated with delayed gastric emptying in the HSCT setting, 18 of 151 consecutive patients had symptoms of gastroparesis, most of whom had the diagnosis confirmed by scintigraphic emptying studies." Age, conditioning regimen, and acute GVHD were not factors, but type of transplant was, with no recipients of autologous transplants and 26% of recipients of allogeneic transplants exhibiting delayed gastric emptying. Prokinetic agents or jejunal feedings have been use to successfully manage this complication'"; however, not all patients tolerate the administration of prokinetic agents.
EFFICACY OF ENTERAL FEEDING
Diarrhea
The published literature on tube feedings in HSCT patients is predominantly limited to pilot studies and case series,4,53,54,57-63 with only one randomized trial by Szeluga and co-workers," in which tube feeding was one aspect of the "enteral feeding arm." The Cochrane review, in which the efficacy of TPN versus enteral nutrition was evaluated, included only the Szeluga et al. study and two abstracts for a total of 144 patients, but none of the data could be used for outcomes of interest, such as GVHD,
Diarrhea does not appear to be as much of a limitation to tube feeding as are nausea and vomiting, although some of the regimens that result in large-volume diarrhea were not represented in these studies (e.g., regimens using multiple alkylating agents). Switching to elemental formulas is a successful strategy in some patients, but when large-volume diarrhea occurs after conditioning or with GVHD, it is very difficult to continue with enteral nutrition. 3•58,61,62
survival, and blood lnfections." In two of the studies, improved weight maintenance with TPN was seen. Although clinicians in some transplant centers purport that tube feeding should be the first option for nutritional support,62,64 in fact there are no studies that prove the benefit of enteral feedings over TPN.The collective findings from the studies detailed in Table 48-6 are summarized in the next sections.
Dislodgment of Tubes During and immediately after myeloablative conditioning regimens, vomiting of the tube is common, even with a self-propelling tube placed jejunally. The recommendation by some investigators to delay placement until day 1+ after HSCT and immediately before the onset of mucositis'" bypasses the window during conditioning when enteral nutrition might have its greatest physiologic benefit on gut mucosal integrity. Research on timing of tube placement and the start of feeding would be helpful to determine whether it is worth the efforts of the patient and team to endure repeated tube placements during conditioning. In addition, because vomiting of the tube was not restricted to the period of chemotherapy and TBI administration, setting expectations with the patient and family about the possibility of frequent tube replacements might be helpful during the peritransplant period.
Delayed Gastric Emptying
Bisgaard Pederson et al, 199959 Case series
3 HSCT of 17 total cancer, 2 solid tumor, I Hodgkin disease, transplant type not provided N = 5 HSCT of 32 total cancer, diagnosis/ transplant type not provided
=
Pietsch et al, 199953 Pilot study
N
Auto (n = 4); Allo related (n = 5); unrelated (n = 7)
Roberts and Miller, 199858 Case series
Pediatric
Pediatric
Adult
NO
NO
Auto: Cyclophosphamide Allo: CyclophosphamidejTBl
Cyclophosphamide/ TBI (n = 8) Cyclophosphamide/ busulfan (n = 8) IdarubicinjTBI (n = 5)
Pediatric
Auto with solid tumors Phase I: counseling and enteral feeds "as necessary" (n = 10; 5 had enteral) Phase U; TPN (n = 11) PPN + enteral (n = 11) Hematologic malignancies (57%), solid tumors (5%), other (38%) Tube at 5% weight loss Accepted (n = 21) Refused (n = 8)
Mulder et al, 19894 Phase I: Case series Phase U: RCT TPNvs. PPN + enteral Papadapoulou et al, 199757 Pilot study
gjm 2
Busulfan/cyclophosphamide Cyclophosphamide/ TBI Cyclophosphamide/ cyclosporine
Cyclophosphamide 7 Etoposide 0.9-2.5 gjm 2
Pediatric >lOyr and adult
Allo (n = 46) Auto (n = 15) 45 with hematologic malignancies; 10 other cancers; 6 aplastic anemia
Szeluga et aI, 19873 RCTTPNvs. enteral feeding program
Conditioning
Adult
Age
Population
Study
--
Enteral Feeding Studies in Hematopoietic cell Transplantation
NG (time of tube placement not provided); continuous Pediatric free amino acid MCT-based PEG placed "during neutropenia" Details of infusion and formula not provided
NG (time of tube placement not provided); continuous Low-lactose whole protein <20 kg 1.0 kcal >20 kg 1.5 kcal PEG placed median 104 days after HSCT (32-1125 days); bolus Isotonic, intact protein (n = 13) Semielemental (n = 2) Elemental (n = 1)
NG (time of tube placement not provided); continuous Low-Iactose whole protein
Nasoenteric placed when PO <0.5 gjkg (time not provided but before to day 28 after HSCT) Details of infusion and formula not provided
Tube and Formula
All HSCT needed TPN 1 converted to PEG/J due to stomach GVHD
? %HSCT needed TPN
25% needed TPN Mean weight gain 0.7 kg; 68% able to maintain or gain weight
29% needed TPN Mean duration feeds 22 days Increase weight-forheight z score 0.08
13% failures TPN group (unable to place catheter) 23% in enteral feeding program eligible for tube feeding (n = 7); all needed TPN TPN preserved body cell mass Phase I: 10% weight loss Phase II: 2.5% weight loss N balance same both groups Enteral group-twice rate of sepsis; less diarrhea
Clinical Outcomes
20% local infection at PEG
25% failures due to GVHDdiarrhea (3); high residual volumes (1) 44% high residual volumes (most responded to prokinetic agent, 1 converted to PEG/J) 6% local infection at PEG No sinusitis or epistaxis
38% failures due to vomiting (n = 7) and diarrhea (n = 1) Feedings <50% of needs
None noted for aspiration, parotitis, sinusitis, or inflammation of the nose
100% failures-3 not placed due to severe GI symptoms; 1 refused; 3 placed but unsuccessful due to vomiting and diarrhea "Occasional" feeding tube occlusion
Enteral Nutrition Complications
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Hopman et al, 2003 63 Clinical trial, not randomized
Cyclophosphamide (n = 31) TBI (n = 18) ARA-C (n = 9) VP-16 (n = 12) Busuflan (n = 12) Melphlon (n = 9) Regimens not ascribed
Cyclophosphamide/ TBI 7.5-14.4 Gy Busulfan/cyclophosphamide Cyclophosphamide/ATG (+ T-cell depletion in unrelated donor) High dose melphalan BEAM
Tube type ND; nocturnal, continuous
NG placed before or within 1 wk of HSCT Whole protein (n = 19) Semielemental (n = 28) Elemental (n = 2)
NJ with Bengmark tube placed 1 wk before HSCT Peptide MCT-based; glutamine added day 7+
PEG or NJ placed before conditioning Isotonic, peptide-based
8% excluded (early death) 14% needed TPN 8% needed no nutrition support Median duration feedings 52 days (range 5-267 days) Mean change IBW 101% to 97%; malnutrition «85% IBW) increased 6% to 14% Median duration feeds 43d; TPN 7d (P = 0.0001) Greater total calorie/protein intake enteral (P<0.05) Greater oral intake TPN (P<0.05) Less cholestasis enteral (P = 0.057) Less GVHD enteral (P = 0.07) No difference nutritional status, sepsis, diarrhea, mortality
53% retained tube until engraftment Mean duration feeding 16 days (range 0-34 days) Weight loss at discharge 4.5%, 3 mo 7%, 6 mo 5%
100% needed TPN
G tube placed by 64% needed TPN retrograde percutaneous (% HSCT patients technique mean 9 wk not provided) before (n = 9) or mean 34 wk alter (n = 18) HSCT Details of infusion and formula not provided
50% complete and 25% partial failure of enteral at median day 6 (vomiting or diarrhea) 25% exclusively enteral younger (3.3 yr) than others (8 yr)
PEG infection-delay of HSCT 100% failure NJ (3 vomiting, 2 removed at patient request) 100% failure gastrostomytyphlitis or severe diarrhea 47% vomited tubes during conditioning/early alter HSCT Epistaxis tube side (n = I), opposite side (n = 1) Diarrhea requiring decreased infusion rate (n = 2) No sinusitis Enteral feedings <50% of needs
41% local infection at G tube 4.5% peritonitis (% HSCT patients not provided)
Allo, allogeneic graft; ATG,antithymocyte globulin; Auto, autologous graft; BEAM, brain electrical activity mapping; G, gastrostomy; HSCT, hematopoietic stem cell transplantation; IBW, ideal body weight; MCT, medium-chain triglyceride; ND, not determined: NG, nasogastric; NJ, nasojejunal; PEG, percutaneous endoscopic gastrostomy; PEG/J, percutaneous endoscopic gastrostomy/jejunostomy; PPN, peripheral parenteral nutrition; RCT, randomized controlled trial; TBI, total body irradiation; TPN, total parenteral nutrition.
Pediatric
Pediatric
Allo matched related (n = 23); unrelated donor (n = 19) Auto = 11) Hematologic malignancy (n = 31) Solid tumor (n = 9) Other (n = 13)
Langdana et ai, 2001 62 Case series
en
Adult
Allo with hematologic malignancies related (n = 8); unrelated (n = 7)
Sefcick et aI, 2001 54 Pilot study
Cyclophosphamide 120 rng/rnTBI 12-14.4 Gy (+ ATG or T-cell depletion in unrelated donor)
Adult and ND pediatric
Allo related (pEG/J) (n = 1); unrelated (N]) (n = 5); preexisting gastrostomy (n = 2)
ND
Lenssen et ai, 2001 6 1 Pilot study
Pediatric
IV = 27 HSCT of 44 total cancer
Barron et aI, 2000 60 Case series
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48 • Hematopoietic Stem Cell Transplantation
Infections and Gastric Leakage
Cost
It is encouraging to note that no sinus infections and
The expense of HSCT and TPN has undoubtedly been a motivating factor for centers to explore enteral feeding. The ability to provide medications through the tube offers a potential huge cost advantage, both through lower medication cost and the ability to facilitate earlier hospital discharge.P Two studies reported cost: in one, the cost of an enteral approach was one half the cost of TPN in the first month after HSCT,3 and in the second, the cost of the enteral approach was 73% of feeding exclusively by TPN.63 More cost analysis would be helpful and should include the total cost of the entire transplant process through at least 3 months and possibly 12 months post-transplant, not just the cost of the nutrition support therapies. Cost savings from the use of more oral medications or reductions in infection rates could be a benefit of choosing the enteral route, whereas the clinical consequences of weight loss and debilitation or the need to provide dual therapies (enteral nutrition and TPN) might negate the cost advantage of tube feeding.
minimal epistaxis were reported with the use of nasagastric tubes. In all four reports with percutaneous endoscopic gastrostomy (PEG) or gastrostomy tubes, infections at the tube site occurred but were generally perceived as not being problematic. However, in one report PEG infection delayed transplantation." so it is not a technique that should be used immediately before transplantation unless a 3- to 40-week window for healing is available.P This time window is not always available in transplant centers, in which referrals may be external and coordination of tube placement well before transplantation is difficult. Gastric leakage requires special protection of the skin during the neutropenic period to prevent skin breakdown."
Inadequacy of Intake Few studies reported actual delivery of feedings in relation to estimated needs, but in those that did enteral feedings were found to provide less than 50% of energy requirements.Ff'' The high rate of rescue with TPN, ranging from 14% to 100% of patients,3,4.57-62 indicates how difficult it is to depend on enteral feedings as the sole source of nutrition. The study with the lowest percentage of patients requiring rescue with TPN (14%) excluded patients who died during their initial hospitalization from the results 62 and thus the data asserting an 86% success rate with exclusive enteral feedings are not representative of the spectrum of experience with HSCT. A predominantly enteral nutrition approach resulted in weight 10ss,54 a decrease in body cell mass," and, in children, an increase in the incidence of malnutrition.P Weight loss in recipients of allogeneic transplants typically continues after hospital discharge, which led one group of investigators to conclude that successful use of the enteral route requires continuation of feedings after discharge.P In allografting, weight loss in the initial posttransplant period may have adverse consequences later. In a comprehensive data set from several transplant registries, weight loss was found to be an independent risk factor for poor outcome, occurring in 20% to 25% of patients with chronic GVHD.36 It is difficult to nutritionally rehabilitate a patient with chronic GVHD, especially in the ambulatory care setting; thus, the prevention of significant weight loss seems to be a rational component of the nutrition care plan in the initial acute phase after HSCT. In children who have a high risk for growth failure,66 the added insult of undernutrition for any period of time after transplantation should be considered as well. In addition to energy deficits, deficiencies of magnesium, phosphorus, zinc, and selenium during enteral feeding have been observed. 57.62 Patients did not tolerate replacement of magnesium by the enteral route and required intravenous replacement.
Formulas The issue of enteral access has so overshadowed the actual delivery of feeding that there is little information to glean from the studies to date on appropriate formulas. Some investigators have used whole protein, reserving peptide-based or elemental formulas for patients exhibiting intolerance to intact protein.V whereas others favor the use of semielemental formulas from the start. 54,6! Based on the failure of oral glutamine to reduce mucosal toxicity, there is no evidence for use of glutamine-fortified formulas. Future research using formulas with glutamine should include tracking of GVHD and relapse-free survival.
Patient Tolerance and Acceptance Discomfort during mucositis does not seem to be a problem,62 but, as with diarrhea, the use of regimens with more GI toxicity was not represented in the reports published to date. Patient refusal of tube placement or replacement is an issue.57.61.63 The multidisciplinary team, which includes the patient, must be committed to supporting enteral feeding as the primary mode of therapy, as emphasized by several transplant centers. 54,62.63 As more tube feeding is implemented in HSCT, it will be interesting to gather data on the patient's perspective. In a recent survey of hospitalized oncology patients, the vast majority preferred TPN rather than tube feeding and among those who previously had tube feeding, 93% would choose TPN.67In environments in which available resources do not limit the use of TPN and patients essentially have a choice, it is imperative that a case for enteral feeding be built around evidence of improved outcome.
SECTION VII • Transplant
GUIDELINES FOR INITIATION, MONITORING, AND MANAGEMENT OF COMPLICATIONS
Candidates Without evidence to support tube feeding rather than TPN, candidates for nasoenteral tube feeding in HSCT might include those who 1. Receive nonmyeloablative or reduced intensity regimens and have poor oral intake and mild malnutrition (or children failing to gain weight or grow). 2. Receive myeloablative regimens with a lower GI toxicity profile so that sufficient feedings can be provided to maintain weight and growth and development; these are difficult to catalog because so many different regimens are used. At our center, they would include cyclophosphamide-only regimens used primarily for nonmalignant disorders or cyclophosphamide/busulfan regimens. 3. Receive HLA-matched related donor transplants with an expected lower incidence of GVHD and earlier recovery, so that inadequate nutrition via enteral feedings would not have long-termsequelae. 4. Are critically ill and are receiving mechanical ventilation and in whom trophic feedings may be initiated without the intent to provide full nutrition support. 5. Fail to make a transition to oral intake after resolution of regimen-related toxicities as measured by healing of mucositis and weaning from intravenous analgesics and have minimal diarrhea volumes. Candidates for gastrostomy feeding might include those who 1. Have enteral access established before HSCT. 2. Experience weight loss or protein malnutrition due to long-term post-transplant complications. These complications are predominantly related to chronic GVHD, but may include other rare complications, such as neurologic events that preclude the ability of the patient to feed orally. In chronic GVHD, establishment of long-term access is recommended in patients with the following: (a) Severe oral GVHD (b) Esophageal strictures that do not respond to dilatation (c) Profound anorexia that is refractory to appetite stimulants (d) Hypermetabolism and inability to meet energy needs (e) Open wounds and ulceration as a result of severe skin GVHD CO Chronic intestinal GVHD except during acute flares or GI bleeding
Tube Placement and Care The unique considerations for tube placement in HSCT relate primarily to the complete blood count. For
555
placement of a PEG tube, most centers desire an absolute neutrophil count of 500 to 1000/mm3 and a platelet count boosted by transfusions to more than 50,000/mm3. For nasal tubes, a platelet count in the range of 10,000 to 20,000/mm3 is probably adequate; however, irrespective of the platelet count, the clinical risk for bleeding needs to be determined by the attending oncologist. For gastrostomy care, the recommendation is that it should be washed daily with mild soap and during neutropenia or if a local infection is suspected, a detergent containing 4% chlorhexidine should be used." Local antibiotics should be used if microorganisms are isolated from culture specimens. For gastric leakage, the skin can be protected with water-resistant cream or temporary antacids and the fixation plate can be tightened.P As with any tube, adequate flushing protocols are important. Patients undergoing allogeneic HSCT typically have dozens of pills to take over the course of the day, and occlusion of nasoenteric tubes is a risk if all these are administered via the nasogastric tube. For patients with nasojejunal tubes, the absorption of immunosuppressive medications should be assessed in terms of the ability to maintain therapeutic drug levels and obtain adequate control of GVHD. At our center, we do not have a protocol for replacing nasoenteric tubes, but recommend that the team consider changing a tube after 8 weeks.
Formulas Ideally only commercially sterile products, preferably in a closed feeding system, would be administered in the hospital. Mortality associated with contaminated formula powders has heightened awareness among pediatric practitioners about the risks of powders in immunosuppressed patients." This is a dilemma when a pediatric elemental formula is indicated for the patient undergoing HSCT, as is the lack of closed systems for pediatric products. Strict adherence to 4-hour feeding hang times should be emphasized, and in patients with unexplained fever or diarrhea, the enteral formula should always be considered as a source and a culture specimen should be obtained. For patients receiving feedings in the home setting, food and formula safety guidelines need to be presented, reviewed, and monitored. Patients or their caregivers often have interesting ideas about what they believe should be put down a feeding tube! As discussed earlier, no clear guidelines on formula selection exist. Whole protein formulas may be tried in the absence of diarrhea; however, semielemental or elemental formulas may be better tolerated and a semielemental formula is our choice when feeding is implemented after myeloablative regimens. In our experience, use of a range of pediatric and adult formulas has been necessary, depending on other organ complications, for example, renal formulas in patients receiving dialysis or in patients with elevated serum phosphorus or potassium levels, 2 kcal/mL formulas in patients with fluid
556
48 • Hematopoietic Stem Cell Transplantation
overload, or low-calcium formulas in infants with osteopetrosis. Diarrhea is the most common reason for changing a formula, especially in patients with GVHD who often have flares of gut symptoms. When we have been most successful with enteral feeds in patients with chronic GIGVHD, it seems patients require an elemental formula. Finally, we have been reluctant to implement use of any immune enhancing formulas outside a clinical trial because of concerns for stimulating the immune system in the direction of GVHD.
Schedules The feeding schedule will be determined by many factors, including the phase of the HSCT process, the goals of feeding (e.g., as a supplement to oral intake, TPN, or complete feeding), the overall function of the gut, and the presence of any contraindication to bolus feedings (such as gastroparesis). If feeding is a transition from TPN after major gut toxicity, continuous feeding started at a very low rate and advanced slowly is recommended.
Nutrient Needs The nutrient needs of patients undergoing HSCT have been reviewed in detail elsewhere. 69,7o Energy needs are somewhat elevated after myeloablative conditioning, decrease after engraftment, and thereafter depend on the level of activity and presence of GVHD. Both acute and chronic GVHD are associated with mild to moderate hypermetabolism.I-P Protein support at twice normal recommendations is the target goal after myeloablative therapy or in patients treated with corticosteroids. Unless the patient needs fluid restriction for impaired renal, cardiac, or hepatic function, enteral feedings should be calculated to provide maintenance fluid needs if the patient is not drinking volitionally. Patients, especially after allografting, are receiving many renal-toxic drugs and adequate fluid intake affords the kidneys some protection. Other key nutrients that are often needed in excess of typical enteral formula composition include calcium, phosphorus, magnesium, and potassium, primarily owing to drug effects. Hyperglycemia occurs often during corticosteroid treatment and may be aggravated by administration of tacrolimus. This has not presented a problem with enteral feeding except in an occasional patient with labile blood glucose levels. We use intermediate-acting insulin such as NPH for continuous feedings and shortacting insulin for bolus feedings with the goal of keeping the blood glucose level well below 180 mg/dL. Glucose control is especially important in patients with GVHD because of the increased risk of infection associated with hyperglycemia. Because the steroid dose can change often, it is important that needed changes in the insulin coverage are anticipated. Hypertriglyceridemia is less common and is typically observed in patients who also have hyperglycemia. In addition to control of blood glucose levels, use of a lipid-lowering agent and low-fat formula may be indicated,
Goals of Therapy The goals of therapy do not differ from those in other clinical settings and include weight gain or maintenance, growth and development in children, successful weaning from any concurrent TPN, and maximizing the patient's and family's quality of life. It is gratifying to see that enteral nutrition in recent years is more widely used and accepted as a feeding modality in HSCT, and we can expect more studies as confidence with techniques for access grows. There are unlimited opportunities for research in the role of enteral nutrition. Practitioners are encouraged to publish their experience and disseminate knowledge on established benefits, techniques, and complications of enteral nutrition in HSCT.
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SECTION VII • Transplant
18. Storb R, Deeg HJ, Thomas ED, et al: Marrow transplantation for chronic myelocytic leukemia: A controlled trial of cyclosporine versus methotrexate for prophylaxis of graft-versus-host disease. Blood 1985;66:698-702. 19. Stiff P: Mucositis associated with stem cell transplantation: Current status and innovative approaches to management. Bone Marrow Transplant2001;27(suppI2):S3-S11. 20. BeschornerWE, YardleyJH,Tutschka PJ,Santos GW: Deficiency of intestinal immunity with graft-vs-host disease in humans. J Infect Dis 1981;144:38-46. 21. Johansson J-E, Ekman T: Gastro-intestinal toxicity related to bone marrowtransplantation: disruption of the intestinalbarrier precedes clinical finds. Bone Marrow Transplant 1997;19:921-925. 22. Hill GR, Ferrara JLM: The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: Rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood2000;95:2754-2759. 23. Filicko J, Lazarus HM, Flornenger N: Mucosal injury in patients undergoing hematopoietic progenitor cell transplantation: New approaches to prophylaxisand treatment. Bone Marrow Transplant 2003;31:1-10. 24. Johansson J-E, Brune M, Ekman M: The gut mucosa barrier is preserved during allogeneic, haemopoietic stem cell transplantation with reduced intensityconditioning. Bone Marrow Transplant 2001;28:737-742. 25. Parker JE, Shafi T, Pagliuca A, et al: Allogeneic stem cell transplantation in the myelodysplastic syndromes: Interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens. BrJ HaematoI2002;119:144--154. 26. Mielcarek M, Martin PJ, Leisenring W, et al: Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003;102:756-762. 27. Sale GE, Shulman HM, McDonaldGB, Thomas ED: Gastrointestinal graft-versus-host disease in man. A clinicopathologic study of the rectal biopsy.Am J Surg Pathol 1979;3:291-299. 28. Snover DC, Weisdorf SA, Vercellotti GM, et al: A histopathologic study of gastric and small intestinal graft-versus-host disease following allogeneic bone marrow transplantation. Hum Pathol 1985;16: 387-392. 29. Glucksberg H, Storb R, Fefer A, et al: Clinical rnanifestations of graft-versus-host disease in human recipients of marrow from HLAmatched sibling donors. Transplantation 1974;18:295-304. 30. Rowlings PA, Przepiorka 0, Klein JP, et al: IBMTR SeverityIndex for grading acute graft-versus-disease: Retrospective comparison with Glucksberg grade. BrJ Haematol I997;97(4-Il):855-864. 31. Weisdorf SA, Salati LM, Longsdorf JA, et al: Graft-versus-host disease of the intestine:Aprotein losingenteropathy characterized by fecal alpha I-antitrypsin. Gastroenterology 1985;85:1076-1081. 32. SchwartzJM, Wolford JL, Thornquist MD, et al: Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987-1997: Incidence, causes, and outcome. Am J Gastroenterol 2001 ;96: 385-393. 33. Kornblau S, Benson AB III, Catalano R, et al: Management of cancer treatment-related diarrhea: issues and therapeutic strategies.J Pain Symptom Manage2000;19:118-129. 34. Weisdorf OJ, Snover DC, Haake R, et al: Acute upper gastrointestinal graft-versus-host disease: Clinical significance and response to immunosuppressivetherapy. Blood 1990;76:624-629. 35. McDonald GB, Bouvier M, Hockenberry OM, et al: Oral beclomethasone dipropionate for treatment of intestinal graftversus-host disease:Arandomized, controlled trial. Gastroenterology 1998;115:28-35. 36. Lee SJ, Klein JP, Barrett AJ, et al:Severityof chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood 2002;100:406-414. 37. Patey-Mariaud de Serre N. Reijasse 0, Verkarre V, et al: Chronic intestinal graft-versus-host disease: clinical, histological and immunohistochemical analysis of 17 children. Bone Marrow Transplant 2002;29:223-230. 38. Roberts S, Vanzee J: Nonmyeloablative stem cell transplantation (NMSCT) and its nutritional consequences. Support Line 2003: 25:3-9. 39. Cheney CL, Weiss NS, Fisher LD, et al: Oral protein intake and the risk of acute graft-versus-host disease after allogeneic marrow transplantation. Bone Marrow Transplant 1991 ;8:203-210.
557
40. Lenssen P, Bruemmer B, Bowden RA, et al: Intravenous lipid dose and incidence of bacteremia and fungemia in patients undergoing bone marrow transplantation. AmJ Clin Nutr 1998;67:927-933. 41. Muscaritoli M, Conversano L, Torelli GF. et al: Clinical and metabolic effects of different parenteral nutrition regimens in patients undergoing allogeneic bone marrow transplantation. Transplantation 1998;66:61 ~ 16. 42. Takatsuka H, Takemoto Y, Iwata N, et al: Oral eicosapentaenoic acid for complications of bone marrow transplantation. Bone MarrowTransplant 2001;28:769-774. 43. Murray SM, Pindoria S: Nutrition support in bone marrow transplant patients (Cochrane Review). In The Cochrane Library, Issue 3, 2002. Oxford, UK: Update Software. 44. Ziegler TR, Young LS, Benfell K, et al: Clinical and metabolic efficacyof glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann Intern Med 1992;116:821-828. 45. Schloerb PR, Amare M: Total parenteral nutrition with glutamine in bone marrow transplantation and other clinical applications (a randomized, double-blind study). JPEN J Parenter Enteral Nutr 1993;17:407-413. 46. Pytlik R, Penes P, Patorkova M, et al: Standardized parenteral alanyl-glutamine dipeptide supplementation is not beneficial in autologous transplant patients: A randomized, double-blind, placebo controlled study. Bone Marrow Transplant2002;30:953-961. 47. Powell-Tuck J, Jamieson CP, Bettany GEA, et al: A double blind, randomized, controlled trial of glutamine supplementation in parenteral nutrition. Gut 1999;45:82-88. 48. Jebb SA, Marcus R, Elia M: A pilot study of oral glutamine supplementation in patients receiving bone marrow transplants. ClinNutr 1995;14:162-165. 49. Anderson PM, Ramsay NKC, Shu XO, et al: Effectof low-dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant 1998;22:339-344. 50. Schloerb PR, Skikne BS: Oral and parenteral glutamine in bone marrow transplantation: A randomized, double-blind study. J Parenter Enteral Nutr 1999;23:117-122. 51. Coghlin Dickson TM, Wong RM, Offrin RS, et al: Effect of oral glutamine supplementation during bone marrow transplantation. JPEN J Parenter Enteral Nutr 2000;24:61-66. 52. Charland SL, Barlett DL, Torosian MH: A significant methotrexateglutamine pharrnokinetic interaction. Nutrition 1995;11:154-158. 53. Pietsch JB, Ford C, Whitlock JA: Nasogastric tube feedings in children with high-risk cancer: A pilot study. J Pediatr Hematol Oncol 1999;21:111-114. 54. Sefcick A, Anderton 0, Byrne JL, et al: Naso-jejunal feeding in allogeneic bone marrow transplant recipients: Results of a pilot study. Bone MarrowTransplant 2001;28:1135-1139. 55. Newsholme EA: The possible role of glutamine in some cells of the immune system and the possible consequences for the whole animal. Experientia 1996;52:455-459. 56. ZieglerTR, ByeRL, Persinger RL, et al: Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: A pilot study. ArnJ Med Sci 1998;315:4--10. 57. Papadopoulou A, MacDonald A, Williams MD, et al: Enteral nutrition after bone marrow transplantation. Arch Dis Child 1997;77: 131-136. 58. Roberts SR, Miller JE: Success using PEG tubes in marrow transplant recipients. Nutr Clin Pract 1998;13:74--78. 59. Bisgaard Pedersen A-M, Kok K, Petersen G, et al: Percutaneous endoscopic gastrostomy in children with cancer. Acta Paediatr 1999;88:849-852. 60. Barron MA, Duncan OS, Green GJ, et al: Efficacy and safety of radiologically placed gastrostomy tubes in paediatric haematology/ oncology patients. Med Pediatr OncoI2000;34:177-182. 61. Lenssen P, Bruemmer B, McDonaldGB, AkerS: Nutrientsupport in hematopoietic cell transplantation. JPEN J Parent Enteral Nutr 2001;25:219-228. 62. Langdana A, Tully N, Molloy E, et a1: Intensive enteral nutrition support in paediatric bone marrow transplantation. Bone Marrow Transplant 2001;27:741-746. 63. Hopman GD, Pella EG, Ie Cessie S, et al: Tube feeding and bone marrow transplantation. Med Pediatr Oncol 2003;40:375-379. 64. Mercadante S: Parenteral versus enteral nutrition in cancer patients: indications and practice. Support Care Cancer 1998:6:85-93.
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68. Enterobacter sakazakii infections associated with the use of powdered infant formula-Tennessee, 2001. MMWR Morb Mortal Wkly Rep 2001;51:29~300.
69. Charuhas PM: Pediatric hematopoietic stem cell transplantation. In Hasse JM, Blue LS (eds): Comprehensive Guide to Transplant Nutrition, pp 226-247. Chicago, American Dietetic Association, 2002.
70. Lenssen P, Aker SN:Adult hematopoietic stem cell transplantation. In Hasse JM, Blue LS (eds): Comprehensive Guide to Transplant Nutrition, pp 123-152. Chicago, American Dietetic Association, 2002. 71. Szeluga OJ, Stuart RK, Brookmeyer R, et al: Energy requirements of parenterally fed bone marrow transplant recipients. JPEN J Parenter Enteral Nutr 1985;9:139-143. 72. Zauner C, Rabitsch W, Schneeweiss B, et al: Energy and substrate metabolism in patients with chronic extensive graft-versus-host disease.Transplantation 2001 ;71 :524-528.
Index
AA, 234. See also Vitamin C. AAA,468 Abdominal distension, 168 Abdominal examination, 197-198, 198t, 246 Abdominal surgery, 270 Abnormal upper esophageal sphincter (UES) relaxation, 407t Absorption, II Accelerated gastric emptying, 14 Access to GItract, 202-215 catheter removal/exchange, 212-214 combined nasogastric-jejunal tubes, 206 factors to consider, 202 Indtcations/contralndtcattons, 203t materials for enteral access, 203-204 nasoenteric tube placement, 204-206 nasogastrlc tube placement, 204 patient considerations, 202-203 post procedure initiation of enteral feeding, 210-211 route of feeding considerations, 203 tube enterostomies, 206-210, 211-212 Acetaldehyde, 130 Acetaminophen, 297t Acidic amino acids, 12lf ACTH, 84, 87 Active transport, 119 Acute diarrhea, 269 Acute hepatic dysfunction, 464-470 BCAAs, 469, 469t caloric requirements, 469 definitions, 465 FHF, 465, 465t future direction, 469 liver, 465 nutrition assessment, 466-467 nutritional therapies, 467-468 Acute lung injury/acute respiratory distress syndrome, 234-236 Acute pancreatitis, 269-270, 436-444 arginine, 443 citrulline, 443 CT severity index, 437, 437t enteral nutrition, 441 European guidelines, 44lt glutamine, 442-443 guidelines, 439t, 44lt, 443 guidelines for surgical management, 439t mortality, 438 nutrition assessment, 439-441 nutritional goals, 442t pathophysiology, 438-439 PN,440 Ranson score, 436, 437t SIRS, 438, 439 who should be fed?, 440-441 Acute pulmonary disease, 414-435 AJUDS,415-416,422 caloric intake, 420 complications, 421
Acute pulmonary disease (Continued) COPD. See COPD. energy requirements, 419 enteral access, 418-419 epidemiology, 414 indications for enteral nutrition, 418 malnutrition, 414, 417, 418 medications, 418 micronutrients, 420 NIPPV, 415, 416, 418 nutrition assessment, 416-417 nutrition management, 420-421 patient monitoring, 421 protein needs, 420 typical nutritional findings, 417-418 Acute renal failure, 368-369 Acute respiratory disease. See Acute pulmonary disease. Acute respiratory distress syndrome (AJUDS),415-416,422 Acute spinal cord injury (ASCI), 381, 386-387 Acute stress response, 80--84 carbohydrate-glucose delivery, 82-83 clinical relevance, 83 clinical significance, 84 lipid,83 metabolic changes, 82 neuroendocrine modulation, 83-84 protein catabolism, 82 time course of response, 81-82 Acyl-CoA, 116 Adam's apple, 194 Adaptation, 452, 455 Adenosine triphosphate (ATP), 39 Adequate intake (AI), 126,253 Adjusted body weight, 369, 400 Administration of enteral nutrition, 243-247 Administrative law judge (AU), 315 Adrenal insufficiency, 87 Adrenocorticotropic hormone (ACTH), 84,87 Advera, 160t Adverse effects, 295 Aerolate, 298t Aging, 75-79 body composition changes, 76 effect of, on organ systems, 75-76 fluid requirements, 78 macronutrients, 76-78 micronutrients, 78 ROAs,77t AH, 464. See also Acute hepatic dysfunction. AI,126,253 AIDS. See HIV infection. Aiko, Satoshi, 516 Alanine, 12lf Albina, Jorge E., 306 Albumin, 199,246,466 Alcohol, 189,447 Alcoholic hepatitis (AH), 464. See also Acute hepatic dysfunction.
Aliphatic amino acids, 12lf AlitraQ, 326t ALJ,315 All-racemic o-tocopherol, 257 All-trans-fkarotene, 257 Allium sativum, 259 a-amidating monooxygenase, 144 lX-amylase, 118 lX-linolenic acid, 112 children, 7lt, 72f, 73 metabolic pathways, 72f pregnancy, 61 lX-tocopherol elderly persons, 77t nutritional requirements, 257 vitamin E, 136 Alterna, 117t Aluminum, 147t, 152-153 Aluminum hydroxide antacids, 277t Aluminum poisoning, 153 American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), 4,200 Amin-Aid, 117t Amino acid animal species, 48 BCAA,219 brush border peptidase activity, 122 burns, 354 critically III children, 322t dietary protein, 120 digestion/absorption, 120-122 essential, 120 formulas, 12lf hepatic metabolism, 122 metabolism, 122-123 nonessential, 120 pregnancy, 60 wound healing, 173-175 Amino acid absorption, 122 Amino acid carrier systems, 121, 122f Amino acid flux measurements, 71 Amino acid metabolism, 122-123 Amino acid sequence, 34, 35 Aminophylline, 297t Amoxlclllin, 298t Ampicillin, 28lt, 298t Amylose maize, 267 Anabolic compounds, 370-371 Anabolic steroids, 429t, 431 Anabolic substances, 431 Anantharaju, Abdinandana, 464 Anemia, 36 Aneroid (portable) manometer, 191 Angular stomatitis, 129 Animal species, 43-54 carbohydrates, 49 diets for tube feeding, 52-53 digestive processes, 45-46 energy, 47-48 enteral nutrition, 50-53 esophagostomy tube, 51
559
560
Index
Animal species (Continued) fat, 48-49 gastrointestinal anatomy, 43-44 gastrostomy tube, 51-52 GI barrier function, 46 human enteral formula, 53t jejunostomy tube, 52 micronutrients, 49 nasoesophagealtube, 51 nutritional assessment, 50 nutritional plan, 50 protein/amino acids, 48 vitamins, 49 water, 46-47 Anorexia, 376 Antacids, 302t Anthropometric data, 187 Anthropometric measurements, 524, 532t Anti-lymphocyte serum, 538t Antibiotic-associated diarrhea, 269 Antioxidant-based diets, 236-238, 239t Antioxidants, 267, 376, 392 Antonopoulos, Olga, 509 AOAC, 252 APACHE II,230-232, 436 Apoptosis, 163 Appetite stimulants, 432, 493 Arabinogalactins, 157f Arablnorhamnogalactans, 157f Arabinoxylans, 156, 157f Arachidonic acid, 112, 113,234 Arginine, 173-175 acute pancreatitis, 443 burns, 354 chemical formula, 1211 critically ill children, 322t functions, 228 sepsis, 375, 376 short bowel syndrome, 453-454 Arginine-supplemented diets, 228-232, 239t clinical recommendations, 232 clinical review, 228-232 nutrient breakdown, 229t scientific rationale, 228 Ariboflavinosis, 128-129 Armenti, Vincent, 530 Arnoletti, Juan Pablo, 516 Aromatic amino acid (AAA), 468 Aromatic/heterocyclic amino acids, 1211 Arsenic, 147t, 151 Asbron-G, 298t ASCI, 381, 386-387 Ascorbic acid (M). See Vitamin C. Asklepos,3 Asparagine, 1211 Aspartic acid, 1211 A.S.P.E.N., 4, 200 A.S.P.E.N. Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Pediatric Patients, 307 Aspiration, 278, 410 41Ot, Aspiration of oropharyngeal secretions, 410 Aspiration pneumonia, 278-280 Assessment. See Nutrition-focused history; Nutrition-focused physical examination; SGA.
Association of Analytical Communities (AOAC),252 ATBC study, 130 ATGAM,538t ATP, 39 Atrophic gastritis, 76, 78 Atrpine, 277t Attain, 117t Available carbohydrates, 118 Azathioprine, 538t Azithromycin, 298t
B vitamins, 128-132 Bacterial antagonism, 24 Bacterial overgrowth, 18 Bacterial translocation, 24, 25-26 Bactrim, 298t Balanced Budget Act of 1997,307 Balthazar CT score, 437, 437t Bananas, 267 Bankhead, Robin, 202 Barbul, Adrian, 172 Basal energy expenditure (BEE), 59 Basiliximab, 538t BCAA. See Branched-chain amino acid (BCM). BCAA-enrlched formula, 222 Bearman grades for stomatitis and GI (toxicity), 548 BEE,59 Bengmark, Stlg, 265 Benzodiazepines, 50 Berdanier, Carolyn D., 32 Berg, Melanie, 75 Berger, Mette M., 389 Beri-beri, 392 Beriberi, 128 I}-agonlsts, 277t !>-carotene, 133,257-258 Bethanechol, 500 Bezoar formation, 168 Bicarbonate chronic pancreatitis, 446 dosage range, 102 Gl secretions, 98t Bile acids, 15 Bile salts, 15, 25, 115 Bioactlve prebiotics, 266-267 Bloavailability, 253 Biochemical indexes, 525t Biochemical markers, 246 Biotin, 129 deficiency, 129 DRls, 127t middle/late adulthood, 77t pregnancy, 62t summary (overview), 134t Biotin deficiency, 129 Bisacodyl, 28lt Bishop, Michele, 445 Bismuth, 283t Bliss, Donna Zimmaro, 155 Blood pressure, 191-192 Blood pressure cuff, 1911 Blue cohosh, 258t Blue dye, 279 Blue-green algae, 258t BMI, 187, 398, 425 Body composition changes, 76 Body lipids, 110-111 Body mass index (BMI), 187,398,425 Body water content, 95 Body weight, 187, 369 Bolus feeding, 19 Bolus method, 244, 244t Boost High Protein, 294t Boost Plus, 294t, 385t Boost with Fiber, 160t Boron, 147t, 151-152 BouUata, J., 248 Bowel disease. See Short bowel syndrome. Bowel ischemia, 390 Bowel pattern, 189 Brain injuries, 381-386 energy, 383-384 enteral formulas, 385t gutdellnes, 381 initiation of enteral feeding, 383f nutrition assessment, 382
Brain injuries (Continued) nutrition management, 383-385 patient monitoring, 385-386 protein, 384-385 route, 383 Branched-chain amino acid (BCM), 219 acute hepatic dysfunction, 464, 468, 469 enteral formulas, as part of, 469t liver disease/transplantation, 534 wound healing, 175 Breast milk, 266 Brewer, Connie, 276 Brush border glycohydrolases, 70 Bullae, 192 Buried bumper syndrome, 211 Burning foot syndrome, 130 Burns, 236. See also Severe burn. Butanediol, 258t Butyrate, 161. See also Short-chain fatty acids (SCFAs).
C. difficile, 163, 245 C-reactive protein measurement, 369 Caffeine, 28lt Calamus, 258t Calcitonin, 277t Calcitriol, 90 Calcium, 140-141 amount of, in body, 99 critically ill children, 323t deficiency/toxicity, 141 dietary supplement, as, 258 dosage range, 102t elderly persons, 77t electrolyte abnormality, 10lt extracellular, 100 food source, 141 function, 140 gene expression, 38t liver disease/transplantation, 535t, 540t renal disease, 474 summary (overview), 146t Calcium channel blockers, 277t Calcium deficiency, 141 Calcium disorders, 107-108 Canada, Todd W., 95 Cancer, 509-520 chemoradiation, 512 early postoperative enteral nutrition, 517-518 esophageal and gastric, 516-519 head and neck, 509-515 pancreatic, 516-519 quality of life (HEN), 345-346 radiation treatment, 512 SCFAs, 165-166 swaliowlng. See Swallowing. TPN,517 Candidiasis, 512 CAPD, 478, 48lt Carbamazepine, 297t, 300-301 Carbohydrates absorption, 119-120 acute pancreatitis, 442t acute stress response, 82-83 animal species, 49 brush border enzyme renewal, 120 children, 70, 71t, 73-74 classification, 118 definition, 118 diabetes, 498-499 dietary, 118 digestion, 118-119 enteral formulations, 218 enzymes,69t food processing, 120 intestinal transplantation, 526
Index Carbohydrates (Continued) liver disease/transplantation, 536-537 metabolism/energy storage, 120 pregnancy, 59-60 renal disease, 473-474 wound healing, 175-176 Carbonated beverages, 291 Carboxyl ester lipase, 69t, 70 Carboxypeptidase, 69t Cardiac cachexia, 390 Cardiac surgery, 389-397 antioxidants, micronutrients, trace elements, 392 common problems, 396t energy/substrate requirements, 393 enteral access, 394-395 enteral route,393-394 gastrointestinal complications, 390-391 GIK infusion, 391-392 glutamine, 392 metabolic support, 391 nutritional status, 389-390 nutritional support, 392-396 patient monitoring, 395 preoperative intervention, 395 Cardiopulmonary bypass (CPB), 390 Carnation Instant Breakfast, 294t Carnitine, 116, 220, 526 Carnitine deficiency, 474 Carnitine depletion, 493 Carotenoids, 133 Carpal tunnel syndrome, 130 Casein, 69, 219 Castor oil, 303t Catabolic hormone antagonists, 358 Catheter removal/exchange, 212-214 CCI. See Chronic critical illness (CCI). CCK, 15,446 Cefaclor, 298t Celadroxll, 298t Cefuroxime, 298t Cell wall polysaccharides, 157f CellCept, 539t Cellular defense function, 225 Cellulose, 118, 156, 157f, 158 Cephalexin, 298t Cephradine, 298t Certificate of medical necessity (CMN), 31Of, 313 CF,449 cGMP, 374 Chaparral, 258t Charney, Pam, 216 Chemical hydrolysis, 12 Chemically defined and elemental formulas, 221 Chemoradiation, 512 Chest examination, 196-197, 197t Children, 68-74 acute illness, 317-331. See also Critically ill pediatric patient. anthropometric measurement, 524 burns, 352,353 carbohydrate, 70, 7lt, 73-74 cholestatic liver disease, 524 fat, 69-70, 7lt, 72-73 intestinal trans plantation, 524 macronutrients, 70 protein, 68-69, 70-72 Chiolero, Rene L., 389 Chloride, 98t Chlorothiazide, 297t Choice OM Beverage, 160t Choice OM TF, 160t Cholecystokinin (CCK), 15,446 Cholestatic liver disease, 524
Cholesterol ester hydrolase, 70 Cholestyramlne, 303t, 458 Choline, 131 deficiency/toxicity, 131 ORIs, 127t elderly persons, 77t enteral formulations, 220 pregnancy, 62t summary (overview), 134t Choline deficiency, 131 Chromatin, 35 Chromium, 145, 148 deficiency/toxicity, 148 food sources, 148 function, 145, 148 pregnancy, 64t summary (overview), 146t Chromium deficiency, 148 Chromosomes, 32 Chronic ambulatory peritoneal dialysis (CAJPD),478,48It Chronic critical illness (CCI),84-91 epidemiology, 85-86 fluid/electrolyte abnormalities, 90 malnutrition, 86 metabolic bone disease, 89-90 neuroendocrine dysfunction, 86-89 neuromuscular disease, 90-91 Chronic kidney disease (CKD), 471. See also Renal disease. Chronic liver disease and transplantation calories, 536 carbohydrates, 536-537 chronic liver disease, 530 electrolytes/fluids, 534, 535t, 539 enteral nutrition, 535, 539-541 enteral formula, 535, 540, 541t glucose, 534 lipid, 534, 537 liver transplantation, 530-531 malnutrition, 531, 531t medications, 538-539t minerals, 534, 535t, 540t NASH,531 nutrition assessment, 531, 532t nutrition management, 536t, 537t nutrition support algorithm, 54lf obesity, 531-532 protein, 533-534, 537 vitamins, 534, 535t, 537 Chronic obstructive pulmonary disease. See COPD. Chronic pancreatitis, 445-450 caloric needs, 447-448 CF,449 clinical presentation, 446 diagnostic methods, 446-447 etiology/epidemiology, 445 nutrition methods, 447 pain management, 448 pancreatic enzyme replacement, 448 pancreatic pseudocyst, 448-449 pathophysiology, 445-446 patient monitoring, 449 Chylomicrons, 70, 110, 115 Chymotrypsin, 69t Ciccoleila, David, 414 Cimetidine, 297t ClP, 90-91 Ciprofloxacin, 298t, 300 Cirrhosis, 530. See also Chronic liver disease and transplantation. Cisapride, 245, 278, 442, 500 Citrulline, 443 CKD, 471. See also Renal disease. Clarithromycin, 298t Clindamycin, 281t, 298t
561
Clinical history, 186-189. See also Nutritionfocused history. Clofibrate, 303t Clogging, 211, 2llt, 337-338 Clohessy, Sheila, 243 Clostridium difficile, 163, 245 CMN, 310f, 313 eNOS, 375 CNSinjury. See Brain injuries; Spinal cord injuries. Coarse wheat bran, 164 Cobalamin. See Vitamin B12• Coenzyme Q/Q10, 260,392 Coichicine, 281t, 302t Colestipol, 303t Colipase, 115 Colitis, 267 Colon, 18-19 Colonic bacteria, 120 Colonic brake, 18 Colonic fermentation, 18 Colonic transit time, 164, 166 Colonocytes, 161 Coloring enteral feedings, 279 Coltsfoot, 258t Combined nasogastric-jejunal tubes, 206 Comfrey, 258t Commercial diets, 117t Compher, Charlene, 140 Compleat, 160t Compleat Mod, 117t Compleat Reg, 117t Complementary and alternative medicine, 248 Complete medical foods, 187 Complications. See also Monitoring. acute pulmonary disease, 421 burns, 359 cardiac surgery, 390-391, 396t children, 328t enteral access devices, 211-212 enteral tube site, 338-339 gastrointestinal, 276-277, 328t, 390-391 HEN,337-339 metabolic, 284-285 nasal tubes, 211 obesity, 402-403, 402t renal disease, 477, 483 short bowel syndrome, 457-459 trauma patients, 369-371 tube enterostomy, 211-212 Comply, 117t Constipation, 76, 283-284 cardiac surgery, 396t children, 328t defined, 166 diabetes, 500 elderly persons, 76 gastric retention, 245 HEN,338t SCFAs,166 spinal cord injuries, 387 Constitutive NOS(eNOS), 375 ConsumerLab, 254 Continuous tube feedings, 244, 244t Continuous venous-venous hemofiltration hemodialysis (CWHD), 368 Continuous venous-venous home filtration, hemidiafiltration (CWHDF), 368 Controlled GI transit, 11-22 clinical relevance, 19-20 colon, 18-19 mouth/esophagus, 11-12 small intestine, 15-18 stomach, 12-14
562
Index
COPD, 415, 422, 424-435 anabolic steroids, 431 appetite stimulants, 432 dimension of problem, 424-425 effects of, 425 effects of nutritional supplements, 428 energy requirement, 426-427 future directions, 433 growth hormone, 432 hypermetabolism, 417 incidence, 414 malnutrition, 424, 425, 426t nonresponse to nutritional support, 432 nutrition assessment, 425 nutritional management, 428-430 patient monitoring, 432-433 studies,429,429t,43Q-432,430t weight loss/muscle wasting, 425, 427-428 Copper, 144-145 critically ill children, 323t deficiency/toxicity, 145 food sources, 145 function, 144 gene expression, 38t liver disease/transplantation, 535t, 540t pregnancy,64t,65 summary (overview), 146t wound healing, 178 Copper deficiency, 145 Copper toxicity, 145 Copper-zinc superoxide dismutase, 144 Corticotropin-releasing hormone (CRH), 84 Cortisol, 84, 87 CPB,390 Cranberry juice, 291 Crane, Tracy, 291 CRE,37 Creatine, 260 Creatinine-height index, 199 CRH,84 Critical illness myopathy, 90-91 Critical illness polyneuropathy (CIP), 90-91 Critically ill pediatric patient, 317-331. See also Children. amino acids, 322t biochemical monitoring, 328t body composition, 318-319 children 1-3years of age, 325, 326t children 4-9 years of age, 325, 326t children 10 and over, 325-326, 326t early enteral nutrition, 327 energy requirements, 319-320, 32lt gastrointestinal complications, 328t infants, 324-325 inflammatory response to acute illness, 318 macrominerals, 323t, 324t macronutrient requirements, 319-322 micronutrient requirements, 322, 323t minerals, 323-324, 323t monitoring, 327-328 nutritional screening/assessment, 319 protein requirements, 320-322, 322t route of administration, 326-327 sliding scale intermittent tube feedings, 329t trace elements, 323-324, 323t transition to oral diet, 328-329 vitamins, 324 Criticare HN, 117t Crucial, 229t Crude fiber, 158 Crushing capsules, 292, 293, 293t Crypt hyperplasia, 490f Crypt villus junction, 490f Cryptosporldia, 490f Cullen sign, 436
Current health status, 186 Curreri formula, 352 CWHD,368 CWHDF,368 Cyclic tube feedings, 244-245, 244t Cyclooxygenase pathway, 113 Cycloserine, 302t Cyclosporine, 475, 538t Cyproheptadine, 50, 493 Cysteine, 1211, 322t Cystic fibrosis (CF), 449 Cystine, 1211 Cytochrome c oxidase, 144 Cytokine inhibitors, 494 Cytokine patterns, 225 Daily caloric infusion, 19 Dangerous herbals, 258t Decliximab, 538t Declogging kits, 337 Deglutition, 12 Dehydration, 95 Deitch, Edwin A., 23 Dejong, C. H. C., 436 Delayed gastric emptying, 14, 19,245, 277-278 DeLegge, Mark H., 406 Deliver 2.0, 117t, 294t, 385t fi6-desaturase, 114, 115 Dementia, 411 Deutschman, Clifford S., 80 Dexamethasone, 303t Dexfenfluramine, 277t DHA, 61, 219, 234 Dhaliwal, Ruplnder, 224 DHLA,112 Diabetes, 498-505 carbohydrate metabolism, 498-499 cardiac surgery, 391 constipation, 500 diarrhea, 500 enteral formulations, 221 fecal incontinence, 500 gastroparesls, 499-500 gene expression, 41 glucose goals, 501 glucose testing, 502t glycemic management, 502-504 hyperglycemia, 500-501 hypoglycemia, 501, 504t Insulin, 503 nutrition assessment, 500 nutrition management, 501-502 parenteral nutrition, 502 pregnancy, 60 stress, 370 trauma patients, 370 tube feeding, 501-502 vitamin A, 41 wound healing, 176 Diabetic gastroparesis, 499-500 Diabetisource AC, 160t Diarrhea, 280-283 acute, 269 antibiotic-associated, 269 antldiarrhea medication, 283t cardiac surgery, 396t children, 328t dangerous medications, 28lt definitions, 245 diabetes, 500 enteral feeding, and, 245 fiber, 267 HEN,338t HIV infection, 489 HSCT, 545t, 551 incidence/etiology, 280-281
Diarrhea (Continued) ORS,168 osmotic, 217 SCFAs, 166, 168 treatment, 245-246, 281-283 tube feeding, 17 Diazepam, 297t Dicloxaclllin, 298t Dicyandiamide, 260 Dietary carbohydrates. 118 Dietary fat. 112-115 Dietary fiber, 17, 155-171 amount of, in food, 159t analytical methods, 157-159 benefits, 263 clinical studies, 167t, 168 composition, 156-157 defined, 155-156 enteral formulations, 218 feeding tubes, 168 fermentation, 159-161 intestinal transplantation, 526-527 liquid enteral formulas. 159, 160t Prosky method. 157-158 SCFAs. See Short-chain fatty acids (SCFAs). short bowel syndrome, 454 solubility, 158-159 Upssala method, 158 Dietary protein, 120 Dietary reference intakes (ORIs), 126, 127t, 253 Dietary Supplement Act, 251 Dietary Supplement Health and Education Act (OSHEA), 249, 251 Dietary supplements, 248-264 bioavailabillty. 253 clinician's role, 252-254 closing standards, 253 current usage, 249-250 dangerous herbals. 258t definitions. 248-249 efficacy/safety. 254-260 herbals, 258-260 legislation. 251 monographs, 254, 254t multivitamins, 256-258 nutrients, 256 nutrition support practice, 261-262 quality assessment programs, 254 regulatory issues, 250-252 Dietitian's role. 4 Digestion. 11. 12-13 Digoxin,28lt Dihomo-a-linoleic acid (OHLA), 112 Diphenhydramine, 297t Direct percutaneous endoscopic jejunostomy (OPEJ), 411 Disaccharides, 118 Distal duodenai placement, 205 Diuresis, 90 DME,306 DMEcompanies, 306 DMERC manuals and Information, 312t DNA. 32. See also Gene expression and nutrition. DNApolynucleotide chain, 33f Docosahexaenoic acid (DHA),61. 219.234 Domperidone, 442, 500 Dong quai, 258t Doxycycline. 298t DPEl,411 DRls. 126, 127t, 253 Dronabinol, 493
Index Drug-nutrient interactions, 291-303 avoiding incompatibles, 303 how avoided, 293t pharmaceutical incompatibility, 292-293 pharmacokinetic incompatibility, 296-302 pharmacologic incompatibility, 294-295 physical incompatibility, 291-292 physiologic incompatibility, 295-296 practice guidelines, 304t Drugs. See Medications. Drugs, administration through feeding tubes, 303-304 Druml, Wilfred, 471 DSHEA, 249, 251 Dual-energy X-ray absorptiometry, 531 Dumping syndrome, 14 Durable medical equipment (DME), 306 Dynamic hyperinflation, 425 Dysphagia, 407
EAR, 126 Early iron deficiency, 143 Ecchymosis of umbilicus, 436 Echtnacea, 259 Editing, 38 EFAD, 72, 112, 176, 285t EGF,455 EGFreceptor (EGFr), 455 Eicosanoid synthesis, 113, 115f Eicosanoids, 72, 112, 114 Eicosapentaenoic acid (EPA), 112,219,234 Elastase, 69t Elderly persons. See Aging. Electrolyte abnormality, 100-102 Electrolytes. See Fluid and electrolytes. Elemental formula, 366, 367t Elements, 36 Elixophyllin-GG, 298t Elongation, 37 Embryogenesis, 37 Endonucleases, 38 Endopeptidases, 68 Endoscopic retrograde cholangiopancreatography (ERCP), 446, 447 Endoscopic techniques, 206 Energy acute pancreatitis, 442t acute pulmonary disease, 419-420 animal species, 47-48 BEE,59 brain injury, 383-384 burns, 351-352 cardiac patients, 393 children, 319-320, 32lt chronic pancreatitis, 447-448 COPD,426-427 equations, 400t ERR, 59 FFM,399 obesity, 399, 400 PBEE,351-352 pregnancy, 58-59 REE,351,352,426t, 466 renal disease, 476 TEE,351 Ensure, 117t, 294t Ensure Fiber with FOS, 160t Ensure Plus, 117t, 294t Ensure Plus HN, 294t Ensure with Fiber, 117t Entera, 117t Entera lso, 117t Entera OPD, 117t Enteral access. See Access to Gl tract. Enteral feeding tube removal, 344
Enteral formula. See a/so Enteral formulations. BCAAs,469t brain injury, 385t HSCT, 554, 555-556 liver disease/transplantation, 535, 540,54lt obesity, 401-402 renal disease, 479-481 transplantation, 527t trauma patients, 366-367, 367t vitamin K content, 294t Enteral formulary, 222 Enteral formulations, 216-223. See a/so Enteral formula. carbohydrate, 218 carnitine, 220 chemically defined and elementary formulas, 221 choline, 220 enteral formulary, 222 fat, 218-219 fiber, 218 historical overview, 216-217 homemade formulas, 220 minerals, 220 nucleotides, 220 protein, 219 regulations, 217 special formulas, 221-222 standard polymeric formulas, 220-221 vitamins, 220 water, 217-218 Enteral intake monitoring, 287 Enteral nutrition, 243. See a/so Total enteral nutrition. Enteral nutrition suppliers, 306-307 Enteral Product Reimbursement Guide for Skilled Nursing Facilities and Homecare Providers, 307
Enteral tube site complications, 338-339 Enterocyte brush border oligosaccharidases, 120 Enteroglucagon, 455 Enterokinase, 15,68 Enteropeptidase, 69t Enterostomy tubes, 204t Enzymes, 69t EPA, 112,219,234 Ephedra, 258t Epidermal growth factors (EGFs), 455 Epithelium, 453 Equalyte, 160t ERCP, 446, 447 ERR,59 Erythromycin diarrhea, 28lt gastric emptying, 409 gut motility, 500 induced nutrient defects, 302t motilin release, 245, 278, 500 proximal peristalsis, 442 sorbitol, 298t Erythromycin ethylsuccinate, 298t Erythropoietin, 475 Esophageal and gastric cancer, 516-520 Esophageal cancer, 511 Esophageal dysphagia, 407 Esophagogastroduodenoscopy, 410 Esophagostomy tube, animal species, 51 Esophagus, 11-12 Essential amino acids, 120, 1211 Essential fatty acid deficiency (EFAD), 72, 112, 176, 285t Essential fatty acids, 72, 112 Estimated average requirement (EAR), 126 Estimated energy requirement (ERR), 59
563
Estrogen-containlng, 303t Ethical dilemma, 200 Euglycemia, 395, 498 Euglycemic hyperinsulinemia, 357 Euthyroid sick syndrome, 88 Exocrine insufficiency, 448 Exonucleases, 38 Extracellular calcium, 100 Extracellular fluid compartment, 96 Extracellular fluid volume, 97 Eye Disease Case Control Study, 133 Eye examination, 195, 196t Facilitated diffusion, 119 FAD,128 Famotidine, 297t Fat animal species, 48-49 children, 69-70, 7lt, 72-73 enteral formulations, 218-219 enzymes, 69t intestinal transplantation, 526 pregnancy, 60-61 wound healing, 176 Fat absorption, 15 Fat digestion, 12 Fat-free mass (FFM), 399, 427 Fat hydrolysis, 115 Fat intolerance, 14 Fatty acids acute pulmonary disease, 420 biosynthesis, 114f children, 72 classification, 111-112 dietary fat, 112-115 EFAD, 72, 112, 176, 285t essential, 112 fuel source, as, 116 gene expression, 38t Immune modulation, 116-118 LCFAs,111 MCFAs, III postprandial motility, 15 pregnancy, 60-61 PUFAs,111 SCFAs. See Short-chain fatty acids (SCFAs). schematic representation, 112f 3-<0, 112, 118, 219 6-<0, 112, 116, 117 wound healing, 176 FDACenter for Food Safety and Applied Nutrition, 252 Feeding pumps, 336-337 Feeding tube clogging, 211, 21lt, 337-338 Feeding tube patency, 168 Feeding tube removal, 344 Fermentation of dietary fiber, 159-161 Ferreira, Ivone Martins, 424 Ferritin, 38 Ferroxidases, 144 Fetal hypothyroidism, 149 FFM,399,427 FHF, 465, 465t Flber-contalnlng liquid enteral formulas, 159, 160t Fiber fermentation, 159 Fibers, 17. See also Dietary fiber. Fibersource, 117t Fibersource HN, 117t, 160t, 294t Fibersource Standard, 160t Fick equation, 419 Fish oils, 233-236, 239t. See also 0>-3 fatty acid-enriched diets. FK506,539t Flank ecchymosis, 436
564
Index
Flavin adenine dinucleotide (FAD), 128 Flavin mononucleotide (FMN), 128 Flavonoids, 376 Fluid and electrolytes, 95-109 calcium disorders, 107-108 chronic critical illness, 90 electrolyte abnormality, 100-102 fluid balance in health, 98t fluid compartments, 95-96 fluid disorders, 100 formulas, 97t gastrointestinal secretions, 98t homeostasis, 95-100 magnesium disorders, 105-106 phosphate disorders, 106-107 potassium disorders, 105 sodium disorder, 102-105 Fluid compartments, 95-96 Fluid disorders, 100 Fluoride, 64t, 77t Fluoroquinolones, 301-302 Fluoroscopic technique, 206 Flushing the feeding tube, 335 Folate, 130-131 ATBC study, 130 deficiency, 131 DRls, 127t elderly persons, 77t pregnancy,62t summary (overview), 134t Folate deficiency, 131 Folic acid supplementation, 63 Food, Drug, and Cosmetic Act, 251 Food folates, 131 Food sources aluminum, 153 arsenic, 151 boron, 151 calcium, 141 chromium, 148 copper, 145 iodine, 148-149 iron, 143 magnesium, 142 manganese, 149 molybdenum, 150 nickel, 152 selenium, 150 silicon, 152 vanadium, 152 zinc, 144 Food starches, 120 Food supplement, 249. See also Dietary supplements. Formula. See Enteral formula; Enteral formulations. Formula hang time, 337, 337t Formulary system, 222 Formulation, 253 Formulations, enteral. See Enteral formulations. Freeman, Lisa, 43 Fructoollgosaccharides, 218,267 Fructose, 118, 120 Fuhrman, Trlsh, 398 Fulminant hepatic failure (FHF'), 465, 465t Functional biomarkers, 126 Functional food, 249 Furosemide, 297t Galactose, 118, 120 Galacturonans, 157f GALT,25 Galveston formulas, 352 )'-butyrolactone (GBL),258t )'-hydroxybutyrate (GHB), 258t )'-tocopherol, 136
Garlic,259 Gastric atony, 277 Gastric cancer, 516-520 Gastric digestion, 12-13 Gastric emptying, 13-14, 19, 277 Gastric feeding, 411 Gastric lipase, 12, 69, 69t Gastric lipolysis, 12 Gastric proteases, 12 Gastric proteolysis, 12 Gastric residual volume (GRV), 14,277-278 Gastric retention, 245 Gastric sieving, 12 Gastrin, 454 Gastroesophageal reflux (GER), 279,408 Gastroesophageal regurgitation and aspiration, 278-280 Gastrointestinal complications, 276-277 Gastrointestinal graft-versus-host disease, 549-550 Gastrointestinal motility, 407-408, 408t Gastrointestinal secretions, 98t Gastrointestinal (GI) tract, 11, 98 Gastroparesls, 20 cause, 14,408 critically ill patients, 245 diabetes, 277, 499-500 head trauma, 245 neurological diseases, 408 Gastroparesls dlabencorum, 499 Gastroschisis, 452 Gastrostomy, 205t Gastrostomy button, 210 Gastrostomy tube animal species, 51-52 HSCT,555 placement, 208 GBL,258t Gel formation, 164 Gene expression and nutrition, 32-42 DNAcharacteristics, 35 mutation us. polymorphisms, 34-35 nutrient-gene interactions, 40-41 protein synthesis, 32-34 transcription, 35-38 translation, 38-40 Gene expression pathway, 36f Genes, 32 GER, 279, 408 Geriatrics. See Aging. Germander, 258t Germanium, 258t Gestational weight gain, 58 GH,84, 421, 429t, 432 GHB,258t GHRH,88 GHRP,88 GI GVHD, 549-550 GI motility, 409, 409t GI tract, 11, 98 GIK, 391-392 G1K Infusion, 391-392 Ginkgo (Ginkgo blloba), 258t Ginseng, 259 GLP-2,455 Glucagon,82,277t Glucerna, 117t, 160t Glucerna Shake, 160t Glucoamylase, 69t Glucokinase, 37 Gluconeogenesis, 82, 176 Glucosamine, 260 Glucose acute stress response, 82 diabetes, 50 I, 502t excess, 120
Glucose (Continued) gene expression, 38t lactase activity, 118 liver disease/transplantation, 534 wound healing, 175-176 Glucose-Insulin-potassium (GIK), 391-392 Glucose Intolerance, 82, 118, 284t Glucuronoarablnoxylans, 157f Glucuronoxylans, 157f Glutamic acid, 1211 Glutamine, 12l! acute pancreatitis, 442-443 burns, 354 cardiac patients, 392 chemical formula, 12l! critically ill children, 322t functions, 232 short bowel syndrome, 454 Glutamine-supplemented diets, 232-233, 239t Glutamine synthetase, 82 Glutathione, 468 Glutathione peroxidase, 376 Glycemic management, 502-504 Glycerol, 83 Glycine, 1211 Glytrol, 160t Goiter, 149 Good manufacturing practices (GMPs), 251 Graft-versus-host disease (GVHD), 545-546, 549-550 Graft-versus-Ieukemla (GVL) effect, 547 Gravity feedings, 336 Greve, J. W. M., 436 Grey-Turner sign, 436 Growth hormone (GH), 84, 421, 429t, 432 Growth hormone-releasing hormone (GHRH),88 Growth hormone-releasing peptide (GHRP), 88 GRV, 14,277-278 Guaifenesln, 297t, 298t Guar, 164 Guenter, Peggt, 3 Gupta, Dlpin, 110 Gut, 23 Gut-associated lymphoid tissue (GALT), 25 Gut barrier, 24 Gut barrier function nad failure, 23-31 bacterial translocation, 25-26 gut-origln sepsis, 30f human studies, 29 mesenteric lymphatic vessels, 29-30 MODS, 29, 30f nutrition, 26-28 physiology, 23-25 strengthening gut barrier, 165 Gut failure, 226 Gut immune system, 266 Gut-Induced MODS, 29 Gut-origln sepsis, 30f Gut peptides, 15 GVL effect, 547 Hair, 194, 195t Han, Myeongslk, 140 Han-Markey, Theresa L., 68 Hang times (enteral formulas), 337, 337t Harris-Benedict equation, 351, 386, 400t, 417, 419,447 Hasse, Jeanette, 530 Hatton, Jimml, 381 HDLs,110 HE, 222. See also Acute hepatic dysfunction. Head and neck cancer, 509-515 Head/neck, 194-195, 195t
Index Health Professionals Follow-up Study, 133 Heart, examination of, 196-197, 197t Hemachromatosis, 143 Hematopoietic stem cell transplantation (HSCT) Bearman grades, 548t candidates for tube/gastrostomy feeding, 555 conditioning regimen-related toxicities, 547-549 conditioning therapy, 545 cost, 554 delayed gastric emptying, 551 diarrhea, 551 diseases treated by HSCT, 545t enteral feeding, 551-556 feeding schedule, 556 formulas, 554, 555-556 gastric leakage, 554 GIGVHD, 549-550 GIsymptoms, 545t goals of therapy, 556 GVHD, 545-546 GVL effect, 547 infections, 554 nutrient needs, 556 nutrition support, 550-551 steps in process, 544, 546t TPN,544 Hemicellulose, 156, 157f HEN. See Home enteral nutrition (HEN). Hepatic-Aid II, 117t, 469t Hepatic encephalopathy (HE), 222, 533. See also Acute hepatic dysfunction. Hepatic failure formula, 222 Herbal medicine, 249 Herbals, 258-260 Herbs, 249 Heyland, Daren K., 224 hGH,455 High-density lipoproteins (HDLs), 110 Hippocrates, 3, 464 Hise, Mary, 57 Hisidine, 12lt Histones, 35 Historical overview, enteral formula development, 216-217 History. See Nutrition-focused history. HIV, 271 HIV infection, 271, 486-497 adjunct therapies, 494-495 appetite stimulants, 493 diarrhea, 489 enteral nutrition, 492-493, 494t food intake, 488, 489t macronutrients, 486-487 malabsorption, 489, 492t malnutrition, 486, 488-491 metabolic alterations, 489-491 micronutrients, 487-488 nolvolitional feeding, 493-494 nutritional support, 491 oral enteral supplements, 492-493 TPN, 493-494 Home enteral nutrition (HEN), 332-346 administering medications, 337 care of enteral tubes, 334, 335 care planning, 339 caregiver aspects, 344 complications, 337-339 enteral feeding tube removal, 344 enteral tube site complications, 338-339 feeding administration, 336-337 feeding intolerance, 338 feeding tube clogging, 337-338 feeding tubes, 335 flushing the feeding tube, 335
Home enteral nutrition (HEN) (Continued) formula hang time, 337, 337t formula selection, 335 gastric residual volume, 335-336 gravity feedings, 336 home Infusion provider, 333 monitoring, 339 outcomes, 344-345 patient assessment, 333 patient education, 333-334, 334t patient selection, 332-333 patient showers, 335 pumps, 336-337 quality of life, 345-346 reimbursement, 306-316. See also Home enteral nutrition reimbursement. syringe bolus, 336 transitioning to oral intake, 339, 344 U. of Michigan care plan, 340-343t Home enteral nutrition reimbursement, 306-316 appeals process, 313, 315 certificate of medical necessity (CMN), 310f,313 checklist to determine Medicare eligibllity, 314f DMERC manuals and information, 312t enteral nutrition suppliers, 306-307 equipment, 312-313 IC0-9 codes, 308-309t indications for HEN, 307-309 Medicare, 309-312, 314f Medicare product classification, 311-312 nutritional support practitioners, 315 professional (physician) services, 313 skilled nursing facilities, 307 verification of eligibility and coverage, 307 Home infusion provider, 333 Homemade formulas, 220 Homeostasis hypothesis, 265-266 How avoided, 293t HPA axis, 87 HSCT. See Hematopoietic stem cell transplantation (HSCT). Human Genome Project, 32 Human growth hormone (hGH), 455 Human immunodeficiency virus. See HIV Infection. Hunter, John, 3 Hurley, Daniel L., 498 Hydralazine, 28lt Hydrochlorothiazide, 297t Hydrogen bonding, 33 Hydrolized soy protein, 17 Hydrophobic amino acids, 122 Hydroxyapatite, 140 Hygieia,3 Hyperacute hepatic failure, 465 Hypercalcemia, 108, 141, 295t Hypercapnia, 285t Hyperglycemia, 82, 97t, 176, 287, 295t, 370, 403,421,500-501 Hypericum perforatum, 259 Hyperinflation, 425 Hyperinsulinemia, 60 Hyperkalemia, 105, 285t, 295t Hyperlipidemia, 104,402 Hypermagnesemla, 106, 143, 295t Hypermetabolism, 417 Hypernatremia, 90, 102-103, 103f, 285t, 295t Hyperoxaluria, 459 Hyperparathyroidism, 89 Hyperphosphatemla, 90, 107, 142, 285t, 295t Hypertension, 403 Hypertonic dehydration, 284t Hypertonic medications, 295, 296t Hypertrlglycerldemia, 295t, 402
565
Hypervitaminosis 0, 136 Hypervolemia, 100 Hypervolemlc hypernatremia, 103 Hypervolemic hyponatremia, 104 Hypoalbuminemia, 97t, 199,281 Hypocalcemia, 107-108, 141, 295t, 433 Hypocaloric nutritional support, 400-401 Hypoglycemia, 285t, 295t, 466, 501, 504t Hypogonadism, 89, 489 Hypokalemia, 105, 284t, 295t, 433 Hypomagnesemia, 105-106, 107f, 285t, 295t, 433 Hyponatremia, 90, 103-104, 104f,295t Hypophosphatemia, 90, 106, 142, 285t, 295t, 417,433 Hypoproteinemia, 100 Hypothalamus-pituitary-adrenal (HPA) axis, 87 Hypotonic hyponatremia, 104 Hypovolemia, 100, IOlt Hypovolemic hypernatremia, 103 Hypovolemic hyponatremia, 104 Hypozincemia, 285t IBD,271-272 Ibuprofen, 297t IBW,187 IC0-9 codes, 308-309t ICU-acquired paresis (lCUAP),90 ICUAP,90 Ideal body weight (lBW), 187 lED. See Immune-enhancing diet (lED). IgA, 25, 46 IGF, 84, 455 IGF-l,84,357,427,455 IGF-I-IGFBP-3,357 IGF-2,455 IGFbinding protein-3 (lGFBP-3), 357 Ileal brake, 16 Ileocecal junction, 18 Ileocecal valve, 524 Ileostomy, 105 Illegal drug use, 189 Immun-Aid, 117t, 229t Immune dysfunction, 403 Immune dysregulation, 226 Immune-enhancing diet (lED) sepsis, 374-376 terminology, 224 trauma patients, 365-366, 367t Immune-enhancing diets, 224 Immune system, 225-226 Immunonutrition, 224-242 antioxidants strategies, 236-238 arginine-supplemented diets, 228-232 fish oils, 233-236 glutamine-supplemented diets, 232-233 gut failure, 226 immune system, 225-226 ROS, 226, 236 scientific basis, 225-228 summary/discussion, 238-239 terminology, 224 Impact, 117t, 229t Impact Recover, 229t Impact with Fiber, 160t Imuran, 538t IncompatibilIty of drugs. See Drug-nutrient interactions. Indigenous intestinal microflora, 24 Indirect calorimetry, 399 Inducible form of NOS(iNOS), 175, 375 Infection fiber, 267 wound healing, 178-179 Inflammatory bowel disease (lBD), 271-272
566
Index
Initiation of enteral nutritional support, 243-246 iNOS, 175, 375 Insulin, 503 Insulin-like growth factor (IGF), 84, 455 Insulin-like growth factor-I (IGF-l), 357 Insulin resistance, 267 Intact protein, 219 IntensiCal, 229t Interleukin-l,277t Intermediate end points, 224 Intermittent gravity drip tube feeding, 244, 244t Intestinal adaptation, 452 Intestinal epithelium, 24 Intestinal immune system, 25 Intestinal mucosal trophism, 162 Intestinal transplantation, 523-529 anthropometric assessment, 524 biochemical tests, 525, 525t carbohydrate, 526 enteral formulas, 527, 527t enteral nutrition, 526 fat, 526 feeding history, 525 fiber, 526-527 future goals, 528 indication of, 523-524 macronutrlent requirements, 525 nutritional implications of intestinal failure, 524 physical examination, 524 PN,525-526 post-transplant nutrition management, 527-528 protein, 526 Intestinal xanthine oxidase, 26 Intracellular fluid compartment, 95 Intradialytic enteral nutrition, 483 Intravascular space, 96 Introns,33 Inulins, 218 Iodine, 148-149 deficiency/toxicity, 149 food sources, 148-149 function, 148 pregnancy.Bet summary (overview), 147t Iodine deficiency, 149 Iodine supplementation, 149 lonescu, Gabriel, 486 Ireton-Jones equation, 400t Iron, 143-144 critically ill children, 323t deficiency/toxicity, 143 food sources, 143 function, 143 gene expression, 38t liver disease/transplantation, 535t, 540t old age, 78 pregnancy, 64t renal disease, 475 summary (overview), 146t wound healing, 178 Iron deficiency, 143 Iron overload, 143 Iron toxicity, 143 Isocal, 117t, 294t Isocal-HCN,467 Isocal HN, 117t, 294t, 385t Isoenzyme nitric oxide synthases (NOSs), 175 Isoleucine, 12lf, 219, 468 Isomaltase, 118 IsoSource 1.5, 117t, 160t, 294t IsoSource HN, 117t, 294t IsoSource Standard, 294t
Isotein HN, 117t Isotope nitrogen studies, 71 Jejunal brake, 16 Jejunal feeding rate, 19 Jejunal perfusion, 20 Jejunostomy, 205t, 209-210 Jejunostomy feeding, 411 Jejunostomy-related complications, 370 Jejunostomy tube, 52 Jejunum, 453, 524 Jensen, Gordon, 75 Jevity, 117t, 294t, 326t Jevity 1 Cal, 160t Jevlty 1.2 Cal, I60t Jevity 1.5 Cal, I60t Jevity Plus, 294t Jung, Hans-Joachim G., 155 Kanamycin, 302t Kaolin, 283t Kashln-Bek disease, 151 KCI,303t Keshan disease, 151 Ketosis, 60, 82 Kidney disease. See Renal disease. Kindercal with Fiber, 160t Kotler, Donald P., 486 Kovacevich, Debra 5., 332 Kowalski, Lori, 523 Kozar, Rosemary A., 364 Kwashiorkor-like malnutrition, 86 L-arginine,375, 376. See also Arginine. L-Emental Hepatic, 469t LAB, 266, 268 Laboratory findings, 199 Lactase, 69t Lactation. See Pregnancy and lactation. Lactic acid bacteria (LAB), 266, 268 Lactobacillus, 165 Lactobacillus casei, 268 Lactobacillus GG (LGG), 269 Lactobacillus rhamnosus, 268 Lactose, 118, 120 Lactulose, 281t, 534 Laparoscopic gastrostomy jejunostomy, 208 Laplace's law, 425 Laryngeal cancer, 511 Lb. plantarum, 268 LCFAs, 111, 116 LCTs, 112, 116,219,469 LDLs,110 Lean body mass-to-fat ratio, 95 Lenssen, Polly, 544 Leucine, 69, 12lf, 219, 468 Leukotriene B4, 114 Levodopa, 277t Levofloxacin, 301 LGG,269 LH,89 LH-releasing hormone (LHRH), 89 Ligand binding, 37 Lignin, 156-157 Lin, Henry C., 11 linolenic acid, 112 children, 7lt, 72f, 73 dietary fat, 112, 114 enteral formulation, 219 metabolic pathways, 72f pregnancy, 61 wound healing, 117 Lipase-collpase, 69t Lipid, 110-118 acute pancreatitis, 442t acute stress response, 83 biochemistry. See Fatty acids.
Lipid (Continued) body, 110-111 liver disease/transplantation, 534, 537 renal disease, 474 structured, 116,219 Lipid metabolism, 77, 402-403 Lipisorb, 117t Lipodystrophy, 486 Lipolysis, 15, 16,83 Lipooxygenase pathway, 113 Lipoproteins, 110 Liquid enteral formulas, 159, 160t Lithium, 277t Liver, 122,464,465. See also Acute hepatic dysfunction; Chronic liver disease and transplantation. Liver transplantation, 270-271. See also Chronic liver disease and transplantation. Load-dependent inhibition of gastric emptying, 13-14 Lobelia, 258t Local structural lesions, 407t Lomotil, 283t Long-chain fatty acids (LCFAs), 111, 116 Long-chain triglycerides (LCTs), 112, 116, 219,469 Loperamide, 283t, 297t, 442, 458 Loracarbef, 298t Lorazepam, 297t Lord, Linda, 185 Low-density lipoproteins (LDLs), 110 Low-profile gastrostomy device, 210 Luteinizing hormone (LH), 89 Lysine, 12lf Lysyloxidase, 144,178 Ma huang, 258t Macronutrient digestive enzymes, 69t Macronutrients, 110-125. See also individual subject headings. carbohydrate, 118-120 children, 70 critically ill children, 319-322 elderly persons, 76-78 HlV infection, 486-487 intestinal transplantation, 525 lipid, 110-118 protein, 120-123 Macule, 192, 192f Magnacal, 117t Magnacal Renal, 48lt Magnesium, 142-143 amount of, In body, 99 critically ill children, 323t deficiency/toxicity, 142-143 dosage range, 102t elderly persons, 77t electrolyte abnormality, lOIt food sources, 142 function, 142 liver disease/transplantation, 535t, 540t pregnancy, 64t renal disease, 474-475 summary (overview), 146t wound healing, 178 Magnesium-containing preparations, 28It Magnesium depletion, 142 Magnesium disorder, 105-106 Magnotti, Louis 1., 23 Major histocompatibility complex class II (MHC-II), 375 Malnutrition assessment tools, 417 cardiac surgery, 395, 396t characterization, 426t chronic critical illness, 86
Index Malnutrition (Continued) chronic kidney disease, 471 chronic liver disease, 531, 533t COPD, 424, 425 effects of, 414, 418, 418t gene expression, 36, 38 hepatic failure, 466 HIV infection, 486, 488-491 kwashiorkor-like, 86 liver transplantation, 533t metabolic syndrome, 266 renal disease, 471, 478 symptoms, 36 Malone, Ainsley, 276 Mammals. See animal species. Manganese chemistry, 149 deficiency/toxicity, 149 food sources, 149 function, 149 liver disease/transplantation, 540t metabolism, 149 monitoring, 150 pregnancy, 64t nutritional requirements, 147t Manganese deficiency, 149 Manganese toxicity, 149 Mannan, 156, 157! Marik, Paul E., 373 Marinol, 493 Maslow's hierarchy's of needs, 186 Maternal ketosis, 60 MCFAs. Ill, 116 McMahon, M. Molly, 498 McQuiggan, Margaret M., 364 MCTs. See Medium-chain triglycerides (MCTs). Meconium ileus, 452 Medical ethics, 200 Medicare, 309-312, 314f Medicare product classification, 311-312 Medications acute pulmonary disease, 418 diarrhea, 28lt, 283t history, 188 hypertonic, 295, 296t liver disease/transplantation, 538-539t Medium-chain fatty acids (MCFAs), 111,116 Medium-chain triglycerides (MCTs) acute hepatic dysfunction, 469 brain/spinal cord injuries, 384 enteral formulas, 218, 219 fuel source, as, 116 HIV, 492 intestinal transplantation, 526 where found, 113 Megace, 493 Megestrol acetate, 432, 493 Melatonin, 260 MELD score, 531 mEq/L,95 Mercury manometer, 191 Mesenteric lymphatic vessels, 29-30 Metabolic acidosis, 473 Metabolic bone disease, 90 Metabolic complications, 284-285 Metabolic profile, 246 Metabolic resuscitation, 226 Metabolic syndrome, 266 Metformin, 303t Methionine, 12lf Methods of delivery, 244-245 Methotrexate, 28lt, 302t Methyldopa, 302t Methylmalonic acid, 132 Methylprednisolone, 538t
Metoclopramide, 245, 278, 28lt, 297t, 409, 500 Metoclopramide (Reglan) syrup, 291 Metronidazole, 459 mg/dL,95 MHC-II,375 Micelles, 115 Michel, Kathryn E., 43 Microcytic hypochromic anemia, 143 Microinflammation, 473 Micronutrients, 420. See also Minerals. acute pancreatitis, 442t animal species, 49 critically ill children, 322, 323t H[V infection, 487-488 old age, 78 renal disease, 475, 477 wound healing, 178 Microsporidlosis, 490f Migrating motor complex (MMC), 18 Milk amylase, 69t Milk bile salt-dependent lipase, 69t Milk proteins, 69 Mineral oil, 303t Minerals. See also Micronutrients; Indlvldual minerals. calcium, 140-141 copper, 144-145 critically ill children, 323-324, 323t enteral formulations, 220 iron, 143-144 liver disease/transplantation, 534, 535t, 540t magnesium, 142-143 phosphorus, 141-142 pregnancy, 63-66 sulfur, 145 zinc, 144 Mitch, William E., 471 Mitochondria, 32 Mitochondrial DNA, 35 Mitochondrial DNA map, 34f Mitochondrial genome, 33 Mixed micelles, 15 MMC, 18 mmol/L,95 Mobarhan, Sohrab, 464 Model for End-Stage Liver Disease (MELD) score, 531 MODS, 29, 30f, 80, 84 Molybdenum, 64t, 147t, 150 Monitoring, 245-246. See also Complications. acute pulmonary disease, 421 brain injuries, 385-386 cardiac surgery, 395 children, 327-328 chronic pancreatitis, 449 complications, for, 286t, 287 enteral intake, 287 head and neck cancer, 514 HEN,329 nutritional efficacy, for, 287, 288t spinal cord injuries, 387 Monitoring frequency, 287 Monoamine OXidase, 144 Monosaccharides, 118 Moore, Frederick A., 364 Motilin, 278 Mouth, 11-12 Mouth, examination of, 195-196, 197t mRNAsynthesis, 35 Mucosal growth, 267 Mucosal hyperplasia, 162 Multiple hit phenomenon, 26f Multiple organ dysfunction syndrome (MODS), 29, 30f, 80, 84
567
Multivitamins, 256-258 Muromonab-CD3, 539t Musculoskeletal systems, 198-199 Mutation, 34 Mycophenolate mofetil, 539t Myo 01, 37 N-acetylcysteine, 237 N-o>-L-arginine, 376 Na' absorption, 119 Na'-K'-ATPase pump, 96, 99 NAD, 128-129, 129 NADP, 129 Nails, 193, 194t Naproxen, 297t Nasa[tubes, 204-210,204t, 211 NASH, 272, 531 Nasoenteric tube placement, 204-206 Nasoesophageal tube, 51 Nasogastnc tube placement, 204 National Center for Complementary and Alternative Medicine, 252 Natural herbal remedies, 188 Neck, examination of, 194-195, 195t Needle-catheter jejunostomy, 210 Neligan, Patrick, 80 Neocate, 527t Neocate Junior, 527t Neomycin, 28lt, 302t Neoral, 538t Nephrolithiasis, 133 Nepro, 160t, 48lt Neurologic diseases, 406-413 aspiration of oropharyngeal secretions, 410 background, 406 chronic diseases, 406-411 dysphagia, 407 ethics, 411 factors to consider, 409 gastric us. jejunal feeding, 411 gastroesophageal reflux, 410 G[ dysfunction, 407-409 levels of consciousness, 409 new access devices, 411 PEG tubes, 407, 409-411 short- us. long-term enteral access, 410 swallowing function, 410 TPN,406 Neurologic systems, 198-199 Neuromuscular diseases, 407t Neutral detergent fiber, 158 Newtrition I & 1/2, 117t Newtrition HN, 117t Newtrition [so, 117t Newtrition lsoflber, 117t NF-lCB,375 NHANES II, 133 NHANES III, 137 Niacin, 129 deficiency/toxicity, 129 ORIs, 127t elderly persons, 77t pregnancy, 62t summary (overview), 134t Niacin deficiency, 129 Niacin toxicity, 129 Nickel, 147t, 152 Nicotinamide adenine dinucleotide (NAD), 128-129, 129 Nightingale, Florence, 3 NIPPV,415, 416, 418 Nitric oxide, 26 Nitric oxide (NO), 175, 228, 374-376, 454 Nitrofurantoin, 297t Nitrogen balance, 71, 199,420 NO, 175, 228, 374-376, 454
568
Index
NOsynthase (NOS) isoforms, 375 NOBN,370 Non-nutritive supplements. See Dietary fiber. Non-VVN losses, 199 Nonalcoholic steatohepatitis (NASH), 272, 531 Nonessential amino acids, 120, 1211 Noninvasive intermittent positivepressure ventilation (NIPPV), 415, 416, 418 Nonocclusive bowel necrosis (NOBN), 370 Nonplant-based products, 188 Nonprotein nitrogen compounds, 72 North American Home Parenteral and Enteral Registry, 344-345 NOSs, 175 Nova Source Renal, 48lt NovaSource 2.0, 294t NSS, 3,5 NuBasics 2.0, 294t Nucci, Anita, 523 Nuclear DNA, 32 Nucleotides, 72, 220 Nunnally, Mark, 80 Nurse's role, 4 Nutraceutical, 249 Nutren 1.0, 117t Nutren 1.0 with Fiber, 117t, 160t Nutren 1.5, 117t Nutren Junior with Fiber, 160t Nutren Products, 294t Nutrient-dense liquid meals, 13 Nutrient-regulated gastric emptying, 13 Nutrient-regulated intestinal motility, 16-18 Nutrients, 256 NutriFocus, 160t NutriHep, 469t Nutrition-focused history, 185-189 alternative therapies, 188 anthropometric data, 187 bowel pattern, 189 complete medical foods, 187 current health status, 186 diet, 187 enteral access device, 188 food allergies/intolerances, 189 habits, 189 medical diagnoses, 187 medication allergies/intolerances, 189 medications, 188 nonplant-based products, 188 oral fortified foods, 187 pain assessment, 189 parenteral device, 188 psychosocialcultural review, 186 surgical procedures, 187 TPN,188 unproven herbal products, 188 vitamins/trace elements, 189 Nutrition-focused physical examination, 189 abdomen, 197-198, 198t blood pressure, 191-192 chest/heart, 196-197, 197t equipment, 190 eyes, 195, 196t general survey, 190 hair, 194, 195t head/neck, 194-195, 195t mouth/throat, 195-196, 197t musculoskeletal/neurologic systems, 198-199 nails, 193, 194t pulse rate, 191 respiratory rate, 191 review of systems, 189-190 skin, 192-193
Nutrition-focused physical examination (Continued) symptoms to look for, 189 temperature, 191 vital signs, 191 Nutrition Labeling and Education Act, 217,251 Nutrition support physician, 4 Nutrition support services (NSS),3, 5 Nutrition support team defined,4 dietitian, 4 editor's note, 7-8 goals, 4 impact of, on patient care, 5-6 nurse, 4 pharmacist, 4 physician, 4 purpose, 4, 8 Nutritional melalgia, 130 Nutritional monitoring, 287 Nutritional supplement, 249. See also Dietary supplements. Obesity, 398-405 classification, 398t co-morbidities, 399t complications, 402-403, 402t energy, 399, 400 formula selection, 401-402 hyperglycemia, 403 hypertension, 403 hypocaloric nutritional support, 400-401 immune dysfunction, 403 lipid metabolism, 402-403 liver disease/transplantation, 531-532 nutritional assessment, 399-400 respiratory compromise, 403 tube placement, 401 wound healing, 403 Octreotide, 283t Office of Dietary Supplements (ODS), 252 Ofloxacln, 301 OFR,236 OKT3,539t Old age. See Aging. Oleic acid, 17 OIey Foundation, 344 Oligofructans, 266 Oligosaccharides, 118, 157 ro-3 fatty acid-enrlched diets, 233-236, 239t acute lung injury/acute respiratory distress syndrome, 234-236 burns, 236 clinical recommendation, 236 postsurgical stress, 236 scientific rationale, 233-234 ro-3 fatty aclds, 112, 118,219 ro-6 fatty acids, 112, 116, 117 Omeprazole, 277t Omphalocele, 451 Ondansetron, 277t Open gastrostomy, 208-209 Ophthalmoscopic examination, 195, 196f Opiates, 277t Optimental, 1601, 229t Oral-anal transit time, 164 Oral cancer, 511 Oral rehydration solution (ORS), 168 Oropharyngeal dysphagia, 407, 407t Orphan Drug Act, 217 ORS,168 Osler, Sir William, 177 Osmolite, 117t, 294t Osmolite HN, 117t, 294t, 326t Osmolite HNPlus, 294t Osmotic diarrhea, 217
Osteopenia, 141,534 Osteoporosis, 141 Over the wire (Sacks-Vine) technique, 207 Overfeeding, 86 Overhydration, 284t Oxandrolone, 358, 370, 468 Oxepa, 236, 326t Oxidant peroxynltrite, 26 Oxidative stress, 493 Oxygen free radical (OFR), 236 P. ovata, 165 p-Aminosalicylic acid, 303t Pain assessment, 189 Palpation, 198 Panacea, 3 Panax ginseng, 259 Panax qulnquefolius, 259 Pancreatic amylase, 69t Pancreatic cancer, 516-520 Pancreatic enzyme replacement, 448 Pancreatic lipase, 69t Pancreatic proteolytic enzymes, 121 Pancreatic pseudocyst, 448-449 Pancreatitis. See Acute pancreatitis; Chronic pancreatitis. Pantothenic acid, 129-130 deficiency/toxicity, 130 ORIs, 127t eiderly persons, 77t pregnancy, 62t summary/overview, 134t Pantothenic acid deficiency, 130 Papule, 192, 193f Paracetamol, 393, 393f Parathyroid hormone (pTH), 90 Paregoric Opium tincture, 283t Parenteral nutrition. See Total parenteral nutrition (fPN). Parenteral nutrition (PN), 440. See also Total parenteral nutrition (fPN). Park, Julie E., 172 Partial villus atrophy, 490f Passive diffusion, 119 Patient education, 333-334, 334t Patient monitoring. See Monitoring. Patients with sepsis, 373-380 antioxidants, 376 lED,374-376 nutrient composition, 374 permissive underfeeding, 376-377 route of feeding, 373-374 time of feeding, 374 PBEE, 351-352 Pectic polysaccharides, 156 Pectin, 156, 157f, 158, 267, 283t Pedlasure, 117t, 326t PediaSure Enteral Formula with Fiber, 160t Pediatrics. See Children; Critically ill pediatric patient. PEG, 206-207 PEG/J,411 PEG-jejunostomy tube, 207 PEGtube, 407,409-411,479,514 Pellagra, 129 Penicillamine, 281t Penicillin VK, 298t Pennick, Victoria, 433 Pennyroyal, 258t Pentobarbital, 382 Pentoxlfylline, 494 Pepdite One Plus, 527t Pepsin, 68, 69t Pepslnogena, 68 Peptamen, 117t Peptamen Junior, 527t Peptamen with Prebio, 160t
Index Peptic ulcers, 267 Peptide-based formulas, 221 Peptide hydrolases, 122 Peptide YV, 455 Peptinex DT, 527t Perative, 160t, 294t Percent Daily Value (%DV), 253 Percussion, 198 Percutaneous endoscopic gastrojejunostomy (pEGfJ), 411 Percutaneous endoscopic gastrostomy (pEG), 206--207 Percutaneous endoscopic gastrostomy (pEG)tube,407,409-411,479,514 Percutaneous endoscopic gastrostomyjejunostomy, 207 Percutaneous endoscopic jejunostomy, 207 Percutaneous fluoroscopic gastrojejunostomy, 208 Percutaneous fluoroscopic gastrostomy, 207 Periconceptual folic acid supplementation, 63 Peristalsis, 12 Permissive underfeeding, 376--377 Peroxynitrite, 375 Pharmaceutical incompatibility, 292-293 Pharmacist's role, 4 Pharmacokinetic incompatibility, 296--302 Pharmacologic incompatibility, 294-295 Pharmaconutrition regimens, 239 Pharmacotherapeutic issues, 291-305 administration of drugs through tubes, 303-304 drug-nutrient interactions, 291-303. See also Drug-nutrient interactions. vitamin/mineral/electrolyte deficiencies, 302 Pharyngeal cancer, 511 Phenobarbital, 297t, 302t Phenothiazine, 277t Phenylalanine, 1211 Phenytoin, 297t, 300, 302t, 382 Phosphate, 90 dosage range, 102t electrolyte abnormality, lOit nucleic acid production, 90 renal disease, 474 Phosphate disorders, 106--107 Phosphatidylcholine, Ill, 131 Phospholipids, III Phosphorus, 141-142 amount of, in body, 99 critically ill children, 323t deficiency/toxicity, 142 elderly persons, 77t function, 141 liver disease/transplantation, 535t, 540t pregnancy, 64t summary (overview), 146t Phylloquinone, 138 Physical examination. See Nutrition-focused physical examination. Physical fragmentation, 12 Physical incompatibility, 291-292 Physician's role, 4 Physiologic incompatibility, 295-296 Phytomedicine, 249 Pierson, Richard N., Jr., 495 Pigtail catheters, 213 Placement of access port. See Access to Gl tract. Plantago ovata, 165 PLP, 130 PN, 440. See also Total parenteral nutrition (fPN). Polyamines, 454 Polyenylphosphatidylcholine (PPC), 468
Polymeric high-protein formula, 366, 367t Polymorphlsms, 35 Polysaccharides, 118, 156, 157f Polysomes, 39 Polyunsaturated fatty acids (pUFAs), III Ponsky technique, 207, 208f Postperfusion syndrome, 390 Postprandial hyperglycemia, 60 Postprocedure initiation of enteral feeding, 210-211 Postpyloric tube feeding, 419 Potassium, 96 amount of, In body, 98t, 99 dosage range, 102t electrolyte abnormality, lOit gastrointestinal secretions, 98t gene expression, 38t liver disease/transplantation, 535t renal disease, 474 Potassium disorders, 105 PPC, 468 PRE,494 Prealbumln, 199,246 Prebiotics, 266--267 Predicted basal energy expenditure (PBEE), 351-352 Prednisolone, 538t Prednisone, 303t, 538t Pregestlmll, 527t Pregnancy and lactation, 57-67 amino acids, 60 carbohydrate, 59-60 energy, 58-59 fat,6D-61 maternal nutritional needs, 58 minerals, 63-66 protein, 60 vitamins, 61-63 weight gain, 58, 58t Prelack, Kathy, 317 Prenatal weight gain, 58 Primadone, 297t Primary graft nonfunction, 531 Primidone, 302t ProBalance, 160t, 294t Probiotics, 218, 267, 269, 459 Procainamide, 28it Progesterone, 277t Prograf, 539t Progressive dysphagia, 407 Progressive liver disease, 272-273 Progressive resistance exercise (PRE), 494 Project IMPACT, 86 Prokinetic agents, 278 Pro kinetic macrolide, 442 Proline, 1211 Prolonged critical illness. See Chronic critical illness (CCI). Prolonged TPN, 200 Promote, 326t Promote with Fiber, 160t Promotility agents, 419 Propofol, 277t Prosky method, 157-158 ProSure, 160t Protain XL, 160t Protein acute pancreatitis, 442t acute pulmonary disease, 420 acute stress response, 82 amino acids. See Amino acids. animal species, 48 brain injuries, 384-385 burns, 354 cardiac patients, 393 children, 68-69, 70-72 critically ill children, 320-322, 322t
569
Protein (Continued) digestion, 15 elderly persons, 77 enzymes, 69t gene expression, 32-34 intact, 219 intestinal transplantation, 526 laboratory findings, 199 lateral formulations, 219 liver disease/transplantation, 534-535,537 pregnancy,60 renal disease, 472-473, 476 short bowel syndrome, 453-454 soy, 17 wound healing, 173 Protein synthesis, 38 Protein wasting, 83 Proteolytic enzymes, 121 Pseudomucin, 267 Pseudoplantarum, 268
Psychosocialcultural review, 186 Psyllium, 164 PTH,90, 100, 141 PUFAs, III Pull (ponsky) technique, 207, 208f Pulmocare, 117t Pulmonary cachexia, 425 Pulmonary diseases. See Acute pulmonary disease. Pulmonary failure formula, 222 Pulse rate, 191 Pumps, 336--337 Pure Food & Drug Act, 251 Purines, 220 Push (Russell) technique, 207 Pustule, 192 Putative duodenal brake, 16 Pyridoxal phosphate (PLP), 130 Pyridoxine. See Vitamin B6• Pyrimidine synthesis, 36 Pyrimidines, 220 Quercetin, 376 Quibron, 298t QUinidlne,28it Radiation treatment, 512 Radloscintlgraphic measurement, 409 Raffinose, 157 Raimondo, Massimo, 445 Ranitldlne, 297t Ranson score, 436, 437t Rapamune, 539t Rapamycln, 539t RARE,37 RDA, 126, 251 Reabilan, 117t Reabilan HN, 117t Reactive oxygen species (ROS), 226, 236 Recombinant growth hormone, 494 Recombinant human growth hormone (rhGH), 357, 370, 432 Recombinant Interleukln-II, 455 Recombinant keratinocyte growth factor, 455 Recommended dietary allowance (RDA), 126,251 Reduced iron stores, 143 REE,351,352,426t,466 Refeeding syndrome chronic critical illness, 86 definition/incidence, 285-287 physiologic and metabolic sequeiae, 286t prevention/treatment, 287 risk of, 246 trauma patients, 369
570
Index
Region-specific control of transit and absorption, 16-18 Reimbursement. See Home enteral nutrition reimbursement. Renal disease, 471-485 carbohydrate metabolism, 473-474 electrolytes, 474-475, 476-477 energy substrates, 476 enteral formulas, 479-481 enteral nutrition, 472, 478, 479-483 feeding tubes, 479 gastrointestinal complications, 477 intradlalytlc enteral nutrition, 483 lipid metabolism, 474 malnutrition, 471, 478 metabolic alterations, 472-475 micronutrients, 475, 477 nutrient requirements, 476-477 nutritional strategies, 478-479 parenteral nutrition, 483 patient classifications, 478-479 protein, 476 protein catabolism, 472-473 renal replacement therapy, 475-476, 482-483 trace elements, 475, 477 vitamins, 475, 477 Renal failure, 273 Renal failure formula, 221-222, 367 Renal replacement therapy, 475-476, 482-483 Renalcal, 480t Renilon 4.0, 480t Renilon 7.5, 48It Replena, 117t, 480t Replete, 117t Replete with Fiber, 160t Resistant starch, 157,267 Resource Diabetic, 160t Resource liquid, 117t Resource Plus, 117t Respiratory compromise, 403 Respiratory disease. See Acute pulmonary disease. Respiratory rate, 191 Resting energy expenditure (REE), 351, 352, 426t, 466 Restoric Nephro lntensiv, 48It Retinoic acid, 133 Retinoids, 133 Retinol-binding protein, 199 Retrograde jejunoduodenallntussusceptlon, 211 Revised Balthazar score, 437t Reyes, Jorge, 523 Rhamnogalacturonans, 157f rhGH, 357, 370, 432 Riboflavin, 128-129 deficiency/toxicity, 128-129 ORIs, 127t elderly persons, 77t pregnancy, 62t summary (overview), 134t Riboflavin deficiency, 128-129 Ribosomal RNA, 39 Ribosomes, 39 Ridging of nail, 194f RNA,35 Rolandelli, Rolando, 110,202 Rollins, Carol, 291 ROS, 226, 236 Rosbolt, M. Bonnie, 381 Roth, Julie L., 243 Rowe, Heather A., 332 RRR-a-tocopherol, 257 Ruiz, Cesar, 509 Russell, Mary, 216
Russell technique, 207 RXRE,37 5-adenosyl-L-methionine (SAMe), 260, 468 Sabal fruit, 260 Sabal serrulata, 260 Sacks-Vine technique, 207 SADMERC, 311 Salivary amylase, 69t Salivary amylase activity, 15 Salvi peptide Nephro, 480t SAMe, 260, 468 Sandimmune, 538t Sassafras, 258t Saw palmetto, 260 SBBO, 458, 459 SBS, 165 SCFAs. See Short-chain fatty acids (SCFAs). Schaffner, Robert, 185 Schlavone-Gatto, Phyllis, 140 Scolaplo, James S., 445 Scurvy, 133, 177 Secondary Iron overload, 143 Secretory diarrhea, 283t Secretory IgA, 25 Seldlnger technique, 207 Selenium, 15D-151 burns, 354 critically ill children, 323t deficiency/toxicity, 15D-151 ORls,64t elderly persons, 77t function, 150 gene expression, 38t immunonutrltion, 237 intestinal transplantation, 526 renal disease, 475, 477 sepsis, 376 summary (overview), 147t Selenium deficiency, 15D-151 Selenium-dependent glutathione peroxidase, 376 Selenomethionine, 150 Selenosis, 151 Sepsis, 80, 84, 179, 373. See also Patients with sepsis. Septra Grape Suspension, 298t Septra Suspension, 298t Sequential organ failure assessment (SOFA) score, 394 Serenoa repens, 260 Serine, 1211 Serum albumin level, 199 Serum diamlne oxidase activity, 165 Serum electrolyte concentration, 97t Serum electrolyte concentration adjustment, 97t Serum osmolality, 96, 97t Serum protein levels, 199 Serum transferrin, 199 Servimed Renal, 480t Severe burn, 236, 349-363 amino acids, 354 burn mortality, 349t complications, 359 energy expenditure, 351-352 growth factors, 357 management, 352-354 metabolic modulation, 354-359 pathophysiology, 349-351 pediatric patients, 352, 353 protein, 354 selenium, 354 steroids, 357-358 vitamins, 354 zinc, 354
SGA, 417, 466 SGLTl,98 Short bowel syndrome, 451-463 bowel, development of, 451 clinical management, 456-457 complications, 457-459 etiology, 451-452 hormones, 454-456 intestinal adaptation, 452 protein, 453-454 role of enteral nutrition, 452 surgical management, 459 TPN,452 triglycerldes, fatty acids, fiber, 454 Short bowel syndrome (SBS), 165 Short-chaln fatty acids (SCFAs), 111, 161 anti-Inflammatory effects, 162 anti-neoplastic effects, 162-163 bacterial growth, 163 C. difficile, 163 cancer, 165-166 colonic fermentation, 18 constipation, 166 diarrhea, 166, 168 enteral formulations, 218 GI motility, 164 gut barrier strengthening, 165 intestinal adaptation, 165 intestinal cell metabolism, 161 Intestinal trophic effects, 162 oral-anal transit, 164 pathogen suppression, 163 short bowel syndrome, 454 stool weight, 164-165 translocation of bacteria, 163-164 ulcerative colitis, 165 water absorption, 163 Short-term hypocaloric nutrition, 400 SIBO, 18 Sick euthyroid syndrome, 318 Sickle cell anemia, 35 Side effects, 295 Silicon, 152 Simulect, 538t Sirolimus, 539t SfRS,80,84,438,439 Site of feeding, 299, 299t 6-ro fatty acids, 112, 116, 117 Skilled nursing facilities, 307 Skin, 192-193 Skin lesions, 192 Skin level low-profile gastrostomy device, 210 Slo-Phyllin GG, 298t Slow gastric emptying, 299t SLs, 116,219 Small bowel bacterial overgrowth (SBBO), 458,459 Small Intestinal bacterial overgrowth (SIBO), 18 Small Intestine, 15-18,451 Sodium dominant extracellular os mole, as, 96 dosage range, 102t electrolyte abnormality, IOIt extracellular flutd, 97, 98 gastrointestinal secretions, 98t gene expression, 38t liver disease/transplantation, 534, 535t Sodium disorder, 102-105 Soeters, P. B., 436 SOFA score, 394 Sole source of nutrition, 308 Solu-Cortef, 538t Solu-Medrol, 538t Soluble fiber, 218 Somatostatin, 458
Index Sonographic image-guided nasoenterlc tube placement, 206 Sorbitol, 118, 295, 297t, 298t Soy polysaccharide, 159, 168,291 Soy protein, 17 Soy protein Isolate, 219 Special formulas, 221-222 Spencer, Carolyn T., 138 Sphygmomanometer, 191 Spinal cord injuries, 381, 386-387 Splanchnic ischemia, 395 Spooning of nail, 194f St. John's wort, 259 Stachyose, 157 Stamm technique, 208--209 Standard polymeric formulas, 220-221 Stanozolol,431 Starch, 15, 118, 120 Starch hydrolysis, 15 Stearidonic acid, 112 Steatorrhea, 115 Stem cell transplantation. See Hematopoietic stem cell transplantation (HSCT). Steroids acute pulmonary disease, 418 burns, 357-358 COPD, 429t, 431, 433 Stomach, 12-14 Stoner, Nancy Evans, 509 Stool weight, 164-165 Streptozotocin, 176 Stress diabetes, 370 Stress response, 381. See also Acute stress response. Stresstein, 117t Structured lipids (SLs), 116,219 Subjective global assessment (SGA), 199-200,417,466 Submental lymph nodes, 194 Suchner, Ulrich, 224 Sucralfate, 277t Sucrase-isomaltase, 69t Sucrose, 118, 218 Sugar alcohols, 118 Sulfamethoxazole, 297t, 298t Sulfasalazine, 162, 302t Sulfisoxazole, 298t Sulfur, 145 Sulfur deficiency, 145 Surrogate end points, 224 Sustacal, 117t Sustacal HC, 117t Sustacal with Fiber, 117t Swallowing chemoradiation, 512 dysphagia, 407 esophageal cancer, 511 laryngeal cancer, 511 mechanics of, 509-511 neurologic diseases, 407, 410 oral cancer, 511 pharyngeal cancer, 511 radiation treatment, 512 Symbiotic therapy, 459 Synbiotic 2000, 269, 271, 272 Synbiotic compositions, 268--269 Synbiotics, 267-268 Synophylate GG, 298t Syringe bolus, 336 Systemic corticosteroids, 418, 433 Systemic inflammatory response, 225 Systemic inflammatory response syndrome (SIRS), 80, 84, 438, 439 T 3 , 84 T4, 84
T lymphocytes, 175
Tacrollmus, 539t TATA binding protein, 36 TATAbox, 36 TBI, 381-386. See also Brain injuries, Team concept. See Nutrition support team. TEE,351 Tegaserod,409 Temperature, 191 TEN. See Total enteral nutrition. Testosterone, 89, 357 Tetracycline, 297t Tetracyclines, 302t Tetrahydrocannabinol, 277t TH1 responses, 225 TH2 responses, 225 Thalidomide, 494 tHey, 128 Theolair, 298t Theophylline, 281t, 297t, 298t, 301, 418 Thiabendazole, 298t Thiamine, 128 acute hepatic dysfunction, 466 cardiac patients, 392 deficiency/toxicity, 128,392 ORIs, 127t elderly persons, 77t summary (overview), 134t Thiamine deficlency, 128,392 Thioridazine, 298t Thlothixene, 298t Thomson, Cynthia, 291 3-00 fatty aclds, 112, 118,219 Threonine, 12lf Throat, examination of, 195-196, 197t Thromboxane A z, 114 Thromboxane A3, 114 Thymoglobulin, 538t Thyrotropin-releasing hormone (TRH), 84 Thyroxine (TJ, 84 Thyroxine-binding prealbumin, 199 TNF-a, 272, 427 Tobacco, 277t Tobacco use, 189 Tocopherols, 137 Torres, Clarivet, 451 Total body water, 95 Total body water deficit, 95 Total energy expenditure (TEE), 351 Total enteral nutrition administration of, 243-247 effectiveness, 179 methods of delivery, 244-245 mortality rates, 353f Total Hey (tHey), 128 Total lymphocyte count, 199 Total parenteral nutrition (TPN) acute pancreatitis, 440 cancer, 517 critically ill patients, 373 diabetes, 502 discharge plans, as part of, 200 essential fatty acid deficiency, 179 HIV infection, 493-494 HSCT,544 intestinal transplantation, 525-526 mortality rates, 353t neurologic disease, 406 postoperative complications, 179 prolonged TPN, 200 renal disease, 483 short bowel syndrome, 452 TEN, compared, 179 terminally 111 patients, 200 Toterex, 117t TPN. See Total parenteral nutrition (TPN). TPN-associated liver disease, 459
571
Trace elements, 145-151. See also individual subject headings. chromium, 145, 148 cobalt, 148 iodine, 148--149 manganese, 149-150 molybdenum, 150 selenium, 150-151 Trach-collar trials, 90 Transcellular fluid compartment, 96 Transcription, 35-38 Transfer RNA (tRNA), 39 Transferrin, 199,246 Transforming growth factor-B. 446 Transgastric jejunal tubes, 209 Transl1luminatlon of stomach, 206, 206f Transit control. See Controlled GI transit. Transit of a meal, 11 Transitioning to oral diet, 246 children, 328--329 HEN, 339, 344 Translation, 38--40 Transthyretin, 199 Transverse lines (ridging of nail), 194f Traum-Aid HBC, 117t Trauma, 364-372 acute renal failure, 368--369 administration of feedings, 367 anabolic compounds, 370-371 comorbid diseases, 369 complications, 369-371 enteral access, 366 enteral route preferred, 364-365 formula selection, 366-367 gastric feeding, 367 hyperglycemia, 370 lED, 365-366, 367t jejunostomy-related complications, 370 monitoring, 369 NOBN,370 nutritional assessment, 368 nutritional goals, 368, 368t obesity, 369 refeeding syndrome, 369 tolerance, 367-368 TraumaCal, 117t TraumaCal HN, 385t Traumatic brain injury (TBI), 381-386. See also Brain injuries. Travasorb Renal, 480t TRH,84 Tricyclic antidepressants, 277t Triene,72 Triglycerides, 218 Trihexyphenidyl, 298t Triiodothyronine (T3),84 Trimethoprim, 297t, 298t Trimethoprim-sulfamethoxazole, 459 Trismus, 511 Trivalent chromium, 148 tRNA,39 TrophAmine, 525 Trypsin, 15, 69t Tryptophan, 12lf Tube enterostomies, 206-210, 211-212 Tube enterostomy complications, 211-212 Tube feeding, 243 Tube feeding-related diarrhea, 17 Tumor necrosis factor-a (TNF-a), 272 25-hydroxyvitamin 0, 465 TwoCal,160t TwoCal HN, 294t Type 1 diabetes, 498 Type 2 diabetes, 498 Tyrosine, 12lf
572
Index
U.S. Pharmacopeia (USP), 252, 254 Ubiquinone, 260, 392 UC,165 UES relaxation, 407t UL, 126, 253 Ulcerative colitis (UC), 165 Ultracal, 117t, 160t Ultracel HN Plus, 160t Unavailable carbohydrates, 118 Unfermented fiber, 164 University of Michigan home enteral nutrition care plan, 340-343t Unproven herbal products, 188 Upper esophageal sphincter (UES) relaxation, 407t Upper GItract endoscopy, 409 Upper Intake Level (UL), 126 Upper tolerable intake level (UL), 253 Uppsala method, 158 Urea, 123 Urea recycling, 123 Uremia, 472. See also Renal disease. Uremic hypometabolism, 472 Ureolysis, 123 Urinary urea nitrogen (UUN), 199 USP, 252,254 UUN,199 Valine, 1211, 219, 468 Valproic acid, 297t Van Cltters, Gregg W., 11 Vancomycin, 298t Vasoactive drugs, 390 Vasodilatation, 186 VORE,37 Vegetable oils, 112 Very low-density lipoproteins (VLDL), 110 Vesicle, 192, 193f Viral hepatitis, 465 Visceral proteins, 199 Vital HN, 117t Vital signs, 191 Vitamin, 126-139. See also individual vitamins. animal species, 49 B, 128-132 burns, 354 critically ill children, 324 dietary supplements, as, 256-258 ORIs, 126, 127t enteral formulations, 220 indices, 126 liver disease/transplantation, 534, 535t, 537 pregnancy, 61-63 renal disease, 475, 477 summary (overview), 134t wound healing, 176-178 Vitamin A, 133, 135 deficiency/toxicity, 133, 135 diabetes, 41 ORIs, 127t gene expression, 38t
Vitamin A (Continued) pregnancy,61,62t,63 summary (overview), 134t Vitamin B,. See Thiamine. Vitamin B, deficiency, 392 Vitamin B2• See Riboflavin. Vitamin B3• See Niacin. Vitamin B5• See Pantothenic acid. Vitamin B6, 130 deficiency/toxicity, 130 ORIs, 127t elderly persons, 77t gene expression, 38t pregnancy,62t summary (overview), 134t Vitamin B6 deficiency, 130 Vitamin B'2, 131-132 deficiency/toxicity, 131-132 ORIs, 127t old age, 78 pregnancy,62t summary (overview), 134t Vitamin C, 132-133 deficiency/toxicity, 133 dietary supplement, as, 257 ORIs, 127t elderly persons, 77t gene expression, 38t pregnancy, 61,62t summary (overview), 134t wound healing, 177 Vitamin C deficiency, 177 Vitamin 0, 135-136 deficiency/toxicity, 136 ORIs, 127t elderly persons, 77t gene expression, 38t old age, 78 pregnancy,61,62t renal disease, 477 summary (overview), 134t Vitamin 0 deficlency, 136 Vitamin 0 toxicity, 136 Vitamin E, 136-137 deficiency/toxicity, 136-137 dietary supplement, as, 257 ORIs, 127t gene expression, 38t pregnancy, 62t renal disease, 477 summary (overview), 134t wound healing, 177-178 Vitamin E deficiency, 137 Vitamin K, 137-138 antlhemorrhage vitamin, as, 178 content of, In enteral formulations, 294t deficiency/toxicity, 138 ORIs, 127t gene expression, 38t pregnancy, 62t summary (overview), 134t wound healing, 178
Vitamin K deficiency, 138 Vitaneed, 117t Vlvonex TEN, 117t VLOL,110 Volume deficit, 97t Volume depletion, 100 Volume overload, 100 Volume replacement, 100 Wang, Jack, 495 Warfarin, 301 Water, 217-218, 291 Water deficit, 97t Water excess, 97t Water pump, 98 Wesley, John, 3 Wet berl-beri, 392 Wheat bran, 164 Whey, 69 Williams, Jeremy Z., 172 Winkler, Marlon F., 306 Witzel jejunostomy, 209-210 Wolf, Steven E., 349 Woodside, Kenneth J., 349 Wound healing, 172-182 amino acids, 173-175 carbohydrates, 175-176 fats, 176 feeding, 179 infection, 178-179 micronutrlents, 178 obesity, 403 protein, 173 vitamins, 176-178 Xanthine oxidase, 26 Xerostomia, 512 Xylans, 156, 157f Xyloglucans, 156, 157f Zenapax, 538t Zinc, 144 brain Injury, 382 burns, 354 critically ill children, 323t deficiency/toxicity, 144 food sources, 144 function, 144 gene expression, 38t immunonutrition, 237 liver disease/transplantation, 534,535t pregnancy, 64t, 65 renal disease, 475, 477 summary (overview), 146t wound healing, 178 Zinc deficiency, 144 Zinc finger, 37f, 144 Zinc toxicity, 144
