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'
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.
20
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 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 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
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
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
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 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-
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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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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
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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."
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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.
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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
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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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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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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
SECTION III • Nutrient Metabolism
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'
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
178
15 • Nutrition and Wound Healing
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
179
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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16 • Nutrition-Focused History and Physical Examination
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.
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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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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.
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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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_ _ 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.
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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.
198
16 • Nutrition-Focused History and Physical Examination
\(
•
• -3 fatty acids, n-6 fatty acids, 00-6 fatty acids.
1.8 4.9 15:85
-l
5 z
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.
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19 • Immunonutrition
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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.
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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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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.
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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
..
SECTION IV • Principles of Enteral Nutrition
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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21 • Dietary Supplements
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'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.
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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 ~
~
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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, 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.
304
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
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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--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.
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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
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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 lOO.5°F, orally
o Access device changed
N
will administer TEN therapy
Continued
_ _ University of Michigan Home Enteral Nutrition care Plan-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.
349
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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
352
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.)
354
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.)
358
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.)
..-.
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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.)
1. Newsome 1W, Mason AD Jr, Pruitt BA Jr: Weight loss following thermal injury. Ann Surg 1973;178:215-217. 2. Cone JB, Pasley IN, Bond PJ, et al: Alteration in gastrointestinal peptides after thermal injury in humans. J Bum Care Rehabil 1993; 14:663-665. 3. Brizio-Molteni L, Molteni A, Warpeha RL, et al: Prolactin, corticotrophin, and gonadotropin concentrations following thermal injury in adults. J Trauma 1984;24:1-7. 4. Vaughan GM, Becker RA, Allen JP, et al: Cortisol and corticotrophin in burned patients. J Trauma 1982;22:263-273. 5. Molteni A, Warpeha RL, Brizio-Molteni L, et al: Circadian rhythms of serum aldosterone, cortisol and plasma renin activity in bum injuries. Ann Clin Lab Sci 1979;9:518-523. 6. Wolfe RR, Herndon DN,Jahoor F, et al: Effect of severe bum injury on substrate cycling by glucose and fatty acids. N Engl J Med 1987;317:403-408. 7. Hart OW, Wolf SE, Chinkes DL, et al: Determinants of skeletal muscle catabolism after severe burn. Ann Surg 2000;232:455-465. 8. Gore DC, Chinkes 0, Sanford A, et al: Influence of fever on the hypermetabolic response in bum-injured children. Arch Surg 2003; 138:169-174. 9. Wilmore OW, Long JM 3rd, Mason AD, et al: Catecholamines: Mediators of the hypermetabolic response in thermally burned patients. Ann Surg 1974;180:653-659. 10. Milner EA, Cioffi WG, Mason AD, et al: A longitudinal study of resting energy expenditure in thermally injured patients. J Trauma 1994;37:167-170. 11. Hart OW, Wolf SE, Mlcak R, et al: Persistence of muscle catabolism after severe bum. Surgery 2000;128:312-319. 12. Stinnett JD, Alexander JW, Watanabe C, et al: Plasma and skeletal muscle amino acids following severe bum injury in patients and experimental animals. Ann Surg 1982;195:75-89. 13. KinneyJM:Metabolic response to injuries. In Winters RW, Greene HL (eds): Nutritional Support of the Seriously III Patient, p 5. New York, Academic Press, 1983. 14. McClave SA, Mitoraj TE, Thielmeier KA, et al: Differentiating subtypes (hypoalbuminemic vs marasmic) of protein-calorie malnutrition: Incidence and clinical significance in a university hospital setting. JPEN J Parenter Enteral Nutr 1992;16:337-342. 15. Sakurai Y, Aarsland A, Herndon DN, et al: Stimulation of muscle protein synthesis by long-term insulin infusion in severely burned patients. Ann Surg 1995;222:283-294. 16. Jahoor F, Desai M, Herndon ON, et al: Dynamics of the protein metabolic response to burn injury. Metabolism 1988;37:330-337. 17. Shangraw RE, Stuart CA, Prince MJ, et al: Insulin responsiveness of protein metabolism in vivo following bedrest in humans. Am J Physiol 1988;255(4 part 1):E548-E558. 18. Shaw JH, Wolfe RR: An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients. Studies in the basal state and the response to total parenteral nutrition. Ann Surg 1989;209:63-72. 19. Wolfe RR, Herndon DN, Peters EJ, et al: Regulation of lipolysis in severely burned children. Ann Surg 1987;206:214-221. 20. Herndon DN, Wilmore DW, Mason AD, et al: Development and analysis of a small animal model stimulating the human postburn hypermetabolic response. J Surg Res 1978;25:394-403. 21. Muller MJ, Meyer N, Herndon DN, et al: Nutritional support for the burned patient. In Latifi R, Dudrick SJ (eds): Surgical
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Nutrition: Strategies in Critically III Patients, p 103. New York, Springer-Verlag, 1995. 22. Wolfe RR, Burke JF: Effect of glucose infusion on glucose and lactate metabolism in normal and burned guinea pigs. J Trauma 1978;18:800-805. 23. Michie HR, Wilmore DW: Sepsis, signals, and surgical sequelae (a hypothesis). ArchSurg 1990;125:531-536. 24. VindenesHA, Ulvestad E, Bjerknes R: Concentrationsof cytokines in plasma of patients with large bums: Their relation to time after injury, bum size, inflammatory variables, infection, and outcome. EurJ Surg 1998;164:647-656. 25. Furukawa K, Kobayashi M, Herndon DN, et al: Appearance of monocyte chemoattractant protein I (MCP-1) early after thermal injury: Role in the subsequent development of burn-associated type 2 T-cell responses. Ann Surg2002;236:112-119. 26. Marano MA, Fong Y, Moldawer LL, et al: Serum cachectin/tumor necrosis factor in critically ill patients with bums correlates with infectionand mortality. SurgGynecol Obstet 1990;170:32-38. 27. Molloy RG, O'Riordain M, Holzheimer R, et al: Mechanism of increased tumor necrosis factor production after thermal injury. Altered sensitivity to PGE2 and immunomodulation with indomethacin. J ImmunoI1993;151:2142-2149. 28. Yeh FL, Lin WL, Shen HD, et al: Changes in serum tumor necrosis factor-alpha in burned patients. Burns1997;23:6--10. 29. Zhang B, Huang YH, Chen Y, et al: Plasma tumor necrosis factoralpha, itssoluble receptorsand interleukin-Ibeta levelsin critically burned patients. Bums 1998;24:599-603. 30. Becker RA, Vaughan GM, Goodwin CW Jr, et al: Plasma norepinephrine, epinephrine, and thyroid hormone interactions in severelyburned patients.ArchSurg 1980;115:439-443. 31. Gore DC, Chinkes DL, Hart DW, et al: Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients. CritCare Med 2002;30:2438-2442. 32. Bessey PQ, Watters JM, Aoki TT, et al: Combined hormonal infusion simulates the metabolic response to injury. Ann Surg 1984;200:264-281. 33. Watters JM, Bessey PQ, Dinarello CA, et al: Bothinflammatory and endocrine mediators stimulate host responses to sepsis.ArchSurg 1986;121:179--190. 34. Aulick LH, Wilmore DW: Increased peripheral amino acid release following burn injury. Surgery 1979;85:560-565. 35. Clowes GH Jr, Randall HT, Cha CJ: Aminoacid and energy metabolism in septic and traumatized patients. JPEN J Parenter Enteral Nutr1980;4:195-205. 36. Herndon DN, Wilmore DW, Mason AD Jr, et al: Abnormalities of phenylalanine and tyrosine kinetics. Significance in septic and nonseptic burned patients.Arch Surg 1978;113:133-135. 37. AbbottWC, SchillerWR, Long CL, et al:The effectof majorthermal injury on plasma ketone body levels. JPEN J Parenter Enteral Nutr 1985;9:153-158. 38. Ezzell RM, Carter EA, Yarmush ML, et al: Thermal injury-induced changes in the rat intestine brush border cytoskeleton. Surgery 1993;114:591-597. 39. Eaves-Pyles T, Alexander JW: Rapid and prolonged impairment of gut barrier function after thermal injury in mice. Shock 1998;9:95-100. 40. Ramzy PI, Wolf SE, Irtun 0, et al: Gut epithelial apoptosis after severe burn: Effects of gut hypoperfusion. J AmColiSurg2000;190: 281-287. 41. Deitch EA, Ma L, Ma JW, et al: Lethal burn-induced bacterial translocation: Role of genetic resistance. J Trauma 1989;29: 1480-1487. 42. Ma L, Ma JW, Deitch EA, et al: Genetic susceptibility to mucosal damage leads to bacterial translocation in a murine burn model. J Trauma 1989;29:1245-1251. 43. ChoudhryMA, Fazal N, NamakSY, et al: PGE2 suppresses intestinal T cell function in thermal injury: A cause of enhanced bacterial translocation. Shock 2001;16:183-188. 44. Ravindranath T, Al-Ghoul W, Namak S, et al: Effects of bum with and without Escherichia coli infection in rats on intestinal vs. splenic T-cell responses. Crit Care Med2001;29:2245-2250. 45. Fukuzuka K, Edwards CK 3rd, Clare-Salzer M, et al: Glucocorticoid and Fas ligand induced mucosal lymphocyte apoptosis after bum injury. J Trauma 2000;49:710-716.
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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.
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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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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 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)
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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 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.
370
29 • Trauma
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
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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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the septic origin of splanchnic ischemia. World J Surg 1998; 22:6-11. 6. Revelly JP, Tappy L, Berger MM, et al: Early metabolic and splanchnic responses to enteral nutrition in postoperative cardiac surgery patients with circulatory compromise. Intensive Care Med 2001;27:540-547. 7. Rhoden D, Matheson PJ, Carricato ND, et al: Immune-enhancing enteral diet selectively augments ileal blood flow in the rat. J Surg Res 2002;106:25-30. 8. Houdijk AP, van Leeuwen PA, Boermeester MA, et al: Glutamineenriched enteral diet increases splanchnic blood flow in the rat. Am J Physiol 1994;267:Gl035-GI040. 9. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345: 1368-1377. 10. 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. II. Marik PE, Zaloga G: Gastric vs post-pyloric feeding? A systematic review. Crit Care 2003;7:R46-R51. 12. Zaloga GP, Marik P: Promotility agents in the intensive care unit. Crit Care Med 2000;28:2657-2659. 13. Hadfield RJ, Sinclair DG, Houldsworth PE, Evans TW: Effects of enteral and parenteral nutrition on gut mucosal permeability in the critically ill. Am J Respir Crit Care Med 1995;152:1545-1548. 14. Gianotti L, Alexander JW, Nelson JL, et al: Role of early enteral feeding and acute starvation on postbum bacterial translocation and host defense: Prospective, randomized trials. Crit Care Med 1994;22:265-272. 15. Minard G, Kudsk KA: Is early feeding beneficial? How early is early? New Horiz 1994;2:156-163. 16. Chuntrasakul C, Siltharm S, Chinswangwatanakul V, et al: Early nutritional support in severe traumatic patients. J Med Assoc Thailand 1996;79:21-26. 17. Tanigawa K, Kim YM, Lancaster JR Jr, Zar HA: Fasting augments lipid peroxidation during reperfusion after ischemia in the perfused rat liver. Crit Care Med 1999;27:401-406. 18. Bortenschlager L, Roberts PRo Black KW, Zaloga GP: Enteral feeding minimizes liver injury during hemorrhagic shock. Shock 1994;2:351-354. 19. Beier-Holgersen R, Brandstrup B: Influence of early postoperative enteral nutrition versus placebo on cell-mediated immunity, as measured with the Multitest CMI. Scand J Gastroenterol 1999; 34:98-102. 20. Kompan L, Kremzar B, Gadzijev E, Prosek M:Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intensive Care Med 1999;25: 157-161. 21. Gaal T, Mezes M, Miskucza 0, Ribiczey-Szabo P: Effect of fasting on blood lipid peroxidation parameters of sheep. Res Vet Sci 1993;55:104-107. 22. Wohaieb SA, Godin DV: Starvation-related alterations in free radical tissue defense mechanisms in rats. Diabetes 1987;36: 169-173. 23. Brass CA, Narciso J, Gollan JL: Enhanced activity of the free radical producing enzyme xanthine oxidase in hypoxic rat liver. Regulation and pathophysiologic significance. J Clin Invest 1991; 87:424-431. 24. Maruyama E, Kojima K, Higashi T, Sakamoto Y: Effect of diet on liver glutathione and glutathione reductase. J Biochem (Tokyo) 1968;63:398-399. 25. Strubel! 0, Dost-KempfE, Siegers CP, et al: The influence of fasting on the susceptibility of mice to hepatotoxic injury. Toxicol Appl Pharmacol 1981;60:66-77. 26. Marik PE, Zaloga GP: Early enteral nutrition in acutely ill patients: A systematic review. Crit Care Med 2001;29:2264-2270. 27. Houdijk AP, Rijnsburger ER, Emmy R, et al: Randomized trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772-776. 28. Efron D, Barbul A: Role of arginine in immunonutrition. J Gastroenterol 2000;35(suppl 12):20-23. 29. Novak F, Heyland DK,Avenell A, et al: Glutamine supplementation in serious illness: A systematic review of the evidence. Crit Care Med 2002;30:2022-2029.
30. Andrews FJ, GriffithsRD:Glutamine: Essential for immune nutrition in the critically ill. Br J Nutr 2002;87(suppl 1):S3-S8. 31. Alexander JW: Immunonutrition: The role of omega-3 fatty acids. Nutrition 1998;14:627-633. 32. Evoy D, Lieberman MD, Fahey TJ III, Daly JM: Immunonutrition: The role of arginine. Nutrition 1998;14:611-617. 33. Efron DT, Barbul A: Modulation of inflammation and immunity by arginine supplements. Curr Opin Clin Nutr Metab Care 1998;I: 531-538. 34. Kirk SJ, Barbul A: Role of arginine in trauma, sepsis, and immunity. JPEN J Parenter Enteral Nutr 1990;14:2265-229S. 35. Zaloga G, Marik P: Lipid modulation and systemic inflammation. Crit Care Clin 2001;17:201-218. 36. Grimm H, Mayer K, Mayser P, Eigenbrodt E: Regulatory potential of n-3 fatty acids in immunological and inflammatory processes. Br J Nutr 2oo2;87(suppl 1):S59-S67. 37. Beale RJ, Bryg DJ, Bihari DJ: Immunonutrition in the critically ill: A systematic review of clinical outcome. Crit Care Med 1999;27: 2799-2805. 38. Heyland DK, Novak F, Drover JW, et al: Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA2001;286:944-953. 39. Zaloga GP: Immune-enhancing enteral diets: Where's the beef? Crit Care Med 1998;26:1143-1146. 40. Heyland DK: Immunonutrition in the critically ill: Putting the cart before the horse? Nutr Clin Pract 2002;17:267-272. 41. Suchner U, Heyland DK, Peter K: Immune-modulatory actions of arginine in the critically ill. Br J Nutr 2002;87(Suppl 1): S121-5132. 42. Marik PE: Cardiovascular dysfunction of sepsis: A NO- and L-arginine deficient state? Crit Care Med 2003;31:971-973. 43. Park JH, Chang SH, Lee KM, Shin SH: Protective effect of nitric oxide in an endotoxin-induced septic shock. Am J Surg 1996; 171:340-345. 44. Meyer J, Lentz CW, Stothert JC Jr, et al: Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia. Crit Care Med 1994;22:306-312. 45. Kilbourn RG, Cromeens DM, Chelly ro, Griffith OW: NG-methylL-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs. Crit Care Med 1994;22:1835-1840. 46. Torre D, Tambini R, Aristodemo S, et al: Serum levels of nitrite and nitrate in patients with systemic inflammatory response syndrome. Clin Infect Dis 1999;29:687-688. 47. Avontuur JA, Starn TC, Jongen-Lavrencic M,et al: Effect of L-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, 1L-8, TNF ex and nitrite/nitrate in human septic shock. Intensive Care Med 1998;24:673-679. 48. Doughty L, Carcillo JA, Kaplan S, Janosky J: Plasma nitrite and nitrate concentrations and multiple organ failure in pediatric sepsis. Crit Care Med 1998;26:157-162. 49. Moncada S, Higgs EA: Endogenous nitric oxide: Physiology, pathology and clinical relevance. Eur J Clin Invest 1991;21:361-374. 50. Palmer RM, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-526. 51. Kumar A, Haery C, Parrillo JE: Myocardial dysfunction in septic shock. Crit Care Clin 2000;16:251-287. 52. Kumar A, Brar R, Wang P, et al: Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol 1999;276:R265-R276. 53. Unno N, Menconi M, Smith M, Fink MP: Nitric oxide mediates interferon-y-induced hypermeability in cultured human intestinal epithelial monolayers. Crit Care Med 1995;23:1170-1176. 54. Unno N, Wang H, Menconi MJ, et al: Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats. Gastroenterology 1997;113:1246-1257. 55. Szabo C, Zingarelli B, Salzman AL: Role of poly-ADP ribosyltransferase activation in the vascular and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Circ Res 1996;78:1051-1063. 56. Szabo CS, Cuzzocrea B, Zingarelli B, et al: Endothelial dysfunction in a rat model of endotoxic shock: Importance of the activation of the poly(ADP-robose) synthetase by peroxynitrite. J Clin Invest 1997;100:723-735.
SECTION V • Disease Specific
57. Virag L, Szabo C:Inhibitionof poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation. Br1 Pharmacol 1999;126:769-777. 58. Rangel-Frusto MS, Pittet D, Costigan M, et al: The natural history of the systemic inflammatory response syndrome (SIRS): A prospectivestudy. lAMA 1995;273:117-123. 59. Bruins Ml, Soeters PB, Lamers WH, et al: L-Arginine supplementation in hyperdynamic endotoxemic pigs: Effect on nitric oxide synthesis by the different organs. CritCare Med 2002;30:508-517. 60. Bune AJ, Shergill lK, Cammack R, Cook HT: L-Arginine depletion by arginase reduces nitric oxide production in endotoxic shock: An electron paramagneticresonance study.FEBS Lett 1995;366:127-130. 61. Ochoa lB, Strange 1, Kearney P, et al: Effects of L-arginine on the proliferation of T lymphocyte subpopulations. lPEN 1 Parenter Enteral Nutr2001;25:23-29. 62. Rodriguez PC, Zea AH, Culotta KS, et al: Regulationof T cell receptor CD3~ chain expression by L-arginine. 1 Bioi Chern 2002;277: 21123-21129. 63. Taheri F,Ochoa lB, Faghiri Z, et al: L-Arginine regulates the expression of the T-cell receptor ~ chain (CD3~) in lurkat cells. Clin Cancer Res2001;7:958s-965s. 64. Peng HB, Spiecker M, LiaolK: Inducible nitric oxide: An autoregulatory feedback inhibitor of vascular inflammation. 1 Immunol 1998;161:1970-1976. 65. Spiecker M, Darius H, Kaboth K, et al: Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants. 1 Leukoc Bioi 1998;63:732-739. 66. Spiecker M, Peng HB, Liao lK: Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of heBa. 1 BioI Chern 1997;272:30969-30974. 67. Meldrum DR, Mclntyre RC, Sheridan BC, et al: i-Arginine decreases alveolar macrophage proinflammatory monokine production during acute lung injury by a nitric oxide synthase-dependent mechanism. 1 Trauma 1997;43:888-893. 68. Laroux FS, Lefer Dl, Kawachi S, et al: Role of nitric oxide in the regulation of acute and chronic inflammation. Antioxid Redox Signal2000;2:391-396. 69. Walley KR, McDonald TE, HigashimotoY, HayashiS: Modulationof proinflammatory cytokines by nitric oxide in murine acute lung injury. Am1 RespirCritCare Med 1999;160:698-704. 70. Fowler M Ill, Fisher Bl, Sweeney LB, et al: Nitric oxide regulates interleukin-8 gene expression in activated endothelium by inhibiting NF-lCB binding to DNA: Effects on endothelial function. Biochem Cell Bioi 1999;77:201-208. 71. Sundrani R, Easington CR, Mattoo A, et al: Nitric oxide synthase inhibition increases venular leukocyte rolling and adhesion in septic rats. CritCare Med2000;28:2898-2903. 72. De Caterina R, Libby P, Peng HB, et al: Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. 1 Clin Invest 1995;96:60-68. 73. delaTorre A, Schroeder RA, Punzalan C, Kuo PC: Endotoxinmediated 5-nitrosylation of p50 alters NF-lCB-dependent gene transcription in ANA-1 murine macrophages. 1 Irnmunol 1999;162: 4101-4108. 74. Spiecker M, Peng HB, Liao lK: Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IlCBa. 1 Bioi Chern 1997;272:30969-30974. 75. Peng HB, Libby P, LiaolK: Induction and stabilization of IlCBa by nitric oxide mediates inhibition of NF-lCB. 1 Bioi Chern 1995;270: 14214-14219. 76. Gerlach M, Keh D,BezoldG,et al: Nitric oxide inhibits tissue factor synthesis, expression and activity in human monocytes by prior formation of peroxynitrite. Intensive Care Med 1998;24:1199-1208. 77. YangY, Loscalzo1:Regulation of tissue factor expression in human microvascular endothelial cells by nitric oxide. Circulation 2000; 101:2144-2148. 78. Radomski MW, Moncada S: Regulation of vascular homeostasis by nitric oxide. Thromb Haemost 1993;70:36-41. 79. Radomski MW, Vallance P, Whitley G, et al: Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. Cardiovasc Res 1993;27:1380-1382.
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BO. Yao SK, Ober lC, Krishnaswami A, et al: Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation 1992;86: 1302-1309. 81. Grimm M, Spiecker M, De Caterina R, et al: Inhibition of major histocompatibility complex class II gene transcription by nitric oxide and antioxidants. 1 Bioi Chern 2002;277: 26460-26467. 82. Pober lS, CollinsT, Gimbrone MA lr, et al: Lymphocytesrecognize human vascular endothelial and dermal fibroblast la antigens induced by recombinant immune interferon. Nature 1983;305: 726-729. 83. Pou S, Pou WS, Bredt DS, et al: Generation of superoxide by purified brain nitric oxide synthase. 1 Bioi Chern 1992;267: 24173-24176. 84. Kobayashi H, Nonami T, Kurokawa T, et al: Role of endogenous nitric oxide in ischemia-reperfusion injury in rat liver.1 Surg Res 1995;59:772-779. 85. Vollmar B, lanata 1, Yamauchi 11, Menger MD: Attenuation of microvascular reperfusion injury in rat pancreas transplantation by L-arginine. Transplantation 1999;67:950-955. 86. Mueller AR, Platz KP, Heckert C, et al: L-Arginine application improves mucosal structure after small bowel transplantation. Transplant Proc 1998;30:2336-2338. 87. Valero R, Garcia-Valdecasas lC, Net M, et al: L-Arginine reduces liver and biliary tract damage after liver transplantation from non-heart-beating donor pigs. Transplantation 2000;70:730-737. 88. Mueller AR, Platz KP, Schirmeier A, et al: L-Arginine application improves graft morphology and mucosal barrier function after small bowel transplantation. Transplant Proc 2000;32: 1275-1277. 89. Mueller AR, Platz KP, Langrehr 1M, et al: The effects of administration of nitric oxide inhibitors during small bowel preservation and reperfusion. Transplantation 1994;58:1309-1316. 90. Alexander JW, Valente lr, Greenberg NA, et al: Dietary amino acids as new and novel agents to enhance allograft survival. Nutrition 1999;15:130-134. 91. Gibson SW, Valente Jf', Alexander lW, et al: Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506. Transplantation 2000;69:2034-2038. 92. Vos IH, Rabelink TJ, Dorland B,et al: L-Arginine supplementation improves function and reduces inflammation in renal allografts. 1 Am Soc NephroI2001;12:361-367. 93. Alexander lW: Role of immunonutrition in reducing complications following organ transplantation. Transplant Proc 2000;32: 574-575. 94. Spain DA, Wilson MA, Bar-Natan MF, Garrison RN: Nitric oxide synthase inhibition aggravates intestinal microvascular vasoconstriction and hypoperfusion of bacteremia. 1 Trauma 1994;36: 720-725. 95. Spain DA, Wilson MA, Bar-Natan MF, Garrison RN: Role of nitric oxide in the small intestinal microcirculation during bacteremia. Shock 1994;2:41-46. 96. Spain DA, Wilson MA, Garrison RN: Nitric oxide synthase inhibition exacerbates sepsis-induced renal hypoperfusion. Surgery 1994;116:322-330. 97. Pastor C, Teisseire B, Vicaut E, Payen D: Effectsof L-arginine and i-nitro-arginlne treatment on blood pressure and cardiac output in a rabbit endotoxin shock model [see comments]. Crit Care Med 1994;22:465-469. 98. Statman R,Cheng W,Cunningham lN, et al: Nitricoxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation. 1 Surg Res 1994;57:93-98. 99. Ishihara S, Ward lA, Tasaki 0, et al: Inhaled nitric oxide prevents left ventricular impairment during endotoxemia. 1 Appl Physiol 1998;85:2018-2024. 100. Price S, Evans T, Mitchell lA: Atrial dysfunction induced by endotoxin is modulated by L-arginine: role of nitric oxide [abstract]. Br1 Pharmacol 1999;126:77P. 101. Madden HP, Breslin RJ, Wasserkrug HL, et al: Stimulationof T cell immunity by arginine enhances survival in peritonitis.1 Surg Res 1988;44:658-663. 102. Gianotti L, Alexander lW, Pyles T, Fukushima R: Argininesupplemented diets improve survival in gut-derived sepsis and
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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 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"
391
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.
392
32 • Cardiac Surgery
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.
393
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.
394
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 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 7.2) No distension Normal PIA PIA 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 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 (
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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39 • Short Bowel Syndrome
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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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
466
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 30500 mL but 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)
500-1000 >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.
550
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 1.5 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 -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-
