Diet and Nutrition in Critical Care 1461478375, 9781461478379

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Rajkumar Rajendram Victor R. Preedy Vinood B. Patel  Editors

Diet and Nutrition in Critical Care

1 3Reference

Diet and Nutrition in Critical Care

Rajkumar Rajendram Victor R. Preedy • Vinood B. Patel Editors

Diet and Nutrition in Critical Care With 413 Figures and 548 Tables

Editors Rajkumar Rajendram Royal Free London Hospitals Barnet General Hospital London, UK Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London London, UK

Victor R. Preedy Department of Nutrition and Dietetics Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London London, UK

King Khalid University Hospital King Saud University Medical City Riyadh, Saudi Arabia Vinood B. Patel Department of Biomedical Sciences Faculty of Science & Technology University of Westminster London, UK

ISBN 978-1-4614-7837-9 ISBN 978-1-4614-7836-2 (eBook) ISBN 978-1-4614-7838-6 (print and electronic bundle) DOI 10.1007/978-1-4614-7836-2 Library of Congress Control Number: 2015940092 Springer New York Heidelberg Dordrecht London # Springer Science+Business Media New York 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer Science+Business Media LLC New York is part of Springer Science+Business Media (www.springer.com)

Preface

Patients in need of critical care require expert holistic attention from physicians, surgeons, microbiologists, hematologists, clinical biochemists, pathologists, nurses, physiotherapists, and other medical specialties. Management of the dietary and nutritional needs of these patients is crucial, and the evidencebased input of specialists in nutrition and dietetics is central to their care. It is well recognized that malnourished patients spend longer in hospital and have more interventions and higher rates of mortality and comorbid conditions than their well-nourished counterparts. Some illnesses will cause frank malnutrition, which will exacerbate the illness and impede recovery. However, the remedy is not just “feeding” or the use of standard (off-the-shelf) enteral or parenteral solutions. There is a tremendous amount of scientific information relating to the requirements of the critically ill. Depending on the medical condition, some patients may be refractory to nutritional support for a number of reasons. Specific diseases or trauma may require specific treatments or nutrients that may not be applicable to other conditions. On the other hand, some specific protocols may be equally applicable across a wide range of conditions. Thus, the positive outcomes from one well-planned and scientifically sound study may be applicable to other medical conditions. In its purest form, evidence-based clinical practice demands that these studies should be repeated in each specific disease before widespread application. In some cases, treatments may only be at the preclinical stage. Finding all the information necessary to treat or meet the nutritional requirements of patients who are severely ill or establish new protocols has hitherto been problematic. This is addressed in Diet and Nutrition in Critical Care. This book encapsulates the treatments and procedures to meet the dietary and nutritional needs of the critically ill. Preoperative conditions and their connections to diet and nutrition are also described. Frequently, the term critical care is used interchangeably with intensive care, though essentially this book deals with nutrition in those who are seriously ill. The division between the varying severities of illness and the placement of patients within different therapeutic units is bridged by the inclusion of a specific section within each chapter entitled Applications to Critical or Intensive Care. Furthermore, slightly different precautions, innovations, success rates, and outcome measures may apply to illnesses where different conditions (e.g., cancer versus sepsis), organs (e.g., liver versus kidney), or population groups (e.g., young versus old) may be affected. v

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Preface

The section Applications to Other Conditions addresses this too. Thus, Diet and Nutrition in Critical Care provides information that covers all manner of conditions that may arise in the critical care setting with its unique sections. We are also mindful that great advances in enteral and parenteral nutrition have been made via preclinical studies. For example, some of the pioneering studies on branched-chain amino acids involved measuring protein synthesis in incubated muscles in vitro. Later, studies were carried out on perfused hemicorpus skeletal muscle preparations, which were followed by measurements in intact laboratory animals in vivo. Such transitions ultimately aid the patient or provide detailed insights into the mechanisms whereby treatment regimens exert their effect. Thus, this book contains information or chapters on novel therapeutic treatments at various stages of preclinical development. Diet and Nutrition in Critical Care addresses the needs of all those concerned with diet and nutrition in the critically ill. The subject matter is covered as per the following main aspects: General Aspects Enteral Aspects Parenteral Aspects Accordingly, the sections in this title are as follows: General Aspects: General Conditions in the Severely Ill General Aspects: Screening, Assessments, Requirements, and Protocols General Aspects: Nutritional Aspects in Specific Conditions and Scenarios General Aspects: Nutritional Aspects in the Young General Aspects: Specific Nutrients and Components General Aspects: Adverse Aspects, Outcomes, and Considerations General Aspects: Preclinical Studies General Aspects: Electronic and Published Resources Enteral Aspects: General Information, Overviews, and Methods Enteral Aspects: Specific Nutrients and Formulations Enteral Aspects: Specific Conditions Enteral Aspects: Adverse Aspects and Outcomes Enteral Aspects: Parenteral and Enteral Support Enteral Aspects: Preclinical Studies Parenteral Aspects: General Information, Overviews, and Methods Parenteral Aspects: Specific Nutrients and Formulations Parenteral Aspects: Specific Conditions Parenteral Aspects: Adverse Aspects and Outcomes Parenteral Aspects: Enteral and Parenteral Support Parenteral Aspects: Preclinical Studies The Editors recognize the limitations in simplistic divisions, and there is always difficulty in categorizing protocols or treatment regimens. For example, some regimens involve transitions from one feeding protocol to another. Furthermore, while some chapters may be headed with the term “enteral,”

Preface

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they may also contain information relating to parenteral nutrition and visa versa. Thus, some chapters can be adequately assigned to more than one section. The chapters have the following features in addition to the main text: Abstract Applications to Critical or Intensive Care Applications to Other Conditions Guidelines and Protocols Summary Points The contributors are authors of international and national standing, leaders in the field, and trendsetters. Emerging fields of science and important discoveries relating to artificial support will also be incorporated in Diet and Nutrition in Critical Care. This represents a one-stop shop of material related to general nutrition and enteral and parenteral support and is essential reading for those specializing in intensive and critical care, dietitians, nutritionists, gastroenterologists, pharmacologists, health care professionals, research scientists, biochemists, general practitioners, as well as those interested in diet and nutrition in general. London April 2015

Rajkumar Rajendram Victor R. Preedy Vinood B. Patel

About the Editors

Rajkumar Rajendram is an intensivist, anesthetist, and perioperative physician. Dr. Rajendram graduated in 2001 with a distinction from Guy’s, King’s and St. Thomas School of Medicine, London. As an undergraduate, he was awarded several prizes, merits, and distinctions in preclinical and clinical subjects. This was followed by training in general medicine and intensive care in Oxford, during which period he attained membership of the Royal College of Physicians (MRCP) in 2004. Dr. Rajendram went on to train in anesthesia and intensive care in the Central School of Anaesthesia, London Deanery, and became a fellow of the Royal College of Anaesthetists (FRCA) in 2009. He has completed higher training in regional anesthesia, pain medicine, and intensive care. Dr. Rajendram returned to Oxford as a Consultant in General Medicine at the John Radcliffe Hospital, Oxford, before moving to the Royal Free Hospital as a Consultant in Intensive Care, Anaesthesia, and Perioperative Medicine. He coauthored the Oxford Case Histories in Cardiology, which was published by the Oxford University Press in 2011. Dr. Rajendram is currently preparing the text for the Oxford Case Histories in Intensive Care. Dr. Rajendram recognizes that nutritional support is a fundamental aspect of critical care. He has therefore devoted significant time and effort into nutritional science research. As a visiting research fellow in the Nutritional Sciences Research Division of King’s College London, he has published over 50 textbook chapters, review articles, peer-reviewed papers, and abstracts from his work. Victor R. Preedy is a senior member of King’s College London (Professor of Nutritional Biochemistry) and King’s College Hospital (Professor of Clinical Biochemistry; Hon). He is attached to both the Diabetes and Nutritional Sciences Division and the Department of Nutrition and Dietetics. He is also Director of the Genomics Centre and a member of the School of Medicine. Professor Preedy graduated in 1974 with an Honours Degree in Biology and Physiology with Pharmacology. He gained his University of London Ph.D. in 1981. In 1992, he received his Membership of the Royal College of ix

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Pathologists, and in 1993 he gained his second Doctoral degree for his contribution to the science of protein metabolism in health and disease. Professor Preedy was elected as a Fellow of the Institute of Biology in 1995 and to the Royal College of Pathologists in 2000. Since then, he has been elected as a Fellow to the Royal Society for the Promotion of Health (2004) and The Royal Institute of Public Health and Hygiene (2004). In 2009, Professor Preedy became a Fellow of the Royal Society for Public Health and in 2012 a Fellow of the Royal Society of Chemistry. In his career, Professor Preedy worked at the National Heart Hospital (part of Imperial College London) and the MRC Centre at Northwick Park Hospital. He has collaborated with research groups in Finland, Japan, Australia, USA, and Germany. Professor Preedy is a leading expert in biomedical sciences and has a long standing interest in how nutrition and diet affects well-being and health. He has lectured nationally and internationally. Professor Preedy has published over 500 articles, which include peer-reviewed manuscripts based on original research, reviews, abstracts, and numerous books and volumes.

Vinood B. Patel is currently a Senior Lecturer in Clinical Biochemistry at the University of Westminster and honorary fellow at King’s College London. He presently directs studies on metabolic pathways involved in liver disease, particularly related to mitochondrial energy regulation and cell death. Research is being undertaken to study the role of nutrients, antioxidants, phytochemicals, iron, alcohol, and fatty acids in the patho-physiology of liver disease. Other areas of interest are: identifying new biomarkers that can be used for diagnosis and prognosis of liver disease, and understanding mitochondrial oxidative stress in Alzheimers disease and gastrointestinal dysfunction in autism. Dr. Patel graduated from the University of Portsmouth with a degree in Pharmacology and completed his PhD in Protein Metabolism from King’s College London in 1997. His post-doctoral work was carried out at Wake Forest University Baptist Medical School studying structural–functional alterations to mitochondrial ribosomes, where he developed novel techniques to characterize their biophysical properties. Dr. Patel is a nationally and internationally recognized liver researcher and was involved in several NIH-funded biomedical grants related to alcoholic liver disease. He has edited biomedical books in the area of nutrition and health prevention, autism, and biomarkers, and has published over 150 articles. In 2014, Dr. Patel was elected as a Fellow to The Royal Society of Chemistry.

About the Editors

Organization of the Book

This title is organized into the following parts: Part I General Aspects: General Conditions in the Severely Ill Part II General Aspects: Screening, Assessments, Requirements, and Protocols Part III General Aspects: Nutritional Aspects in Specific Conditions and Scenarios Part IV General Aspects: Nutritional Aspects in the Young Part V General Aspects: Specific Nutrients and Components Part VI General Aspects: Adverse Aspects, Outcomes, and Considerations Part VII General Aspects: Preclinical Studies Part VIII General Aspects: Electronic and Published Resources Part IX Enteral Aspects: General Information, Overviews, and Methods Part X Enteral Aspects: Specific Nutrients and Formulations Part XI Enteral Aspects: Specific Conditions Part XII Enteral Aspects: Adverse Aspects and Outcomes Part XIII Enteral Aspects: Parenteral and Enteral Support Part XIV Enteral Aspects: Preclinical Studies Part XV Parenteral Aspects: General Information, Overviews, and Methods Part XVI Parenteral Aspects: Specific Nutrients and Formulations Part XVII Parenteral Aspects: Specific Conditions Part XVIII Parenteral Aspects: Adverse Aspects and Outcomes Part XIX Parenteral Aspects: Enteral and Parenteral Support Part XX Parenteral Aspects: Preclinical Studies

Rajkumar Rajendram Victor R. Preedy Vinood B. Patel

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Contents

Volume 1 Part I

General Aspects: General Conditions in the Severely Ill

1

1

Hemodynamic Monitoring in Critical Care . . . . . . . . . . . . . . Laurence Busse, Danielle Davison, Lakhmir Chawla, and Priscilla Jang

3

2

Acid-Base Balance in Context of Critical Care . . . . . . . . . . . Phil Ayers, Carman Dixon, Andrew Mays, and D. Timothy Cannon

21

3

Liver Dysfunction in Critically Ill Patients Jennifer M. Newton, Andrew Aronsohn, and Donald M. Jensen

..............

35

4

Nutrition and Acute Lung Injury in Critical Care: Focus on Nutrition Care Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . Corrine Hanson, Eric P. A. Rutten, Christina Rollins, and Stephanie Dobak

5

6

Eicosanoid Synthesis and Respiratory Distress Syndrome in Intensive Medicine . . . . . . . . . . . . . . . . . . . . . . . Abelardo Garcia-de-Lorenzo y Mateos, Juan Carlos Montejo González, and Manuel Quintana Diaz Muscle Weakness, Molecular Mechanism and Nutrition During Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ilse Vanhorebeek

49

63

75

7

Thyroid Function in Critical Illness . . . . . . . . . . . . . . . . . . . . Foteini Economidou, Evangelia Douka, Marinella Tzanela, Stylianos Orfanos, and Anastasia Kotanidou

91

8

Obese Patient in Intensive Care Unit . . . . . . . . . . . . . . . . . . . 105 Antonia Koutsoukou, Magdalini Kyriakopoulou, Anastasia Kotanidou, and Fotini Ekonomidou

9

Adipose Tissue and Endocrine Function in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Mirna Marques and Lies Langouche xiii

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Contents

10

Extent and Nature of Infectious Diseases in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Steven J. Martin and Celeste A. Sejnowski

11

Critically Ill Patients and Circulating Amino-Terminal Pro-C-Type Natriuretic Peptide . . . . . . . . . . . . . . . . . . . . . . . 143 Alexander Koch and Frank Tacke

12

Enteral and Parenteral Feeding and Monocyte Gene Expression in Critically Ill Patients . . . . . . . . . . . . . . . . . . . . 153 Dena Arumugam, Stephen C. Gale, and Steve E. Calvano

13

Immunonutrition in Intensive Care . . . . . . . . . . . . . . . . . . . . 163 Arved Weimann and Dominique Ludwig

14

Critical Nutrition in Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Mandy L. Corrigan and Arlene A. Escuro

15

Perioperative Immunonutrition in Major Abdominal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 Martin H€ ubner, Yannick Cerantola, Markus Sch€afer, and Nicolas Demartines

16

Glutamine Supplementation in Multiple Trauma of Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Ruqaiya M. Al Balushi, Jennifer D. Paratz, Jeremy Cohen, and Merrilyn Banks

17

Plasma Phospholipid Fatty Acid Profiles in Septic Shock . . . 219 Sylvie Caspar-Bauguil and Michelle Genestal

18

Constipation in Intensive Care . . . . . . . . . . . . . . . . . . . . . . . . 235 Tatiana de Souza Lopes Guerra, Norma Guimarães Marshall, and Simone Sotero Mendonça

19

Educational, Recording and Organizational Interventions Regarding Critical Care Nutritional Support . . . . . . . . . . . . 249 Andrés Luciano Nicolas Martinuzzi, Sergio Santana Porben, Eduardo Ferraresi, Víctor Hugo Borrajo, and Victor R. Preedy

Part II General Aspects: Screening, Assessments, Requirements, and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

263

20

Extent and Impact of Malnutrition in Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Lisa L. Kirkland

21

Nutrition Status and Length of Hospital Stay . . . . . . . . . . . . 279 Vania Aparecida Leandro-Merhi, José Luiz Braga de Aquino, and Maria Rita Marques de Oliveira

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22

Nutritional Screening Tools in Critical Care . . . . . . . . . . . . . 293 Fawaz Alzaid, Rajkumar Rajendram, Vinood B. Patel, and Victor R. Preedy

23

Nutritional Screening and Assessment Tools for Cardiac Surgery and ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Sergey Efremov and Vladimir Lomivorotov

24

Pediatric ICU and Nutritional Assessments . . . . . . . . . . . . . . 325 Rubens Feferbaum and Patrícia Zamberlan

25

Diagnosis and Prevalence of Iron Deficiency in the Critically Ill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 Sigismond Lasocki, Thomas Gaillard, and Emmanuel Rineau

26

Metabolic Rate in Older Critically Ill Patient . . . . . . . . . . . . 351 David C. Frankenfield

27

Bioenergetic Gain of Citrate-Anticoagulated Continuous Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 359 M. Balik and M. Zakharchenko

28

Protein Intake in Critically Ill Adults . . . . . . . . . . . . . . . . . . . 371 Suzie Ferrie and Samantha Rand

29

Nutrition in Critically Ill and Injured Patients: Focus on Pathophysiology, Initiation, Choice, Energy Requirements and Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383 Rifat Latifi and Ibrahim Afifi

30

Critical Illness and Intestinal Microflora: pH as a Surrogate Marker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Irma Fleming, Jennifer Defazio, Olga Zaborina, and John C. Alverdy

31

Perioperative Malnutrition: Focus on Scheduled Surgery Performed in Adult Patients . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Robert Cohendy

32

Top Ten Quality Indicators for Nutritional Therapy . . . . . . 417 Cristiane Comeron Gimenez Verotti, Guilherme Duprat Ceniccola, and Rajkumar Rajendram

33

Micronutrient Function, Status and Disposition in Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Joseph I. Boullata

34

Micronutrient Supplementation for Critically Ill Adults: Practical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 Janicke Visser and Renée Blaauw

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Magnesium and Cardiac Surgery in the Critical Care Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 Maria L. Carrio, Juan Carlos Lopez-Delgado, Casimiro Javierre, Herminia Torrado, Elisabet Farrero, David Rodríguez-Castro, and Josep L. Ventura

36

Vasoactive Substances and Nutrition in Critical Care John M. Allen

37

Nutritional Supplements for Critically Ill Patients: Efficient Tools to Improve Wound Healing . . . . . . . . . . . . . . 483 Sabine Ellinger

38

Importance of n-3 Polyunsaturated Fatty Acids in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 Nakamichi Watanabe

39

Transition from Parenteral to Enteral Nutrition in Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Carmel O’Hanlon, Nicola Dervan, Julie Dowsett, and Clare Corish

40

Controlling Oxidative Stress as a Potential Tool for Perioperative Management to Reduce Morbidity After Surgical Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 Satoshi Aiko

41

Intermittent and Bolus Methods of Feeding in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 Satomi Ichimaru and Teruyoshi Amagai

42

Oral Feeding, Dysphagia and Aspiration in Tracheostomized Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549 Edward A. Bittner and Ulrich Schmidt

. . . . . 473

Part III General Aspects: Nutritional Aspects in Specific Conditions and Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

561

43

Enteral and Parenteral Nutrition in Cancer Patients: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 Avani Changela, Evangelia Davanos, and Hemangkumar Javaiya

44

Feeding Routes After Pancreatoduodenectomy . . . . . . . . . . . 575 Arja Gerritsen, I. Quintus Molenaar, A. Roos W. Wennink, Elles Steenhagen, Elisabeth M. H. Mathus-Vliegen, Dirk J. Gouma, and H. Marc G. Besselink

45

Nutritional Support in Adult Patients Undergoing Allogeneic Stem Cell Transplantation Following Myeloablative Conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . 593 Nicolas Danel Buhl and David Seguy

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46

Probiotics Prophylaxis of Nosocomial Pneumonia in Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607 Kai-xiong Liu, Jie-ming Qu, Jing Zhang, and Qi-chang Lin

47

Nutrition in Abdominal Aortic Repair . . . . . . . . . . . . . . . . . . 623 Arthur R. H. van Zanten

48

Parenteral Nutrition and Cardiogenic Shock Ronan Thibault and Karim Bendjelid

49

Diet and Nutrition in Orthopedics . . . . . . . . . . . . . . . . . . . . . 653 Sotiria Everett, Rupali Joshi, Libi Galmer, Marci Goolsby, and Joseph Lane

50

Critically Ill Patient on Renal Replacement Therapy: Nutritional Support by Enteral and Parenteral Routes Alice Sabatino and Enrico Fiaccadori

. . . . . . . . . . . . 635

. . . . 671

51

RETRACTED CHAPTER: Brain Trauma and Nutritional Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685 Wolfgang A. Wetsch, Bernd W. Böttiger, and Stephan A. Padosch

52

Severe Head Trauma and Omega-3 Fatty Acids . . . . . . . . . . 695 Michael D. Lewis

53

Parkinson’s Disease, Nutrition and Surgery in Context of Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 Jamie M. Sheard and Susan Ash

54

Prolonged Mechanical Ventilation and Nutritional Support Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727 Jennifer A. Doley and Michelle Sandberg

55

Preoperative Nutrition in Elderly Patients and Postoperative Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741 Julia van Wissen, Nathalie Bakker, Colin Heus, and Alexander P. J. Houdijk

56

Nutrition and Critical Care in Very Elderly Stroke Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753 Hitoshi Obara, Natsuki Ito, and Mamoru Doi

Part IV

General Aspects: Nutritional Aspects in the Young . . .

767

57

Use of Probiotics in Preterm Neonates . . . . . . . . . . . . . . . . . . 769 Thomas Havranek, Mohamad Alhosni, and Rita Chrivia

58

Feeding Intervals in Very Low Birth-Weight Infants in Intensive or Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779 Sara B. DeMauro and Megan M. Gray

59

Human Milk and Premature Infant: Focus on Use of Pasteurized Donor Human Milk in NICU . . . . . . . . . . . . . . . 795 Mark A. Underwood and Jennifer A. Scoble

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Human Milk Feedings in the Neonatal Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807 Paula P. Meier, Aloka L. Patel, Harold R. Bigger, Yimin Chen, Tricia J. Johnson, Beverly Rossman, and Janet L. Engstrom

61

Withdrawal of Artificial Nutrition and Hydration in Neonatal Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823 Constance Williams and Jonathan Hellmann

62

Low-Profile Balloon Gastrostomy Tubes for Nutritional Support in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835 Riad M. Rahhal

63

Nutritional and Surgical Management of Pediatric Intestinal Motility Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 845 Mikko P. Pakarinen, Laura Merras-Salmio, and Annika Mutanen

64

Critical Ill Infants with Gastro-Oesophageal Reflux Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859 Kim Psaila and Jann P. Foster

65

Nutrition Support for the Critically Ill Infant Post Cardiac Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871 Bodil M. K. Larsen and Megan R. Beggs

66

Adequacy of Nutritional Support in Critically Ill Children with Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . 885 Ursula G. Kyle, Ayse Akcan-Arikana, Renán A. Orellana, and Jorge A. Coss-Bu

Part V General Aspects: Specific Nutrients and Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

897

. . . . . . . 899

67

Specific Considerations Relevant to Critical Illness Karin Amrein, Christian Schnedl, Dima Youssef Alan N. Peiris, and Harald Dobnig

68

Dietary and Nutritional Aspects of Zinc in Critically Ill Adult Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917 Beth Besecker

69

Polyunsaturated Fatty Acids and Cytokines: Their Relationship in Acute Lung Injury . . . . . . . . . . . . . . . . . . . . . 929 Paolo Cotogni, Antonella Trombetta, Giuliana Muzio, Maria Felice Brizzi, and Rosa Angela Canuto

70

Sodium Loading in Critical Care . . . . . . . . . . . . . . . . . . . . . . 943 Shailesh Bihari and Andrew D. Bersten

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71

Thiamine (Vitamin B1) Deficiency in Intensive Care: Physiology, Risk Factors, Diagnosis, and Treatment . . . . . . . 959 Heitor Pons Leite and Lúcio Flávio Peixoto de Lima

72

Vitamin B12 and Mortality in Critically Ill . . . . . . . . . . . . . . 973 Sigal Sviri, Ayman Abu Rmeileh, Marc Romain, David Michael Linton, Ilana Stav, and Peter Vernon van Heerden

73

Vitamin C, Extremity Trauma and Surgery . . . . . . . . . . . . . 983 Naohiro Shibuya, Monica R. Agarwal, and Daniel C. Jupiter

74

Intensive Care and Vitamin D Status . . . . . . . . . . . . . . . . . . . 989 Dima Youssef, Karin Amrein, Christian Schnedl, Harald Dobnig, and Alan N. Peiris

75

Over the Counter Nutritional Supplements: Implications for Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005 Philip Gregory, Darren Hein, Mark Malesker, and Lee E. Morrow

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Probiotic Agents in Critically Ill Patients . . . . . . . . . . . . . . . . 1017 Lee E. Morrow, Albert Naveed, and Mark A. Malesker

77

Perioperative Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025 Greta L. Piper and Adrian A. Maung

Part VI General Aspects: Adverse Aspects, Outcomes, and Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035 78

Intestinal Dysmotility of Critical Illness . . . . . . . . . . . . . . . . . 1037 David C. Evans and Robert G. Martindale

79

Calorie and Protein Deficit in the ICU . . . . . . . . . . . . . . . . . . 1051 Anne Coltman, Sarah Peterson, and Diane Sowa

80

Etiology and Complications of Refeeding Syndrome in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065 José Joaquín Alfaro Martínez, Isabel Huguet Moreno, Francisco Botella Romero, and Antonio Hernández López

81

Overview of Nutritional Deficiencies After Bariatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079 Farzin Rashti, Ekta Gupta, Timothy R. Shope, and Timothy R. Koch

82

Bioethical and Medico-legal Implications of Withdrawing Artificial Nutrition and Hydration from Adults in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . 1093 Carlo Moreschi and Ugo Da Broi

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Volume 2 Part VII

General Aspects: Preclinical Studies . . . . . . . . . . . . . . . . 1107

83

Amniotic Fluid and Colostrum as Potential Diets in the Critical Care of Preterm Infants . . . . . . . . . . . . . . . . . 1109 Ann Cathrine Findal Støy, Mette Viberg Østergaard, and Per Torp Sangild

84

Zinc Supplementation in Murine Sepsis . . . . . . . . . . . . . . . . . 1123 Matthew N. Alder and Hector R. Wong

85

Hydroxymethylbutyrate and Eicosapentaenoic Acid: Preclinical Studies to Improve Muscle Function in Critical Care Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135 Gerald S. Supinski and Leigh A. Callahan

86

Arginine in Critical Care: Preclinical Aspects . . . . . . . . . . . . 1149 Juan B. Ochoa Gautier

87

Effects of Nutrition on Neutrophil Function in Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165 Keisuke Kohama, Joji Kotani, and Atsunori Nakao

88

Anemia of the Critically Ill Patient: Pathophysiology, Lessons from Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . 1179 Emmanuel Rineau, Thomas Gaillard, and Sigismond Lasocki

Part VIII General Aspects: Electronic and Published Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191 89

Expanding the Knowledge Base in Diet, Nutrition and Critical Care: Electronic and Published Resources . . . . . . . . 1193 Fawaz Alzaid, Rajkumar Rajendram, Vinood B. Patel, and Victor R. Preedy

Part IX Enteral Aspects: General Information, Overviews, and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201 90

Commercial Enteral Formulas and Nutritional Support Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1203 Consuelo Carmen Pedrón-Giner, Victor Manuel Navas-López, Cecilia Martínez-Costa, and Ana Martínez-Zazo

91

Blood Glucose Control: Strategy for Treatment of Hyperglycemia in Patients Receiving Enteral Nutrition . . . . 1221 Fiorenzo Cortinovis, Sara Cassibba, and Ottavia Colombo

92

Calorimetry for Enteral Feeding in Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233 Rakesh Garg and Indubala Maurya

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93

Colorimetric Capnometry and Feeding Tube Placement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247 Jean-Rémi Lavillegrand, Georges Offenstadt, Eric Maury, Bertrand Guidet, and Arnaud Galbois

94

Home Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255 Lilianne Gómez López, Consuelo Carmen Pedrón-Giner, Cecilia Martínez-Costa, and Caterina Calderón Garrido

95

Incretin Effects and Enteral Feed Transitions . . . . . . . . . . . . 1269 Ummu Kulthum Jamaludin, Paul Docherty, and Jean Charles Preiser

96

Enteral Nutrition and Glucagon-Like Peptide-1 in Intensive Care Unit Patients . . . . . . . . . . . . . . . . . . . . . . . . . . 1283 Okan Bakiner and M. Eda Ertorer

97

Intestinal Absorption and Enteral Nutrition Support During Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1297 Dep Huynh and Nam Q. Nguyen

98

Intestinal Transit Time, Video Capsule Technology, and Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1313 Stefan Rauch and Matthias Fischer

99

Prokinetic Agents with Enteral Nutrition . . . . . . . . . . . . . . . 1323 Ron R. Neyens, Melissa L. Hill, Michelle R. Huber, and Julio A. Chalela

100

Mortality in Intensive Care and the Role of Enteral Nutrition in Trauma Patients . . . . . . . . . . . . . . . . . . . . . . . . . 1333 Gordon S. Doig, Fiona Simpson, and Philippa T. Heighes

101

Critical Care Setting of Bedside Positioning of Electromagnetically Guided Nasointestinal Tubes Magnus F. Kaffarnik and Johan F. Lock

. . . . . . . . 1339

102

Bedside Placement of Nasoenteric Feeding Tubes Using Fluoroscopic Guidance by Trained Mid-level Practitioners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347 Richard G. Barton, Tricia B. Hauschild, Katy Y. Fu, Mary C. Mone, Edward J. Kimball, and Raminder Nirula

103

Radiologic Percutaneous Gastrostomy for Enteral Access in Patients Requiring Long-Term Nutritional Support . . . . . 1355 Diego A. Covarrubias, Gabriel M. Covarrubias, and Jessica M. Ho

104

Use of pH Cutoff Level for Enteral Nutrition . . . . . . . . . . . . 1369 Heather Gilbertson

105

Initiating Safe Oral Feeding in Critical Care . . . . . . . . . . . . . 1383 Steven B. Leder, Debra M. Suiter, and Lewis J. Kaplan

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Contents

106

Aid to Enteral Feeding in Critical Care: Algorithm . . . . . . . 1393 Anneli Reeves, Caroline Kiss, Hayden White, Kellie Sosnowski, and Christine Josephson

107

Enteral Decision Tree in Critical Illness . . . . . . . . . . . . . . . . . 1413 Jean-Charles Preiser and Mathieu De Ryckere

Part X Enteral Aspects: Specific Nutrients and Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421 108

Inadequate Vitamin B-6 Status in Critical Care . . . . . . . . . . 1423 Yi-Chia Huang and Chien-Hsiang Cheng

109

Protein-Enriched Enteral Nutrition in Childhood Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1433 Javier Urbano, Sarah N. Fernández, and Jesús López-Herce

110

Enteral Support and N-3 Fatty Acids in Critically Ill Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1447 Karina V. Barros, Ana Paula Cassulino, and Vera Lúcia Flor Silveira

111

Viscosity Thickened Enteral Formula Satomi Ichimaru and Teruyoshi Amagai

Part XI

. . . . . . . . . . . . . . . . . . 1463

Enteral Aspects: Specific Conditions . . . . . . . . . . . . . . . . . 1479

112

Enteral Feeding and Infections in Preterm Neonates . . . . . . 1481 Gianluca Terrin, Maria Giulia Conti, and Antonella Scipione

113

Enteral Nutrition, Critically Ill Children, and Lung Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1499 Rupal T. Bhakta and Brian R. Jacobs

114

Short Bowel Syndrome in Neonatal Intensive Care Unit and Enteral Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513 Sachin C. Amin, Sabrina Livshin, and Akhil Maheshwari

115

Enteral Nutrition in Open Abdomen After Injury Clay Cothren Burlew

116

Enteral Nutrition Support in Burns . . . . . . . . . . . . . . . . . . . . 1539 Abdikarim Abdullahi and Marc G. Jeschke

117

Nutritional Rehabilitation in Severe and Critical Anorexia Nervosa: Role of Enteral Nutrition . . . . . . . . . . . . 1551 Gabriella Maria Gentile

118

Obese Patients in Critical Care: Nutritional Support Through Enteral and Parenteral Routes . . . . . . . . . . . . . . . . 1563 Magdalini Kyriakopoulou, Stavrina Avgeropoulou, Anastasia Kotanidou, Foteini Economidou, and Antonia Koutsoukou

. . . . . . . . 1529

Contents

xxiii

119

Influence of Postoperative Enteral Nutrition on Cellular Immunity: Investigative Procedures, Tests and Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577 Mette Platz, Anja Poulsen, and Randi Beier-Holgersen

120

Enteral Nutrition in Neurological Patients . . . . . . . . . . . . . . . 1591 Francisco Botella-Romero, Antonio Hernández-López, José Joaquín Alfaro-Martínez, Marta Gómez-Garrido, and Cristina Lamas-Oliveira

121

Percutaneous Endoscopic Gastrostomy (PEG) in Elderly: Medical Indications, Ethical Limits . . . . . . . . . . . . . . . . . . . . 1599 Christian Löser

122

Early Enteral Nutrition in Postoperative Cardiac Surgery Patients with Severe Hemodynamic Failure and Venoarterial (VA) Extracorporeal Membrane Oxygenation (ECMO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609 Luis Daniel Umezawa Makikado, José Luis Flordelís Lasierra, José Luis Pérez-Vela, and Juan Carlos Montejo González

Part XII

Enteral Aspects: Adverse Aspects and Outcomes . . . . 1623 . . . . . . . . . 1625

123

Mechanical Complications of Nasoenteric Tubes Christian Jones, Stanislaw P. A. Stawicki, and David C. Evans

124

Clogs and Clots in Enteral Tubes: Prevention and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1637 Michelle R. Huber, Vincent R. Vernacchio, Ron R. Neyens, and Julio A. Chalela

125

Managing Diarrhea During Enteral Feeding in ICU Suzie Ferrie

Part XIII

. . . . . . 1647

Enteral Aspects: Parenteral and Enteral Support . . . . 1659

126

Tight Calorie Control Study (TICACOS) in Critically Ill Patients on both Enteral and Parenteral Support . . . . . . . . . 1661 Pierre Singer and Jonathan Cohen

127

Enteral and Parenteral Feeding and Orexigenic Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671 Przemyslaw J. Tomasik and Krystyna Sztefko

128

Children with Intestinal Failure and Parenteral and Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1681 Kathleen M. Gura

129

Parenteral and Enteral Nutrition with Omega-3 Fatty Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1695 Julie Martin and Renee D. Stapleton

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Part XIV

Enteral Aspects: Preclinical Studies . . . . . . . . . . . . . . . . 1711

130

Nutritional Modulation of Immune Response via Vagus Nerve: Preclinical Studies and Future Perspectives . . . . . . . 1713 Jacco J. de Haan, Tim Lubbers, Misha D. Luyer, and Wim A. Buurman

131

Enteral Diets and Parenteral Feedings with Different n-6/n-3 Ratios in Rats and Mice . . . . . . . . . . . . . . . . . . . . . . . 1729 Nakamichi Watanabe

132

Enteral Supplementation of Palm Vitamin E and Alpha-Tocopherol: Pre-clinical Aspects . . . . . . . . . . . . . . . . . 1733 Mohd Fahami Nur Azlina, Haji Mohd Saad Qodriyah, and Yusof Kamisah

Part XV Parenteral Aspects: General Information, Overviews, and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1749 133

Commercial Parenteral Formulas and Nutrition Support Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1751 Margarita Cuervas-Mons Vendrell, del Río MªTeresa Pozas, and Consuelo Pedrón-Giner

134

Energy Balance in the Intensive Care Unit . . . . . . . . . . . . . . 1767 Enid E. Martinez and Nilesh M. Mehta

135

Use of Ethanol Lock Therapy for Children with Intestinal Failure on Long-Term Parenteral Nutrition . . . . . . . . . . . . . 1779 Hannah G. Piper and Paul W. Wales

136

Home Parenteral Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1791 Abdullah Shatnawei, Shishira Bharadwaj, Denise Konrad, Sandra Austhof, and Ronelle Mitchell

Part XVI Parenteral Aspects: Specific Nutrients and Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805 137

Parenteral Soybean Oil Lipid Emulsion in Very Low Birth Weight (VLBW) in Intensive Care . . . . . . . . . . . . . . . . 1807 Hiromichi Shoji and Toshiaki Shimizu

138

Calcium and Phosphorus Intake by Parenteral Nutrition in Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1817 Luis Pereira-da-Silva, Israel Macedo, Maria Luísa Rosa, and Kayla M. Bridges

139

L-Alanyl-L-glutamine

Dipeptide-Supplemented Total Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1831 José Luis Flordelís Lasierra and Teodoro Grau Carmona

Contents

xxv

140

Glutamine-Enriched Total Parenteral Nutrition and Glutamine Supplementation in Gastrointestinal Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1841 Cheng-Jen Ma and Jaw-Yuan Wang

141

Vitamins During Cycles of Intermittent Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1853 Selma Freire C. Cunha, José Henrique da Silvah, Cristiane Maria Mártires de Lima, and Júlio Sérgio Marchini

142

Vitamin E in Parenteral Lipid Emulsions . . . . . . . . . . . . . . . 1861 Alaadin Alayoubi, Ahmed Abu-Fayyad, and Sami Nazzal

143

Vitamin K and Parenteral Nutrition . . . . . . . . . . . . . . . . . . . 1875 Rezvaneh Azad-armaki and Johane P. Allard

144

Amino Acid Composition in Parenteral Nutrition . . . . . . . . . 1885 Kursat Gundogan and Thomas R. Ziegler

Part XVII

Parenteral Aspects: Specific Conditions . . . . . . . . . . . . 1895

145

Parenteral Nutrition in Advanced Cancer . . . . . . . . . . . . . . . 1897 Edward M. Copeland III

146

Use of Teduglutide to Reduce Parenteral Support in Short Bowel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1913 Palle Bekker Jeppesen

147

Intestinal Failure and Parenteral Omega-3 Fatty Acid Lipid Emulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1929 Justine M. Turner and Paul W. Wales

148

Glutamine Parenteral Nutrition in Pneumonia . . . . . . . . . . . 1945 Meltem T€urkay, Aslıhan Tug, Sıtkı Nadir Sinikoglu, Yakup Tomak, Mehmet Salih Sevdi, Serdar Demirgan, and Aysin Alagol

149

Parenteral Amino Acid Strategies for Nutritional Optimization in Low Birth Weight Infants . . . . . . . . . . . . . . 1957 Cynthia L. Blanco and Julie C. Hisey

150

Parenteral Amino Acids in Preterm Infant and Impact on Bone Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1971 Martina Betto, Paola Gaio, Giorgia Rizzi, and Giovanna Verlato

Part XVIII Parenteral Aspects: Adverse Aspects and Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1983 151

Parenteral Nutrition and Hypersensitivity Reaction . . . . . . . 1985 Corentin Babakissa, Chantal Lemire, and Stephane Larin

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152

Catheter-Related Infections in Pediatric Parenteral Nutrition in Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . 1997 A. Vivanco-Allende, C. Rey, A. Concha, and A. Medina

153

Manganese Intoxication and Encephalopathy . . . . . . . . . . . . 2013 Charles M. Andrews, Christine M. Martin, and Julio A. Chalela

154

Light-Exposed Parenteral Nutrition Solutions and Implications for Preterm Infants . . . . . . . . . . . . . . . . . . . . . . 2019 Shereen Mosa and Nehad Nasef

155

Shortages of Parenteral Nutrition Components: Relevance to Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2037 Corrine Hanson, Melissa Thoene, Julie Wagner, and Ann Anderson-Berry

156

Aluminum in Subjects Receiving Parenteral Nutrition . . . . . 2049 Denise Bohrer

157

Hyperammonemia as an Adverse Effect in Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2065 Joe V. M. Devasahayam, Santhosh G. John, Seth Assar, Zeenat Y. Bhat, Aparna N. Kurup, Suresh Hosuru, Valentina Joseph, and Unnikrishnan Pillai

158

Hypoglycemia with Insulin and Parenteral Nutrition . . . . . . 2079 Kelly Kinnare

159

Thrombosis, Central Venous Lines and Parenteral Nutrition in Pediatric Intensive Care . . . . . . . . . . . . . . . . . . . 2089 Ana Vivanco-Allende, Corsino Rey, Alberto Medina, and Andres Concha

Part XIX Parenteral Aspects: Enteral and Parenteral Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2101 160

Enteral and Parenteral Nutrition in Postoperative Pancreatic Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2103 Stanislaw Klek

Part XX

Parenteral Aspects: Preclinical Studies . . . . . . . . . . . . . . 2113

161

Parenteral Nutrition, Critical Illness, Paneth Cell Function and the Innate Immune Response . . . . . . . . . . . . . . . . . . . . . 2115 Xinying Wang, Joseph F. Pierre, and Kenneth A. Kudsk

162

Parenteral Omega-3 Fatty Acids (Omegaven) and Intestinal Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2127 Sukhotnik Igor Retraction Note to: Brain Trauma and Nutritional Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

E1

Contributors

Abdikarim Abdullahi Sunnybrook Health Sciences Centre, Ross Tilley Burn Center Research Program, Toronto, ON, Canada Ahmed Abu-Fayyad Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA Ayman Abu Rmeileh Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Ibrahim Afifi Trauma Section, Hamad General Hospital, Doha, Qatar Monica R. Agarwal Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Bryan, TX, USA Central Texas VA Health Care System, Temple, TX, USA Satoshi Aiko Department of Surgery, Eiju General Hospital, Tokyo, Japan Ayse Akcan-Arikana Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA Renal Section, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA Ruqaiya M. Al Balushi Department of Nutrition and Health, College of Food and Agriculture, United Arab Emirates University, Al Ain, United Arab Emirates Aysin Alagol Department of Anesthesiology and Reanimation, Bagcılar Training and Research Hospital, Istanbul, Turkey Alaadin Alayoubi Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA Matthew N. Alder Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Department of Pediatrics, Cincinnati Children’s Research Foundation, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

xxvii

xxviii

José Joaquín Alfaro Martínez Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Albacete. Universidad de CastillaLa Mancha, Albacete, Spain Mohamad Alhosni School of Medicine, Department of Pediatrics, Division of Neonatology, Saint Louis University, St. Louis, MO, USA Johane P. Allard Department of Gastroenterology, Toronto General Hospital, Toronto, ON, Canada John M. Allen Department of Pharmacotherapeutics and Clinical Research, University of South Florida College of Pharmacy, Tampa, FL, USA John C. Alverdy Center for Surgical Infection Research and Therapeutics, The University of Chicago Medicine, Chicago, IL, USA Fawaz Alzaid Pathogenèse cellulaire et clinique du diabète, INSERM UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France Teruyoshi Amagai Department of Food Science and Nutrition, School of Human Environmental Sciences, Mukogawa Women’s University, Nishinomiya, Japan Sachin C. Amin Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA Division of Neonatology and the Center for Neonatal and Pediatric Gastrointestinal Disease, University of Illinois at Chicago, Chicago, IL, USA Karin Amrein Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria Ann Anderson-Berry Pediatrics Newborn Medicine, University of Nebraska Medical Center, Omaha, NE, USA Charles M. Andrews Department of Medicine, Division of Emergency Medicine, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA Andrew Aronsohn Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago Medicine, Chicago, IL, USA Dena Arumugam Department of Surgery, Rutgers/Robert Wood Johnson Medical School, New Brunswick, NJ, USA Susan Ash School of Exercise and Nutrition Sciences, Queensland University of Technology, Brisbane, QLD, Australia Seth Assar Department of Medicine, University of Arizona, Tucson, AZ, USA Sandra Austhof Center for Human Nutrition, Cleveland Clinic, Digestive Disease Institute, Cleveland, OH, USA

Contributors

Contributors

xxix

Stavrina Avgeropoulou ICU, 1st Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece Phil Ayers Department of Pharmacy, Mississippi Baptist Medical Center, Jackson, MS, USA Rezvaneh Azad-armaki University Health Network, University of Toronto, Toronto, ON, Canada Corentin Babakissa Department of Pediatrics, University of Sherbrooke School of Medicine, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada Okan Bakiner Division of Endocrinology and Metabolism, Baskent University Faculty of Medicine, Y€uregir, Adana, Turkey Nathalie Bakker Department of Surgery, Medical Center Alkmaar, The Netherlands Trial Center Holland Health, Alkmaar, The Netherlands M. Balik Department of Anaesthesiology and Intensive Care, First Faculty of Medicine, Charles University and General University Hospital, Prague 2, Czech Republic Merrilyn Banks Department of Nutrition and Dietetics, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia Karina V. Barros Departamento de Fisiologia, Universidade Federal de São Paulo-Campus São Paulo, São Paulo, SP, Brazil Richard G. Barton Department of Surgery, Division of General Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA Megan R. Beggs Nutrition Services, Alberta Health Services, Edmonton, AB, Canada Randi Beier-Holgersen Department of Surgery, Hillerod University Hospital, Hilleroed, Denmark Karim Bendjelid Department of Intensive Care, Geneva University Hospital, Geneva 14, Switzerland Andrew D. Bersten Department of Intensive and Critical Care Unit, Flinders Medical Centre and Flinders University, Bedford Park, SA, Australia Beth Besecker Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA H. Marc G. Besselink Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands Martina Betto Department of Woman and Child’s Health, University of Padova, Padova, Italy

xxx

Rupal T. Bhakta Department of Critical Care Medicine, Children’s National Medical Center, Washington, DC, USA Shishira Bharadwaj Cleveland Clinic, Digestive Disease Institute, Cleveland, OH, USA Zeenat Y. Bhat Division of Nephrology, Wayne State University, Detroit, MI, USA Harold R. Bigger Department of Pediatrics, Section of Neonatology, Rush University Medical Center, Chicago, IL, USA Shailesh Bihari Department of Intensive and Critical Care Unit, Flinders Medical Centre and Flinders University, Bedford Park, SA, Australia Edward A. Bittner Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA Renée Blaauw Division of Human Nutrition, Department of Interdisciplinary Health Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, South Africa Cynthia L. Blanco Division of Neonatology, Department of Pediatrics, University of Texas Health Science Center San Antonio, San Antonio, TX, USA Denise Bohrer Department of Chemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil Víctor Hugo Borrajo Terapia Intensiva, Centro Medico Integral del Comahue (CMIC), Neuquen, Argentina Francisco Botella Romero Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Albacete. Universidad de CastillaLa Mancha, Albacete, Spain Bernd W. Böttiger Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany Joseph I. Boullata University of Pennsylvania, Department of Biobehavioral and Health Sciences, Philadelphia, PA, USA Clinical Nutrition Support Services, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Kayla M. Bridges Neonatal Intensive Care Unit, St. John Providence Children’s Hospital, Detroit, MI, USA Maria Felice Brizzi Department of Medical Sciences, University of Turin, Turin, Italy Clay Cothren Burlew Department of Surgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA

Contributors

Contributors

xxxi

Laurence Busse Department of Medicine, Medical Critical Care Services (MCCS), Inova Fairfax Hospital, Falls Church, VA, USA Wim A. Buurman Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands Leigh A. Callahan Division of Pulmonary, Critical care and Sleep Medicine, Department of Internal Medicine, University of Kentucky, Lexington, KY, USA Steve E. Calvano Department of Surgery, Rutgers/Robert Wood Johnson Medical School, New Brunswick, NJ, USA D. Timothy Cannon Jackson Pulmonary Associates, Jackson, MS, USA Rosa Angela Canuto Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy Teodoro Grau Carmona Department of Intensive Care, Hospital Universitario Doce de Octubre, Madrid, Spain Maria L. Carrio Department of Intensive Care, Hospital Universitari de Bellvitge, IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), Universitat de Barcelona, Barcelona, Spain Sylvie Caspar-Bauguil University Paul Sabatier, Toulouse 3, Toulouse, France Nutritional Biochemistry Laboratory, University Hospital Center Purpan, C.H.U., Toulouse, France Sara Cassibba USC Endocrinologia, Azienda Ospedaliera “Papa Giovanni XXIII”, Bergamo, Italy Ana Paula Cassulino Departamento de Fisiologia, Universidade Federal de São Paulo-Campus São Paulo, São Paulo, SP, Brazil Guilherme Duprat Ceniccola Residência de Nutrição Clínica, EMTN, Hospital de Base do DF, Brasília, DF, Brazil Yannick Cerantola Department of Urology, University Hospital CHUV, Lausanne, Switzerland Julio A. Chalela Department of Neurosciences, College of Medicine, Medical University of South Carolina, Charleston, SC, USA Avani Changela Department of Hematology Oncology, Brooklyn Hospital Center, Brooklyn, NY, USA Lakhmir Chawla Department of Anesthesia and Critical Care Medicine, Department of Medicine, Division of Renal Disease and Hypertension, George Washington University Medical Center, Washington, DC, USA

xxxii

Yimin Chen Department of Clinical Nutrition, Rush University Medical Center, Chicago, IL, USA Chien-Hsiang Cheng The Intensive Care Unit, Critical Care and Respiratory Therapy, Taichung Veterans General Hospital, Taichung, Taiwan Rita Chrivia Nutritional Services, Cardinal Glennon Children’s Medical Center, St. Louis, MO, USA Jeremy Cohen Department of Intensive Care, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia Jonathan Cohen Department of General Intensive Care, Rabin Medical Center, Petah Tikva, Israel Robert Cohendy Unité de Réanimation Chirurgicale and Division Anesthésie-Réanimation Douleur Urgences, Centre Hospitalier Universitaire de Nîmes, Nîmes, France Ottavia Colombo USS Dietologia Clinica, Azienda Ospedaliera “Papa Giovanni XXIII”, Bergamo, Italy Anne Coltman Rush University Medical Center, Chicago, IL, USA Andres Concha Pediatric Intensive Care Unit, Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain Maria Giulia Conti Department of Pediatrics, Sapienza University of Rome, Rome, Italy Edward M. Copeland III University of Florida College of Medicine, Gainesville, FL, USA Clare Corish School of Biological Sciences, Dublin Institute of Technology, Dublin 8, Ireland Mandy L. Corrigan Nutrition Consultant, St Louis, MO, USA Fiorenzo Cortinovis USS Dietologia Clinica, Azienda Ospedaliera “Papa Giovanni XXIII”, Bergamo, Italy Jorge A. Coss-Bu Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA Paolo Cotogni Department of Medicine, Anesthesiology and Intensive Care, S. Giovanni Battista Hospital, University of Turin, Turin, Italy Diego A. Covarrubias Interventional Radiology, Diagnostic Imaging Services, Kaiser Permanente West Los Angeles Medical Center, Los Angeles, CA, USA Gabriel M. Covarrubias Department of Radiology, Columbia University Medical Center / New York-Presbyterian Hospital, New York, NY, USA

Contributors

Contributors

xxxiii

Selma Freire C. Cunha Department of Medicine, Division of Medical Nutrition, Ribeirão Preto Medical School, São Paulo University, Ribeirao Preto, SP, Brazil Ugo Da Broi Department of Medical and Biological Sciences, Section of Forensic Medicine, University of Udine, Udine, Italy José Henrique da Silvah Department of Medicine, Division of Medical Nutrition, Ribeirão Preto Medical School, São Paulo University, Ribeirao Preto, SP, Brazil Nicolas Danel Buhl Service de Nutrition, Hôpital Claude Huriez – CHRU de Lille, Lille, France Evangelia Davanos The Brooklyn Hospital Center, Long Island University, Brooklyn, NY, USA Danielle Davison Department of Anesthesia and Critical Care Medicine, Department of Medicine, Division of Renal Disease and Hypertension, George Washington University Medical Center, Washington, DC, USA José Luiz Braga de Aquino School of Medicine, Surgery Department, Pontifical Catholic University of Campinas-SP-Brazil, Campinas, SP, Brasil Jacco J. de Haan Department of Internal Medicine, Universitair Medisch Centrum Groningen, Groningen, The Netherlands Cristiane Maria Mártires de Lima Department of Medicine, Division of Medical Nutrition, Ribeirão Preto Medical School, São Paulo University, Ribeirao Preto, SP, Brazil Lúcio Flávio Peixoto de Lima Pediatric Intensive Care Unit, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil Maria Rita Marques de Oliveira School of Nutrition, Unesp-Botucatu-SPBrazil, Botucatu, SP, Brasil Mathieu De Ryckere Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium Tatiana de Souza Lopes Guerra Center for Nutrition and Dietetics, Asa Norte Regional Hospital, Asa Norte Brasília, DF, Brazil Jennifer Defazio Center for Surgical Infection Research and Therapeutics, The University of Chicago Medicine, Chicago, IL, USA Nicolas Demartines Department of Visceral Surgery, University Hospital CHUV, Lausanne, Switzerland Sara B. DeMauro Division of Neonatology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Serdar Demirgan Department of Anesthesiology and Reanimation, Bagcılar Training and Research Hospital, Istanbul, Turkey

xxxiv

Nicola Dervan Department of Nutrition and Dietetics, St. Vincent’s University Hospital, Dublin 4, Ireland Joe V. M. Devasahayam Hospital Medicine, The Toledo Hospital, Toledo, OH, USA Carman Dixon Mississippi Baptist Medical Center, Jackson, MS, USA Stephanie Dobak Thomas Jefferson University Hospital, Willow Grove, PA, USA Harald Dobnig Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria Schilddr€ usen|Endokrinologie|Osteoporose Institut Dobnig GmbH, Graz, Austria Paul Docherty University of Canterbury, Christchurch, New Zealand Mamoru Doi Department of Rehabilitation, National Hospital Organization Kamaishi National Hospital, Kamaishi-shi, Iwate, Japan Gordon S. Doig Northern Clinical School Intensive Care Research Unit, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia Jennifer A. Doley Carondelet St. Mary’s Hospital with TouchPoint Support Services, Tucson, AZ, USA Evangelia Douka First Critical Care Department, Medical School, National and Kapodistrian University of Athens, Evangelismos General Hospital, Athens, Greece Julie Dowsett Agri-Food Graduate Development Programme, University College UCD, Dublin 4, Ireland Foteini Economidou First Critical Care Department, Medical School, National and Kapodistrian University of Athens, Evangelismos General Hospital, Athens, Greece Sergey Efremov Department of Anesthesiology and Intensive care, Research Institute of Circulation Pathology, Novosibirsk, Russian Federation Sabine Ellinger Faculty of Food, Nutrition and Hospitality Sciences, Hochschule Niederrhein, University of Applied Sciences, Mönchengladbach, Germany Janet L. Engstrom Department of Women, Children and Family Nursing, Rush University Medical Center, Chicago, IL, USA M. Eda Ertorer Division of Endocrinology and Metabolism, Baskent University Faculty of Medicine, Y€uregir, Adana, Turkey

Contributors

Contributors

xxxv

Arlene A. Escuro Center for Human Nutrition, Cleveland Clinic, Cleveland, OH, USA David C. Evans Department of Surgery, Division of Trauma, Critical Care and Burn, The Ohio State University Wexner Medical Center, Columbus, OH, USA Sotiria Everett Dietary Service Metabolic Bone Disease Service, Hospital for Special Surgery, New York, NY, USA Elisabet Farrero Department of Intensive Care, Hospital Universitari de Bellvitge, IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), Universitat de Barcelona, Barcelona, Spain Rubens Feferbaum Division of Neonatology, Department of Pediatrics, Universidade de Sao Paulo, Sao Paulo, Brazil Sarah N. Fernández Department of Pediatric Critical Care, Gregorio Marañón University Hospital, Madrid, Spain Eduardo Ferraresi Unidad de Cuidados Críticos, HIGA, Hospital Interzonal General de Agudos Dr. Rodolfo Rossi, La Plata, Buenos Aires, Argentina Suzie Ferrie Critical Care Dietitian, Intensive Care Service, Royal Prince Alfred Hospital, Camperdown, NSW, Australia Human Nutrition Unit, School of Molecular Bioscience, University of Sydney, Camperdown, NSW, Australia Enrico Fiaccadori Renal Failure Unit, Clinical and Experimental Medicine Department, Parma University Medical School, Parma, Italy Matthias Fischer Department of Anesthesiology and Critical Care, ALB FILS KLINIKEN, Göppingen, Germany Irma Fleming Center for Surgical Infection Research and Therapeutics, The University of Chicago Medicine, Chicago, IL, USA Jann P. Foster School of Nursing, University of Western Sydney, Penrith, NSW, Australia School of Nursing/School of Medicine, University of Sydney, Sydney, NSW, Australia Ingham Institute, Liverpool, NSW, Australia David C. Frankenfield Department of Clinical Nutrition, Department of Nursing, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA Katy Y. Fu Department of Surgery, Division of General Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA Thomas Gaillard LUNAM, Université d’Angers, Angers, France

xxxvi

Contributors

Département d’Anesthésie–Réanimation, Centre Hospitalo–Universitaire d’Angers, Angers, France UMR CNRS 6214 – INSERM 1083, Université d’Angers, Angers, France Paola Gaio Department of Woman and Child’s Health, University of Padova, Padova, Italy Arnaud Galbois Service de Réanimation Médicale, AP-HP, Hôpital SaintAntoine, Paris, France Stephen C. Gale Trauma and Emergency Surgical Services, East Texas Medical Center, Tyler, TX, USA Libi Galmer Dietary Service Metabolic Bone Disease Service, Hospital for Special Surgery, New York, NY, USA Abelardo Garcia-de-Lorenzo y Mateos Servicio de Medicina Intensiva, Hospital Universitario La Paz, Madrid, Spain Rakesh Garg Department of Anaesthesiology, Dr. BRAIRCH, All India Institute of Medical Sciences, New Delhi, India Caterina Calderón Garrido Department of Personality, Assessment and Psychological Treatment, Faculty of Psychology, University of Barcelona, Barcelona, Spain Michelle Genestal University Paul Sabatier, Toulouse 3, Toulouse, France Department of Critical Care Medicine, University Hospital Center Purpan, C.H.U., Toulouse, France Gabriella Maria Gentile Emeritus Director Clinical Nutrition, Eating Disorders Unit, Niguarda Hospital, Milan, Italy Arja Gerritsen Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Department of The Netherlands

Surgery,

Academic

Medical

Center,

Amsterdam,

Heather Gilbertson Department of Nutrition and Food Services, Royal Children’s Hospital, Parkville, VIC, Australia Marta Gómez-Garrido Servicio de Anestesia y Reanimación, Complejo Hospitalario Universitario de Albacete, Albacete, Spain Marci Goolsby Dietary Service Metabolic Bone Disease Service, Hospital for Special Surgery, New York, NY, USA Dirk J. Gouma Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands Megan M. Gray Division of Neonatology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Contributors

xxxvii

Philip Gregory Center for Drug Information and Evidence-Based Practice, Creighton University, Omaha, NE, USA Bertrand Guidet Service de Réanimation Médicale, AP–HP, Hôpital Saint– Antoine, Paris, France UPMC, Université Pierre et Marie Curie, Univ Paris 06, Sorbonne Universités, Paris, France INSERM, UMR_S 707, Paris, France Kursat Gundogan Division of Medical Intensive Care, Department of Medicine, Erciyes University School of Medicine, Kayseri, Turkey Ekta Gupta Section of Gastroenterology and Hepatology and Department of Surgery, MedStar Washington Hospital Center and Georgetown University School of Medicine, Washington, DC, USA Kathleen M. Gura Department of Pharmacy, Clinical Pharmacy Specialist Gastroenterology and Nutrition, Center for Advanced Intestinal Rehabilitation (CAIR), Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA MCPHS University, Boston, MA, USA Corrine Hanson School of Allied Health Professions, University of Nebraska Medical Center, Omaha, NE, USA Tricia B. Hauschild Department of Surgery, Division of General Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA Thomas Havranek School of Medicine, Department of Pediatrics, Division of Neonatology, Albert Einstein University, The Children’s Hospital of Montefiore, Bronx, NY, USA Philippa T. Heighes Northern Clinical School Intensive Care Research Unit, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia Darren Hein Center for Drug Information and Evidence-Based Practice, Creighton University, Omaha, NE, USA Jonathan Hellmann Division of Neonatology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada Antonio Hernández López Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Albacete. Universidad de Castilla-La Mancha, Albacete, Spain Colin Heus Department The Netherlands

of

Surgery,

Medical

Center

Alkmaar,

Melissa L. Hill Department of Neurosciences, College of Medicine, Medical University of South Carolina, Charleston, SC, USA Julie C. Hisey Laredo Medical Center, Laredo, TX, USA

xxxviii

Jessica M. Ho Department of Radiology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA Suresh Hosuru Academic Hospitalist, Ball Memorial Hospital, Muncie, IN, USA Alexander P. J. Houdijk Department of Surgery, Medical Center Alkmaar, The Netherlands Trial Center Holland Health, Alkmaar, The Netherlands Yi-Chia Huang School of Nutrition, Chung Shan Medical University, Chung Shan Medical University Hospital, Taichung, Taiwan Michelle R. Huber Department of Pharmacy, University of Alabama at Birmingham, Birmingham, AL, USA Martin H€ ubner Department of Visceral Surgery, University Hospital CHUV, Lausanne, Switzerland Isabel Huguet Moreno Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Albacete. Universidad de Castilla-La Mancha, Albacete, Spain Dep Huynh Discipline of Medicine, School of Medicine, University of Adelaide, Adelaide, SA, Australia Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia Satomi Ichimaru Department of Nutrition Management, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan Sukhotnik Igor Department of Pediatric Surgery and Pathology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Bnai Zion Medical Center, Haifa, Israel Natsuki Ito Department of Nutrition Management, National Hospital Organization Miyagi National Hospital, Yamamoto-cho Watari-gun, Miyagi, Japan Brian R. Jacobs Department of Critical Care Medicine, Children’s National Medical Center, Washington, DC, USA Ummu Kulthum Jamaludin Faculty of Mechanical Engineering, Universiti Malaysia Pahang, Pekan, Pahang, Malaysia Priscilla Jang Program Manager, Critical Care Service, Inova Fairfax Medical Campus, Falls Church, VA, USA Hemangkumar Javaiya Division Of Internal Medicine, Our Lady Of Lourdes Medical Center, Camden, NJ, USA Casimiro Javierre Department of Physiological Sciences II, IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), Universitat de Barcelona, Barcelona, Spain

Contributors

Contributors

xxxix

Donald M. Jensen Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago Medicine, Chicago, IL, USA Palle Bekker Jeppesen Department of Medical Gastroenterology CA-2121, Rigshospitalet, Copenhagen, Denmark Marc G. Jeschke Department of Surgery, Division of Plastic Surgery, Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, ON, Canada Santhosh G. John Department of Medicine, University of Arizona, Tucson, AZ, USA Tricia J. Johnson Department of Health Systems Management, Rush University Medical Center, Chicago, IL, USA Christian Jones Department of Surgery, Division of Trauma, Critical Care and Burn, The Ohio State University Wexner Medical Center, Columbus, OH, USA Valentina Joseph Department of Neurology, University of Toledo, Toledo, OH, USA Christine Josephson Nutrition and Dietetic Department, Logan Hospital, Meadowbrook, QLD, Australia Rupali Joshi Physical Therapy Department Metabolic Bone Disease Service, Hospital for Special Surgery, New York, NY, USA Daniel C. Jupiter Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galvestone, TX, USA Magnus F. Kaffarnik Department of General, Visceral and Transplantation Surgery, Charité – Universit€atsmedizin Berlin, Berlin, Germany Yusof Kamisah Department of Pharmacology, Faculty of Medicine, PPUKM, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia Lewis J. Kaplan Surgical Critical Care, Philadelphia VAMC, Philadelphia, PA, USA Department of Surgery, Section of Trauma, Surgical Critical Care, and Emergency Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Edward J. Kimball Department of Surgery, Division of General Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA Kelly Kinnare Walgreens Infusion Services, Wood Dale, IL, USA Lisa L. Kirkland Division of Hospital Medicine, Mayo Clinic, Rochester, MN, USA Caroline Kiss Nutrition and Dietetic Department, University Hospital Basel, Basel, Switzerland

xl

Stanislaw Klek General Surgery Unit, Stanley Dudrick’s Memorial Hospital, Skawina, Poland Alexander Koch Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany Timothy R. Koch Section of Gastroenterology and Hepatology and Department of Surgery, MedStar Washington Hospital Center and Georgetown University School of Medicine, Washington, DC, USA Keisuke Kohama Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan Denise Konrad Center for Human Nutrition, Cleveland Clinic, Digestive Disease Institute, Cleveland, OH, USA Joji Kotani Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan Anastasia Kotanidou First Critical Care Department, Medical School, National and Kapodistrian University of Athens, Evangelismos General Hospital, Athens, Greece Antonia Koutsoukou ICU, 1st Dept of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece Kenneth A. Kudsk Department of Surgery, G5/341 Clinical Sciences Center, University of Wisconsin- Madison, Madison, WI, USA Aparna N. Kurup Department of Medicine, St Marys Health Center, St Louis, MO, USA Ursula G. Kyle Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA Magdalini Kyriakopoulou ICU, 1st Dept of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece Cristina Lamas-Oliveira Servicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Albacete, Albacete, Spain Joseph Lane Dietary Service Metabolic Bone Disease Service, Hospital for Special Surgery, New York, NY, USA Lies Langouche Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Laboratory of Intensive Care Medicine, Leuven, Belgium Stephane Larin Department of Pharmacy, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada Bodil M. K. Larsen NICU and PICU, Stollery Children’s Hospital, Edmonton, AB, Canada

Contributors

Contributors

xli

Nutrition Services, Alberta Health Services, Edmonton, AB, Canada José Luis Flordelís Lasierra Intensive Care Unit, Hospital Sur de Alcorcon, Alcorcon, Madrid, Spain Sigismond Lasocki LUNAM, Université d’Angers, Angers, France Département d’Anesthésie–Réanimation, Centre Hospitalo–Universitaire d’Angers, Angers, France UMR CNRS 6214 – INSERM 1083, Université d’Angers, Angers, France Rifat Latifi Division of Trauma, Critical Care and Emergency Surgery, Department of Surgery, University of Arizona, Tucson, AZ, USA Jean-Rémi Lavillegrand Service de Réanimation Médicale, AP-HP, Hôpital Saint-Antoine, Paris, France Vania Aparecida Leandro-Merhi School of Nutrition, Pontifical Catholic University of Campinas-SP-Brazil, Campinas, SP, Brasil Steven B. Leder Department of Surgery, Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA Heitor Pons Leite Discipline of Nutrition and Metabolism, Department of Pediatrics, Federal University of Sao Paulo, Sao Paulo, Brazil Chantal Lemire Department of Pediatrics, University of Sherbrooke School of Medicine, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada Michael D. Lewis Brain Health Education and Research Institute, Potomac, MD, USA Qi-chang Lin Department of Pulmonary Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China David Michael Linton Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Kai-xiong Liu Department of Pulmonary Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China Sabrina Livshin Division of Neonatology and the Center for Neonatal and Pediatric Gastrointestinal Disease, University of Illinois at Chicago, Chicago, IL, USA Department of Clinical Nutrition, University of Illinois Hospital and Health Science System, Chicago, IL, USA Johan F. Lock Department of General-, Visceral-, Vascular- and Paediatric Surgery, University Hospital of Wuerzburg, Wuerzburg, Germany Vladimir Lomivorotov Department of Anesthesiology and Intensive care, Research Institute of Circulation Pathology, Novosibirsk, Russian Federation

xlii

Lilianne Gómez López Pediatric Unit, Health Care Area Ciudad Autónoma de Melilla, Melilla, Spain Juan Carlos Lopez-Delgado Department of Intensive Care, Hospital Universitari de Bellvitge, IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), Universitat de Barcelona, Barcelona, Spain Jesús López-Herce Department of Pediatric Critical Care, Gregorio Marañón University Hospital, Madrid, Spain Christian Löser Medizinische Klinik, Rotes Kreuz Krankenhaus Kassel, Kassel, Germany Tim Lubbers Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands Dominique Ludwig Nutritional Therapy Practitioner, Hampshire, UK Misha D. Luyer Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands Cheng-Jen Ma Division of Gastrointestinal and General Surgery, Department of Surgery, and Nutrition Support Team, Graduate Institute of Clinical Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Israel Macedo NICU, Maternidade Dr. Alfredo da Costa, Centro Hospitalar de Lisboa Central, Lisbon, Portugal Akhil Maheshwari Department of Pediatrics, Division of Neonatology, Morsani College of Medicine, USF Health, Tampa, FL, USA Luis Daniel Umezawa Makikado Intensive Care Medicine, Hospital Universitario Doce de Octubre, Madrid, Spain Mark A. Malesker Pharmacy Practice and Medicine, School of Pharmacy and Health Professions, Creighton University, Omaha, NE, USA Júlio Sérgio Marchini Department of Medicine, Division of Medical Nutrition, Ribeirão Preto Medical School, São Paulo University, Ribeirao Preto, SP, Brazil Mirna Marques Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Laboratory of Intensive Care Medicine, Leuven, Belgium Norma Guimarães Marshall Center for Nutrition and Dietetics, Asa Norte Regional Hospital, Asa Norte Brasília, DF, Brazil Christine M. Martin Department of Nutrition Services, Medical University of South Carolina, Charleston, SC, USA Julie Martin Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA

Contributors

Contributors

xliii

Steven J. Martin Department of Pharmacy Practice, Ohio Northern University Raabe College of Pharmacy, Ada, Ohio, USA Robert G. Martindale Department of Surgery, Division of General Surgery, Oregon Health and Science University, Portland, OR, USA Enid E. Martinez Department of Anesthesiology, Perioperative and Pain Medicine, Division of Critical Care Medicine, Boston Children’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Cecilia Martínez-Costa Department of Pediatrics, School of Medicine. University of Valencia, Hospital Clínico Universitario of Valencia, Valencia, Spain Ana Martínez-Zazo Division of Pediatric Gastroenterology and Nutrition, Hospital Infantil Universitario Niño Jesús, Madrid, Spain Andrés Luciano Nicolas Martinuzzi Critical Care, Centro Medico Integral del Comahue, Unidad de Cuidados Críticos, Neuquén, Neuquén, Argentina Elisabeth M. H. Mathus-Vliegen Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands Adrian A. Maung Department of Surgery, Section of Trauma, Surgical Critical Care, and Surgical Emergencies, Yale University School of Medicine, New Haven, CT, USA Eric Maury Service de Réanimation Médicale, AP–HP, Hôpital Saint– Antoine, Paris, France UPMC, Université Pierre et Marie Curie, Univ Paris 06, Sorbonne Universités, Paris, France INSERM, UMR_S 707, Paris, France Indubala Maurya Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India Andrew Mays Mississippi Baptist Medical Center, Jackson, MS, USA Alberto Medina Pediatric Intensive Care Unit, Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain Nilesh M. Mehta Department of Anesthesiology, Perioperative and Pain Medicine, Division of Critical Care Medicine, Boston Children’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Center for Nutrition, Boston Children’s Hospital, Boston, MA, USA Paula P. Meier Department of Pediatrics, Section of Neonatology, Rush University Medical Center, Chicago, IL, USA Department of Women, Children and Family Nursing, Rush University Medical Center, Chicago, IL, USA

xliv

Simone Sotero Mendonça Center for Nutrition and Dietetics, Asa Norte Regional Hospital, Asa Norte Brasília, DF, Brazil Laura Merras-Salmio Section of Pediatric Gastroenterology, Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland Ronelle Mitchell Center for Human Nutrition, Cleveland Clinic, Digestive Disease Institute, Cleveland, OH, USA I. Quintus Molenaar Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Mary C. Mone Department of Surgery, Division of General Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA Juan Carlos Montejo González Intensive Care Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain Carlo Moreschi Department of Medical and Biological Sciences, Section of Forensic Medicine, University of Udine, Udine, Italy Lee E. Morrow Nebraska–Western Iowa Veterans Affairs Medical Center, Omaha, NE, USA School of Medicine, Creighton University Medical Center, Omaha, NE, USA Pharmacy Practice and Medicine, School of Pharmacy and Health Professions, Creighton University, Omaha, NE, USA Division of Pulmonary, Critical Care, and Sleep Medicine, School of Medicine, School of Pharmacy and Health Professions, Creighton University, Omaha, NE, USA Shereen Mosa Mansoura University Children’s Hospital, Mansoura, Egypt Annika Mutanen Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Giuliana Muzio Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy Atsunori Nakao Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan Nehad Nasef Mansoura University Children’s Hospital, Mansoura, Egypt Department of Pediatrics, Faculty of Medicine, University of Mansoura, Mansoura, Egypt Victor Manuel Navas-López Pediatric Gastroenterology, Hepatology and Nutrition Unit, Hospital Materno Infantil, Málaga, Spain Albert Naveed School of Medicine, Creighton University Medical Center, Omaha, NE, USA

Contributors

Contributors

xlv

Sami Nazzal Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA Jennifer M. Newton Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago Medicine, Chicago, IL, USA Ron R. Neyens Department of Pharmacy, Medical University of South Carolina, Charleston, SC, USA Nam Q. Nguyen Discipline of Medicine, School of Medicine, University of Adelaide, Adelaide, SA, Australia Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia Raminder Nirula Department of Surgery, Division of General Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA Mohd Fahami Nur Azlina Department of Pharmacology, Faculty of Medicine, PPUKM, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia Hitoshi Obara Department of Nutrition Management, National Hospital Organization Miyagi National Hospital, Yamamoto-cho Watari-gun, Miyagi, Japan Juan B. Ochoa Gautier Nestle Health Care Nutrition, Livingston, NJ, USA Georges Offenstadt Service de Réanimation Médicale, AP–HP, Hôpital Saint–Antoine, Paris, France UPMC, Université Pierre et Marie Curie, Univ Paris 06, Sorbonne Universités, Paris, France INSERM, UMR_S 707, Paris, France Carmel O’Hanlon Department of Nutrition and Dietetics, Beaumont Hospital, Dublin 9, Ireland Renán A. Orellana Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA Stylianos Orfanos Second Critical Care Department, Medical School, National and Kapodistrian University of Athens, Attikon General Hospital, Athens, Greece Mette Viberg Østergaard Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg C, Denmark Stephan A. Padosch Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany Mikko P. Pakarinen Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland

xlvi

Jennifer D. Paratz Burns Trauma and Critical Care Research Centre, University of Queensland, Brisbane, QLD, Australia Aloka L. Patel Department of Pediatrics, Section of Neonatology, Rush University Medical Center, Chicago, IL, USA Vinood B. Patel Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK Consuelo Carmen Pedrón-Giner Division of Pediatric Gastroenterology and Nutrition, Hospital Infantil Universitario Niño Jesús, Madrid, Spain Alan N. Peiris Department of Internal Medicine, Division of Endocrinology, Mountain Home VAMC and East Tennessee State University, Johnson City, TN, USA Luis Pereira-da-Silva NOVA Medical School, Lisbon, Portugal NICU, Hospital Dona Estef^ania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal José Luis Pérez-Vela Intensive Care Medicine, Hospital Universitario “12 de Octubre”, Madrid, Spain Sarah Peterson Rush University Medical Center, Chicago, IL, USA Joseph F. Pierre Department of Surgery, G5/341 Clinical Sciences Center, University of Wisconsin- Madison, Madison, WI, USA Unnikrishnan Pillai Nephrology, Indiana University, Ball Memorial Hospital, Muncie, IN, USA Greta L. Piper Department of Surgery, New York University School of Medicine, New York, NW, USA Hannah G. Piper Division of Pediatric Surgery, University of Texas Shouthwestern, Children’s Health, Dallas, TX, USA Mette Platz Department of Surgery, Hillerod University Hospital, Hilleroed, Denmark Sergio Santana Porben Instituto de Gastroenterologia, La Habana, Cuba Anja Poulsen Department of Surgery, Holbaek Sygehus, Holbaek, Denmark del Río MªTeresa Pozas Department of Pharmacy, Hospital Infantil Universitario Niño Jesús, Madrid, Spain Victor R. Preedy Department of Nutrition and Dietetics, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK Jean-Charles Preiser Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium Kim Psaila School of Nursing, University of Western Sydney, Penrith, NSW, Australia

Contributors

Contributors

xlvii

Haji Mohd Saad Qodriyah Department of Pharmacology, Faculty of Medicine, PPUKM, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia Jie-ming Qu Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical School of Fudan University, Shanghai, China Manuel Quintana Diaz Servicio de Medicina Intensiva, Hospital Universitario La Paz, Madrid, Spain Riad M. Rahhal Department of Pediatrics, University of Iowa, Iowa City, IA, USA Rajkumar Rajendram Royal Free London Hospitals, Barnet General Hospital, London, UK Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK King Khalid University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia Samantha Rand Human Nutrition Unit, School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia Farzin Rashti Section of Gastroenterology and Hepatology and Department of Surgery, MedStar Washington Hospital Center and Georgetown University School of Medicine, Washington, DC, USA Stefan Rauch Department of Anesthesiology and Critical Care, ALB FILS KLINIKEN, Göppingen, Germany Outcomes Research Consortium, Cleveland Clinic, Cleveland, OH, USA Anneli Reeves Nutrition and Dietetic Department, Logan Hospital, Meadowbrook, QLD, Australia Corsino Rey Pediatric Intensive Care Unit, Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain Emmanuel Rineau LUNAM, Université d’Angers, Angers, France Département d’Anesthésie–Réanimation, Centre Hospitalo–Universitaire d’Angers, Angers, France UMR CNRS 6214 – INSERM 1083, Université d’Angers, Angers, France Giorgia Rizzi Department of Woman and Child’s Health, University of Padova, Padova, Italy David Rodríguez-Castro Department of Intensive Care, Hospital Universitari de Bellvitge, IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), Universitat de Barcelona, Barcelona, Spain Christina Rollins Memorial Medical Center, Springfield, IL, USA

xlviii

Marc Romain Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Maria Luísa Rosa Pharmacy Department, Hospital Dona Estef^ania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal Beverly Rossman Department of Women, Children and Family Nursing, Rush University Medical Center, Chicago, IL, USA Eric P. A. Rutten Program Development Center, Centre of Expertise for Chronic Organ Failure, Horn, The Netherlands Alice Sabatino Renal Failure Unit, Clinical and Experimental Medicine Department, Parma University Medical School, Parma, Italy Michelle Sandberg Department of Pharmacy, Carondelet St. Mary’s Hospital, Tucson, AZ, USA Per Torp Sangild Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg C, Denmark Markus Sch€ afer Department of Visceral Surgery, University Hospital CHUV, Lausanne, Switzerland Ulrich Schmidt Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA Christian Schnedl Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria Antonella Scipione Department of Pediatrics, Sapienza University of Rome, Rome, Italy Jennifer A. Scoble Department of Pediatrics, University of California Davis, Sacramento, CA, USA David Seguy INSERM U995, Faculté de Médecine, Université de Lille, Lille, France Service de Nutrition, Hôpital Claude Huriez – CHRU de Lille, Lille, France Celeste A. Sejnowski Department of Pharmacy, Promedica Flower Hospital, Sylvania, Ohio, USA Mehmet Salih Sevdi Department of Anesthesiology and Reanimation, Bagcılar Training and Research Hospital, Istanbul, Turkey Abdullah Shatnawei Department of Gastroenterology and Hepatology, The Cleveland Clinic, Digestive Disease Institute, Cleveland, OH, USA Jamie M. Sheard School of Exercise and Nutrition Sciences, Queensland University of Technology, Brisbane, QLD, Australia Naohiro Shibuya Department of Surgery, Texas A&M University Health Science Center, College of Medicine, Bryan, TX, USA Baylor Scott and White Health Care System, Temple, TX, USA

Contributors

Contributors

xlix

Central Texas VA Health Care System, Temple, TX, USA Toshiaki Shimizu Department of Pediatrics, Faculty of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan Hiromichi Shoji Department of Pediatrics, Faculty of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan Timothy R. Shope Section of Gastroenterology and Hepatology and Department of Surgery, MedStar Washington Hospital Center and Georgetown University School of Medicine, Washington, DC, USA Vera Lúcia Flor Silveira Departamento de Ciências Biológicas, Universidade Federal de São Paulo-Campus Diadema, Eldorado, Diadema, SP, Brazil Fiona Simpson Northern Clinical School Intensive Care Research Unit, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia Pierre Singer Department of General Intensive Care, Rabin Medical Center, Petah Tikva, Israel Sıtkı Nadir Sinikoglu Department of Anesthesiology and Reanimation, Bagcılar Training and Research Hospital, Istanbul, Turkey Kellie Sosnowski Nutrition and Dietetic Department, Logan Hospital, Meadowbrook, QLD, Australia Diane Sowa Department of Food and Nutrition, Rush University Medical Center, Chicago, IL, USA Renee D. Stapleton Division of Pulmonary and Critical Care Medicine, University of Vermont College of Medicine, Burlington, VT, USA Ilana Stav Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Stanislaw P. A. Stawicki Department of Surgery, Division of Trauma, Critical Care and Burn, The Ohio State University Wexner Medical Center, Columbus, OH, USA St. Luke’s University Health Network, Bethlehem, PA, USA Elles Steenhagen Department of Dietetics, University Medical Center Utrecht, Utrecht, The Netherlands Ann Cathrine Findal Støy Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg C, Denmark National Veterinary Institute, Technical University of Denmark, Frederiksberg C, Denmark Debra M. Suiter University of Kentucky Voice and Swallow Clinic, Lexington, KY, USA

l

Gerald S. Supinski Division of Pulmonary, Critical care and Sleep Medicine, Department of Internal Medicine, University of Kentucky, Lexington, KY, USA Sigal Sviri Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Krystyna Sztefko Department of Clinical Biochemistry, Polish-American Institute of Pediatrics, Jagiellonian University, Collegium Medicum, Krakow, Poland Frank Tacke Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany Gianluca Terrin Department of Gynecology-Obstetrics and Perinatal Medicine, Sapienza University of Rome, Rome, Italy Ronan Thibault Nutrition Unit, Geneva University Hospital, Geneva 14, Switzerland Melissa Thoene Nebraska Medical Center, Omaha, NE, USA Yakup Tomak Department of Anesthesiology and Reanimation, Faculty of Medicine, Sakarya University, Sakarya, Turkey Przemyslaw J. Tomasik Department of Clinical Biochemistry, PolishAmerican Institute of Pediatrics, Jagiellonian University, Collegium Medicum, Krakow, Poland Herminia Torrado Department of Intensive Care, Hospital Universitari de Bellvitge, IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), Universitat de Barcelona, Barcelona, Spain Antonella Trombetta Department of Medical Sciences, University of Turin, Turin, Italy Aslıhan Tug Department of Anesthesiology and Reanimation, Istanbul Training and Research Hospital, Istanbul, Turkey Meltem T€ urkay Department of Anesthesiology and Reanimation, Bagcılar Training and Research Hospital, Istanbul, Turkey Justine M. Turner Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada Marinella Tzanela Department of Endocrinology, Evangelismos General Hospital, Athens, Greece Mark A. Underwood Department of Pediatrics, University of California Davis, Sacramento, CA, USA Javier Urbano Department of Pediatric Critical Care, Gregorio Marañón University Hospital, Madrid, Spain

Contributors

Contributors

li

Peter Vernon van Heerden Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Julia van Wissen Department of Surgery, Medical Center Alkmaar, The Netherlands Trial Center Holland Health, Alkmaar, The Netherlands Arthur R. H. van Zanten Department of Intensive Care Medicine, Gelderse Vallei Hospital, Hospital Medical Manager Care Division, Ede, The Netherlands Ilse Vanhorebeek Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium Margarita Cuervas-Mons Vendrell Department of Pharmacy, Hospital Infantil Universitario Niño Jesús, Madrid, Spain Josep L. Ventura Department of Intensive Care, Hospital Universitari de Bellvitge, IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), Universitat de Barcelona, Barcelona, Spain Giovanna Verlato Department of Woman and Child’s Health, University of Padova, Padova, Italy Vincent R. Vernacchio Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA Cristiane Comeron Gimenez Verotti Departamento de Gastroenterologia da Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil São Roque, SP, Brazil Janicke Visser Division of Human Nutrition, Department of Interdisciplinary Health Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, South Africa Ana Vivanco-Allende Pediatric Intensive Care Unit, Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain Julie Wagner Alegent Creighton Health Bergan Mercy Medical Center, Omaha, NE, USA Paul W. Wales Group for Improvement of Intestinal Function and Treatment (GIFT), Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, ON, Canada Jaw-Yuan Wang Division of Gastrointestinal and General Surgery, Department of Surgery, and Nutrition Support Team, Graduate Institute of Clinical Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Xinying Wang Department of Surgery, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu, Peoples Republic of China

lii

Nakamichi Watanabe Department of Food Science and Nutrition, Showa Women’s University, Tokyo, Japan Arved Weimann Klinik f€ur Allgemein- und Visceralchirurgie, Klinikum St. Georg gGmbH Leipzig, Leipzig, Germany A. Roos W. Wennink Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Wolfgang A. Wetsch Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, Germany Hayden White Intensive Care, Logan Hospital, Meadowbrook, QLD, Australia Constance Williams Department of Pediatrics, McMaster University, Hamilton, ON, Canada Hector R. Wong Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Department of Pediatrics, Cincinnati Children’s Research Foundation, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Dima Youssef Department of Internal Medicine, Division of Infectious Diseases, East Tennessee State University, Johnson City, TN, USA Olga Zaborina Center for Surgical Infection Research and Therapeutics, The University of Chicago Medicine, Chicago, IL, USA M. Zakharchenko Department of Anaesthesiology and Intensive Care, First Faculty of Medicine, Charles University and General University Hospital, Prague 2, Czech Republic Patrícia Zamberlan Division of Nutrition, Nutritional Team of Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil Jing Zhang Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China Thomas R. Ziegler Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Nutrition and Metabolic Support Service, Atlanta Clinical and Translational Science Institute, Emory University Hospital, Atlanta, GA, USA

Contributors

Part I General Aspects: General Conditions in the Severely Ill

1

Hemodynamic Monitoring in Critical Care Laurence Busse, Danielle Davison, Lakhmir Chawla, and Priscilla Jang

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

The Fluid Challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

Static Measurements of Volume Status and Fluid Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

Dynamic Measurements of Volume Status and Fluid Responsiveness . . . . . . . . . . . . . . . . . . . . . . . . . . .

8

Applications to Critical Care . . . . . . . . . . . . . . . . . . . . . . .

9

Applications to Other Conditions . . . . . . . . . . . . . . . . . . 15 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

L. Busse (*) Department of Medicine, Medical Critical Care Services (MCCS), Inova Fairfax Hospital, Falls Church, VA, USA e-mail: [email protected]; [email protected] D. Davison • L. Chawla Department of Anesthesia and Critical Care Medicine, Department of Medicine, Division of Renal Disease and Hypertension, George Washington University Medical Center, Washington, DC, USA e-mail: [email protected]; [email protected] P. Jang Program Manager, Critical Care Service, Inova Fairfax Medical Campus, Falls Church, VA, USA # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_36

In the critically ill patient, hemodynamic monitoring is vital for determining a patient’s volume status and can assist a clinician in determining potential therapeutic options, including intravenous fluid resuscitation or a fluid challenge. Incorrect determination of volume status or an ill-advised fluid bolus can have grave consequences. Moreover, there are a number of clinical scenarios where volume status is difficult to determine. As such, a myriad of tools have been developed to assist a clinician in assessing volume status or responsiveness to a fluid challenge, with the ultimate objective of optimizing tissues oxygenation and organ perfusion. Hemodynamic monitoring tools rely on the tenets of basic human cardiovascular physiology, which is characterized by the relationship between cardiac output, systemic vascular resistance, and mean arterial pressure. Because measuring stroke volume in real time is difficult, determining cardiac output (SV
heart rate) is the also elusive. Unfortunately for the clinician, cardiac output is also the most relevant to assessing volume status. Newer dynamic measures, which rely on real-time measurements of certain physiological parameters to calculate volume responsiveness, have replaced earlier static measures of volume status, including pulmonary artery occlusion pressure, central venous pressure, and left ventricular end-diastolic area. The static measurements are still widely used in 3

4

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many ICUs and can be determined via transduction of a pulmonary artery catheter or internal jugular or subclavian central venous catheter. The newer techniques rely on analysis of fluctuations in certain vital signs during respiratory variation (as in the case with pulse contour analysis and inferior vena cava diameter variation measurement) or direct measurement of blood volume or flow through the aorta (as in the case with pulmonary artery catheter thermodilution, transpulmonary thermodilution, thoracic electrical bioimpedance, and esophageal Doppler analysis), to determine cardiac output. Data on the benefit of one method of hemodynamic monitoring over another is largely mixed, and certain techniques may be more accurate or feasible in specific clinical scenarios. Ultimately, sound clinical judgment, proper interpretation of measurements, and appropriate therapeutic responses to analyses are the most important aspects of hemodynamic monitoring. Other facets of critical care, such as surgical management, mechanical ventilation strategies, renal therapies, and nutrition, are all related to hemodynamics and are dictated, to some extent, by volume status. Within nutrition, whether to feed a hemodynamically unstable patient remains controversial, as has the use of immune modulating nutritional therapies in patients who are in various states of shock. List of Abbreviations

ARDS CO CVP ED IVCd LVEDA MAP PA PCA PEEP PLR POP PPV

Acute respiratory distress syndrome Cardiac output Central venous pressure Esophageal Doppler Inferior vena cava diameter Left ventricular end-diastolic area Mean arterial pressure Pulmonary artery Pulse contour analysis Positive end-expiratory pressure Passive leg raise Pulse oximetry plethysmographic waveform Pulse pressure variation

SPV SV SVR SVV TD TEB TPTD

Systolic pressure variation Stroke volume Systemic vascular resistance Stroke volume variation Thermodilution Thoracic electrical bioimpedance Transpulmonary thermodilution

Introduction Thoughtful management of cardiac output (CO) and systemic vascular resistance (SVR) allows the clinician to ensure adequate tissue oxygen delivery and end-organ perfusion in a critically ill patient. This is accomplished by hemodynamic monitoring, which can elucidate whether a strategy of volume expansion, vasopressor use, inotropic support, or diuresis is the appropriate course of action. Inappropriate volume expansion can lead to volume overload, pulmonary edema, worsening gas exchange, and acidosis. Moreover, refraining from delivering volume to a patient in oxygen debt can lead to hypoperfusion of any of vital organs. The relationship between CO, mean arterial pressure (MAP), and SVR is illustrated in Eq. 1. This relationship, which is analogous to Ohm’s law, is essential in the management of the hemodynamically unstable patient. Clinicians can manipulate the various components of this equation with the goal of optimizing organ perfusion. In the clinical setting, MAP or systolic blood pressure is often used as a crude measure of organ perfusion, and central venous pressure (CVP) is used as an approximation of volume status. This is an appropriate place to start from a practical perspective. Importantly, however, MAP and CVP are affected by the manipulation of CO and SVR and are less indicative of volume status than CO. In the clinical setting, the manipulation of SVR (via vasopressors or vasodilators) in order to obtain a desired MAP or CO has its limitations, owing to the risk of decreased tissue perfusion and increased myocardial oxygen demand with high doses of vasopressors (Holmes 2005; Obritsch et al. 2004). It is therefore imperative that a

1

Hemodynamic Monitoring in Critical Care

5

Fig. 1 Patients A and B have identical starting preload, but the administration of a volume challenge (reflected in the change in preload) will yield different changes in SV. Patient A is more “volume responsive” than patient B (Reproduced with permission (Busse et al. 2013))

clinician be able to assess CO and its components (Eq. 2) in order to optimize perfusion: ðMAPCVPÞ  80 ¼ CO  SVR

(1)

CO ¼ HR  SV

(2)

Heart rate is easy to determine using fairly rudimentary and noninvasive technology. Stroke volume (SV), on the other hand, is more difficult to directly measure. Classically, SV has been described by its relationship to cardiac filling pressure whereby increases in filling pressures, also known as preload, correspond to an increase in SV. This relationship between pressure and volume is illustrated by the Frank-Starling curve. Traditionally, cardiac preload has been measured with CVP and pulmonary artery occlusion pressure (PAoP). However, it is important to recognize that this relationship is governed by a complex set of variables (i.e., cardiomyopathy, pericardial diseases) that can alter predictive values. Moreover, depending on where a patient lies along the FrankStarling curve, preload measurements can actually lead to incorrect assumptions regarding stroke volume (Fig. 1). Many disease-specific states can alter the relationship between volume and pressure (preload

and SV), making it difficult to accurately determine volume status. The theory behind the use of CVP as a proxy for left atrial filling pressures relies on the assumption that there is nothing within or about the right ventricle or the pulmonary circuitry that may alter the relationship between CVP and left atrial filling pressures. However, by way of example, right ventricular myocardial infarction or pulmonary hypertension will alter CVP as a result of the failing right ventricle but does not reflect left atrial pressures or volume status (Kumar et al. 2004). Patients with acute respiratory distress syndrome (ARDS) and septic patients, despite being intravascularly depleted, can also have misleading cardiac filling pressures (Marik et al. 2008). Positive end-expiratory pressure (PEEP) may also lead to inaccurate CVP and PAoP measurements (Michard and Teboul 2002). Over the years, clinicians have developed a myriad of specialized parameters and devices aimed at determining volume status and guiding fluid management so as to optimize CO and corresponding end-organ perfusion. These parameters can be broken down into static measurements and dynamic tools. Static measurements attempt to measure CO by exploiting its relationship to pressure and/or volume at one particular

6

L. Busse et al.

Fig. 2 A PLR in a semi-recumbent patient. If there are no contraindications to this maneuver (spinal instability or elevated intracranial pressure), it can be performed by

laying the patient’s head down and lifting his or her legs up manually (Reproduced with permission (Teboul and Monnet 2008))

point in time. Alternatively, dynamic tools predict a change in CO over time in response to a fluid challenge as a consequence of intrathoracic pressure changes within the respiratory cycle.

An alternative to the empiric fluid challenge is the passive leg raise (PLR). In the PLR maneuver, the lower extremities are elevated above the heart of a recumbent patient, which has the effect of mimicking a large fluid bolus to the central circulation. An example of the PLR maneuver is seen in Fig. 2. Importantly, the PLR must be performed in conjunction with an analysis of volume responsiveness using one or more of the measurement tools described in this chapter. In other words, the PLR itself is not a tool to measure volume status, but rather a tool to simulate a fluid bolus without having to actually administer one. In this way, the bolus can be removed instantly simply by reversing the PLR maneuver. Evidence suggests that the PLR maneuver is well tolerated and useful in critically ill. Changes in SV and CO (as measured by echocardiography and Doppler analysis) from a PLR maneuver were highly predictive of central hypovolemia (sensitivity 63–89 % and specificity of 89 %) and correlated closely to a fluid bolus of 500 cc of normal saline (Maizel et al. 2007). Moreover, changes in femoral artery flow velocity, pulse pressure, and SV during a PLR maneuver were all highly predictive of fluid responsiveness (sensitivity of 79–86 % and specificity of 80–90 %) (Preau et al. 2010). It should be noted that interpretation of results using the PLR is subject to the same limitations of an actual fluid bolus and that the right choice of hemodynamic monitoring tool in the right patient will provide the most accurate results. Additionally, the PLR is a temporary maneuver, and if it is determined that the patient is volume responsive, the clinician should use this information accordingly.

The Fluid Challenge As previously mentioned, clinicians can manipulate the various components of Eq. 1 above with the goal of optimizing organ perfusion. SVR and MAP are manipulated via the use of vasopressors. CO, on the other hand, is manipulated through volume administration. Because a volume challenge in a patient who is no longer responsive to fluid can have deleterious effects, the use of parameters to predict volume responsiveness may improve outcomes. Oftentimes, administration of a fluid bolus for diagnostic purposes (i.e., indiscriminately giving a fluid bolus to a patient to determine a patient’s fluid responsiveness) is commonly done in clinical practice. Evidence supporting this practice, however, is lacking. One study found that 50 % of hypotensive, critically ill patients are not fluid responsive (Michard and Teboul 2002). Moreover, this practice is not always benign. For example, giving a liter of crystalloid for low urine output can be well tolerated in an otherwise-stable patient, but poorly tolerated in a patient with pulmonary edema or in a postoperative patient with abdominal compartment syndrome. The consequences of fluid administration to an unresponsive patient can affect any number of important physiological processes, including gas exchange and acid base status (Gunn and Pinsky 2001).

Hemodynamic Monitoring in Critical Care

Fig. 3 Pressure tracings of the PA catheter as it travels through the heart. PAoP reflects left atrial pressure. RA right atrium, RV right ventricle (Reproduced with permission (Busse et al. 2013))

RA

7

RV

PA

PAOP

40

30 mm Hg

1

20

10

inside of one of the pulmonary arteries. Subse-

Static Measurements of Volume Status quently, the pressure transducer distal to the baland Fluid Responsiveness loon will measure the pressure of the small Static measurements consist of CVP, PAoP, and left ventricular end-diastolic area (LVEDA). Determining the volume status of a patient using one of these measurements is analogous to estimating the volume of water in a water balloon by measuring the pressure at its opening. As one can imagine, this relationship is unpredictable with changing balloon wall compliance or when pressures outside of the balloon change. Using CVP as a determinant of volume status assumes that the CVP determination of right atrial pressure corresponds to right ventricular end-diastolic volume. As in the water balloon example, a higher CVP corresponds to a greater volume of blood in the right atrium and thus higher preload in the right ventricle (again, a relationship that is questionable in cases of abnormal extracardiovascular pressures or altered ventricular wall compliance). Like CVP, PAoP measures atrial pressures and ventricular preload, but does so on the left side of the heart. Assuming a valid FrankStarling relationship, left ventricular preload corresponds to SV. PAoP is measured with the use of a pulmonary artery (PA) catheter which has a distal pressure transducer as well as a balloon tip. Upon insertion of the PA catheter, the balloon is inflated and floated through the circulation and wedged

pulmonary arteries and the capillary bed, which is open to the left atrium. In the normal physiologic state, the pulmonary capillary bed is a low-pressure system, so the PA catheter pressure transducer will reflect left atrial pressure. With the development of accurate and less invasive hemodynamic monitoring devices, the PA catheter is utilized less frequently today. However, one of the few remaining indications for its use is to determine the presence of pulmonary hypertension, which can be elucidated by observing differences in pathologically elevated PA pressure and pulmonary capillary pressure. Figure 3 shows a schematic of PA catheter tip positions and the corresponding pressure tracings. LVEDA is another static marker used to approximate the volume status of a patient. It is measured by transthoracic or transesophageal echocardiography. Like CVP and PAoP, it relies on the FrankStarling relationship between pressure and volume (cardiac preload and CO). Whereas CVP and PAoP utilize atrial pressure measurement as a proxy for ventricular preload, LVEDA utilizes visual measurement of the ventricle at the end of diastole. In principle, an increase in LVEDA signifies greater stretch of the ventricular myocytes and therefore the larger CO. However, this assumption does not

8

always hold true in conditions of cardiomyopathy, for example, where myocardial wall tension as a result of myocyte stretch can be altered. In recent years, an increasingly large body of evidence suggests that PAoP, CVP, and LVEDA fail to correlate with ventricular performance and are poor predictors of volume status. Moreover, these static measures do not predict whether a fluid challenge will lead to an improvement in CO (Kumar et al. 2004; Marik et al. 2008; Michard and Teboul 2002). A 2002 systematic review concluded that the static measures CVP, PAoP, and LVEDA did not adequately discriminate or predict responders (defined by an increase in CO or SV) to a volume challenge from nonresponders (Michard and Teboul 2002). An additional systematic review concluded that CVP correlated poorly with CO, SV, and blood volume (Marik et al. 2008). Even in presumably fluid responsive (healthy) patients, evidence suggests poor correlation between the static markers of volume status and corresponding cardiac filling pressure or predicted response to a fluid challenge. In a trial of healthy volunteers, initial CVP, PAoP, and LVEDA did not correlate with volume responsiveness, and the observed change in CVP and PAoP after a bolus of 3 l of saline failed to result in predictable changes in cardiac index or stroke volume index. However, changes in LVEDA as measured by echocardiography did correlate with changes in SV (Kumar et al. 2004). Operator variability and the practical inability to continuously or frequently measure heart volumes by echo have been barriers to widespread use of LVEDA as a popular metric. Despite the mounting body of evidence, CVP and PAoP are still widely used to guide fluid management in the critical care setting.

Dynamic Measurements of Volume Status and Fluid Responsiveness Because of the mounting evidence against the aforementioned static measures, many clinicians have adopted dynamic measurement tools in an effort to predict cardiac performance and fluid responsiveness. These dynamic measures establish

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a relationship between changes over time in certain cardiac performance metrics and fluid responsiveness. Dynamic markers are based on the principle of pulsus paradoxus or the variation of SV and blood pressure with the respiratory cycle. Physiologically, this phenomenon occurs as venous return varies in synchrony with the undulation of intrathoracic pressure caused by breathing. In spontaneously breathing patients, venous return will increase with inspiration, and respiratory-cycle variations in cardiac performance metrics, such as SV and pulse pressure, can be seen. Conversely, in patients who are mechanically ventilated, venous return will decrease with a delivered breath, but similar respiratory-cycle variations are present. Importantly, the patient must be in synchrony with the ventilator and/or paralyzed as well as be in normal sinus rhythm for these dynamic markers to maintain accuracy (although research continues in an effort to validate findings in other patient populations) (Biais et al. 2009; Cannesson et al. 2009; Dahl et al. 2009). In ventilated patients, the delivery of a positive-pressure breath causes decreased venous return as well as increased right ventricular afterload. This correlates to a decreased right ventricular and subsequently left ventricular output, which is manifested as a relative decrease in cardiac performance metrics. Because of blood transit time, this decrease is usually seen 2 s later, after the cessation of a delivered breath. A graphical depiction of this phenomenon can be seen in Fig. 4. The variation in pulse pressure or SV is calculated as the maximum pulse pressure (PPMax) minus the minimum pulse pressure (PPMin) divided by the average of the two values. This value (usually represented as a percentage change) is exaggerated during periods of relative volume depletion. Specifically, a wide pulse pressure variation (PPV), stroke volume variation (SVV), or systolic pressure variation (SPV) indicates that the administration of fluid will result in improved cardiac performance and an increase SV or CO. A multitude of studies have validated the use of the dynamic parameters, including SVV and PPV, in predicting volume responsiveness. A 2009 systematic review includes the results of 29 studies in which the dynamic markers of SPV, SVV, and

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Fig. 4 Illustration of pulse pressure variation caused by a delivered positivepressure breath. PA arterial pressure, PAW airway pressure, PPMax maximum pulse pressure, PPMin minimum pulse pressure. Note that a decrease in pulse pressure occurs after the completion of the positivepressure breath (Reproduced with permission (Gunn and Pinsky 2001))

PPV outperformed the static markers of CVP and LVEDA in predicting fluid responsiveness (Marik et al. 2009). Additional studies have validated the uses of these metrics in coronary bypass patients, in neurosurgical patients, and in those with acute lung injury (Davison and Junker 2008). The measurement of the inferior vena cava diameter (IVCd) or more specifically the variation in diameter during the respiratory cycle is another valid dynamic mechanism by which fluid responsiveness can be measured. Measurements are made by Doppler echocardiography. Much like PPV and SVV, IVCd variation during the respiratory cycle undulates with increasing and decreasing intrathoracic pressures. It has been validated in multiple studies as an accurate tool in determining volume responsiveness in both spontaneously breathing and mechanically ventilated patients (Dipti et al. 2012; Feissel et al. 2004; Schefold et al. 2010). The IVCd is measured subcostally using M-mode echocardiography, in the longitudinal direction at a perpendicular angle to the IVC, approximately 0.5–4 cm below the junction of the IVC and the right atrium (Fig. 5) (Barbier et al. 2004; Beaulieu 2007; Machare-Delgado et al. 2011; Moreno et al. 1984; Moretti and Pizzi 2010). IVCd variation is calculated as a percentage change in diameter during inspiration as compared to baseline (expiration). A number of studies have described normative values for IVCd, which range from 8 to 40 mm depending on the clinical scenario (Moreno et al. 1984; Nakao et al. 1987). An IVCd variation

of greater than 10–18 % during a respiratory cycle has been shown to be predictive of volume responsiveness, with a sensitivity ranging from 50 % to 100 %, specificity ranging from 53 % to 100 % for predefined variation (Barbier et al. 2004; MachareDelgado et al. 2011; Moretti and Pizzi 2010). By way of example, Barbier et al. calculated the IVC distensibility index (calculated as the ratio of IVCdmax  IVCdmin =IVCdmin , expressed as a percent) in ventilated septic patients before and after a volume challenge. The authors demonstrated that using an IVC distensibility index threshold of 18 % differentiated responders (predefined as an increase in CI>15 % after volume expansion) from nonresponders with 90 % sensitivity and 90 % specificity (Barbier et al. 2004). Like all forms of echocardiography, determination of IVCd using echocardiography requires operator skill and thus is subject to error. Additionally, interpretation may be difficult in patients with ascites, morbid obesity, and intra-abdominal hypertension (Barbier et al. 2004; MachareDelgado et al. 2011; Moretti and Pizzi 2010).

Applications to Critical Care Hemodynamic monitoring is an essential part of critical care and, arguably, is the sole purpose of many ICU admissions. A number of tools and methods are used in the ICU setting to monitor hemodynamics, as described below.

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Fig. 5 A 2-D view in panel (a) and M-mode view in panel (b) of the suprahepatic (subcostal) IVC. IVCDi (inspiratory) and IVCDe (expiratory) measurements are compared (Reproduced with permission (Moretti and Pizzi 2010))

Thermodilution (TD). The thermodilution technique is based on the Stewart-Hamilton equation, which allows the clinician to directly calculate CO. The Stewart-Hamilton equation is presented below (Eq. 3): Q¼

ðV1  ðTb  T1Þ  K1  K2Þ ðTbðtÞdtÞ

(3)

where Q = cardiac output, V1 = injectate volume, Tb = blood temperature, T1 = injectate temperature, K1 = density factor, K2 = constant, and Tb(t) dt = change in blood temperature as a function of time. In basic terms, the Stewart-Hamilton equation allows for the calculation of flow through a conduit when an injectate of a known temperature is mixed with a fluid, also of a known temperature. Flow is calculated as a function of change in temperature of the injectate-fluid mixture over a known time interval. CO is determined by measuring the change in temperature between the patient’s blood and the injectate and is inversely related to the change in temperature over a known time interval. A smaller change in temperature signifies a higher CO, as a higher volume of warm blood mixes with the cooler injectate. In practice, CO is calculated by a computer algorithm when a saline bolus of known volume and temperature is injected into the proximal port of the PA catheter. The saline mixes with the patient’s blood and the temperature of this mixture is taken at the distal site of the PA

catheter (traditionally, done three times in succession for an average). Newer PA catheters have an embedded proximal heating filament and distal thermistor built into the catheter so as to allow for continuous CO calculation. A multitude of studies have demonstrated that TD is an accurate and valid way to measure CO (Kay et al. 1983; Urban et al. 1987). PA catheter TD has emerged as the gold standard for the calculation of CO and is the method by which all other methods are judged. Despite its accuracy, an increasingly large body of evidence suggests that the use of the PA catheter does not improve outcomes. A 1996 landmark study showed that for a large population of critically ill patients, PA catheterization resulted in increased 30-day mortality, increased cost of healthcare, and a greater length of stay (Connors et al. 1996). A later trial found no difference in mortality or length of stay in a population of surgical patients with and without a PA catheter (Sandham et al. 2003). A more recent systematic review in the Cochrane Database found that PA catheterization was associated with no difference in mortality or length of stay in critically ill or surgical patients, but was associated with increased healthcare costs (Harvey et al. 2006). Commonly cited theories as to why these outcomes exist include direct deleterious effects of the PA catheter itself (i.e., increased incidences of pulmonary embolism, PA rupture, arrhythmia), the PA catheter as a marker for an aggressive

Hemodynamic Monitoring in Critical Care

Fig. 6 Rates of PA catheter use over a 5-year period from 2002 to 2006 in Hamilton Regional Critical Care Units (unadjusted and adjusted for age, APACHE II, admitting diagnosis, and other patient-specific characteristics) (Reproduced with permission (Koo et al. 2011))

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20

16 PA Catheterization (%)

1

12

8

4 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

2002

2003

2004

2005

2006

Year Adjusted PAC rate*

style of ICU care, or the harmful effects of the therapies implemented based on inappropriate interpretation of data (Connors et al. 1996). In practice, the use of the PA catheter has waned over the past decade (Fig. 6), a trend that is expected to continue as clinicians turn to newer, less invasive techniques with proven accuracy. Transpulmonary Thermodilution (TPTD). TPTD utilizes a standard central venous catheter and a separate thermistor which is located on an arterial line, usually inserted in the femoral artery (Fig. 7). An analysis of CO can be generated by using the Stewart-Hamilton equation (Eq. 3) in a method similar to the PA catheter TD. This method is coined “transpulmonary” because the points of measurement are located in the central venous circulation (internal jugular or subclavian vein) and in the systemic arterial circulation (aorta). This method is potentially as accurate as PA catheter TD technique, provided that there is (a) constant blood flow from the central venous circulation through the pulmonary circulation and subsequently through the systemic arterial circulation. Additionally, accuracy depends on minimal loss of injectate, complete mixing of the injectate with blood, and only one pass from the proximal thermistor on the central line to the distal thermistor in the aorta (Proulx et al. 2011). Because TPTD does not require an intracardiac

CVC

Unadjusted PAC rate

Injectate & Proximal thermistor

Computer

Distal thermistor

Fig. 7 A schematic of TPTD, which consists of a central line placed in either the internal jugular or subclavian vein and an arterial line placed in the femoral artery. CO is calculated using the Stewart-Hamilton equation (Reproduced with permission from Pulsion Medical Inc., 2445 Gateway Drive, Suite 110, Irving, TX, 75603, USA)

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catheter, TPTD is less invasive than PA catheter TD and therefore is an attractive alternative. A number of studies have compared TPTD against other methods of hemodynamic monitoring. A study comparing TPTD and TD in critically ill surgical patients demonstrated decent agreement between the two methods (Sakka et al. 2000). Another study evaluated TPTD (using an axillary artery as a distal thermistor site) and TD in critically ill patients, with similar results (Segal et al. 2002). TPTD has been used successfully in clinical practice: TPTD was evaluated in a goal-directed therapy approach in cardiac bypass patients and found to be associated with reduced pressor use, increased colloid administration, fewer days of mechanical ventilation, and a shorter time to achieve the status “fit for ICU discharge” (Goepfert et al. 2007). Thoracic Electrical Bioimpedance (TEB). TEB has only recently become routinely available in the critical care setting, though the technology has been known for the last 80 years. TEB calculates CO based on the principles of Ohm’s law (V=IR), where voltage (V) is directly proportional to current (I) and indirectly proportional to resistance (R). In the human body, a current and known voltage is applied to the thorax in an effort to determine the electrical resistance of the circuit. Resistance (or impedance) of the circuit is affected by the relative water content in the descending aorta and will vary with the amount of blood flow through this vessel. Thus, a volume-depleted patient will exhibit a higher TEB compared to that of a volume-replete patient. In practice, TEB is calculated using a system of connected electrodes through which a high-frequency low-amplitude current is passed (Fig. 8). TEB loses accuracy in the setting of increased extravascular lung water, coarctation of the aorta, cardiac shunt or valvular disease, and arrhythmia (Jensen et l. 1995; Petter et al. 2011). Moreover, the use of TEB has been questioned in obese or pregnant patients and may be subject to differences in body composition between males and females (Jensen et al. 1995). Evidence is mixed with regard to the use of TEB in estimating volume responsiveness. A 2011 study compared fluid responsiveness by TEB versus pulse contour analysis (PCA) in

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Fig. 8 Schematic of an external electrode TEB setup. Impedance is tracked on a recording device (not shown) (Reproduced with permission (Tang and Tong 2009))

healthy patients undergoing a lower body negative pressure maneuver in order to simulate central hypovolemia. The two methods correlated well (Reisner et al. 2011). TEB performed similarly to TD in studies of postoperative cardiac surgical patients and in patients undergoing cardiopulmonary bypass (Gujjar et al. 2008; Sageman et al. 2002). In contrast, Petter found that TEB correlated poorly with TD in 33 heart failure patients (Petter et al. 2011). Additionally, a systematic review concluded that TEB as a hemodynamic monitoring device is neither precise nor accurate (Jensen et al. 1995). Further research and advancements in technology are needed before this method becomes widely adopted in the critical care setting. Esophageal Doppler (ED). ED measures CO via the estimation of aortic blood flow using a continuous Doppler ultrasound positioned in the esophagus. ED is a relatively noninvasive method of measuring CO and is based on the principle that the velocity of blood flow traveling through the aorta is directly related to flow (or CO) and inversely related to the aortic diameter (Eq. 4): v ¼ Q=A

(4)

where v = velocity, Q = flow, and A = crosssectional area. In the setting of reduced CO due to

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Fig. 9 An ultrasound transducer is positioned in the esophagus adjacent to the thoracic aorta. Doppler measurements of aortic blood flow can vary with blood volume (Reproduced with permission (Cariou et al. 1998))

13 Orientation of Probe

Flexible Shaft Shealth Esophagus

Aorta

Water Inflated Balloon

Ultrasound Transducer for Diameter Measurement

hypovolemia, an esophageal probe will measure decreased aortic diameter and flow velocity, as shown in Fig. 9. As with all other tools used to estimate CO, ED has its limitations. Patients must be intubated in order to position the esophageal probe. Turbulent flow through the aorta caused by atherosclerosis or an aneurysm may confound calculations (Laupland and Bands 2002). It should also be noted that a significant portion (~30 %) of blood ejected from the left ventricle never reaches the thoracic aorta but flows to the vessels which stem from the aortic arch. As such, aortic blood flow is only an estimation of CO and relies on the assumption that this proportion of total blood flow that reached the aorta remains constant (an assumption which also holds true for TPTD). Limitations aside, evidence suggests that ED is accurate and valid in determining CO. A 2002

Pulsed Doppler Transducer for Flow Velocity Measurement

review showed adequate correlation between TD and ED (Laupland and Bands 2002). A 2004 systematic review of paired measurements from 314 patients showed similarly positive results: mean bias between TD-calculated and ED-calculated CO was only 0.19 L/min, and the pooled median percentage of clinical agreement for measuring change in CO during a fluid challenge was 86 % (Dark and Singer 2004). Pulse Contour Analysis (PCA). PCA has recently emerged as an accurate method for measuring cardiac performance (CO, CI, and SV) and volume status, as well as the dynamic markers SVV, PPV, and SPV, which assist in determining volume responsiveness. It has gained popularity due to its minimally invasive technique and ease of interpretation. PCA can be determined manually by obtaining a routine arterial line tracing and performing simple mathematics to determine

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variability of the amplitude of the pulse pressure throughout the respiratory cycle. In a clinical setting, this can be accomplished by standing at the bedside for 30 s and observing the undulation on the arterial line monitor. Commercially available proprietary bedside technology allows the clinician to calculate this variability, as well as CO, CI, and SV. There are a number of different commercially available PCA devices available, including the FloTrac (Edwards Lifesciences LLC, Irvine, CA), the PulsCO (LidCO Limited, Cambridge, UK), and the PICCO (Pulsion Medical Systems, Munich, Germany). Of these devices, only the FloTrac does not require calibration before use. The PICCO must be pre-calibrated using TPTD and thus needs a central venous catheter in addition to an arterial line but has the added benefit of being able to calculate extravascular lung water (as seen in cardiogenic pulmonary edema and ARDS). The PulsCO uses a lithium indicator and must be calibrated every 8 h (and is contraindicated in patients on lithium or who are pregnant). However, the lithium-based system requires no central venous catheter since the lithium bolus can be administered via a peripheral line (de Waal et al. 2009). All of these systems perform similarly in comparative trials (Hadian et al. 2010; Hofer et al. 2008). PCA technology has its limitations (in addition to pre-calibration requirements). The level of PEEP, tidal volumes, and chest wall compliance all reduce the accuracy of PCA (Marik et al. 2009; Michard 2005). The presence of atherosclerosis and the choice of arterial catheter site may also adversely impact the accuracy of the technology (Michard 2005). Additionally, PCA may be inaccurate in patients with open chests as a result of coronary-artery-bypass surgery or in major abdominal surgery (de Waal et al. 2009; Lahner et al. 2009). PCA has not been validated in spontaneously breathing patients, unstable patients, or in those with cardiac rhythms other than sinus (though research is ongoing) (Benington et al. 2009; Godje et al. 2002; Teboul and Monnet 2008). Despite these limitations, PCA is rapidly becoming the de facto method of assessing cardiac performance in many ICUs.

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Recently, pulse oximetry plethysmographic waveform (POP) analysis has been studied as a means to calculate volume status. The POP represents the infrared light absorbed by circulating hemoglobin during a cardiac cycle and in theory correlates to the amount of blood ejected by the heart during systole. The principle behind this method is similar to arterial catheter PCA. Specifically, variation in the amplitude of the pulse oximetry curve is mathematically related to the amount of blood in the capillary bed, which is in turn related to a patient’s volume status. A systematic review of POP variation demonstrated that this method accurately predicted volume responsiveness (Sandroni et al. 2012). However, this study stressed that, like all methods relying on PCA, POP analysis loses its accuracy in patients who are spontaneously breathing or who have arrhythmia. Moreover, the accuracy of POP analysis is critically dependent on the quality of the plethysmographic signal, which is reliant on adequate peripheral perfusion. Thus, in situations of hypothermia, reduced CO, or drug-induced vasoconstriction, this method may yield questionable results (Sandroni et al. 2012). Despite these drawbacks, the less invasive nature of this method makes it an attractive option for future directions of research. The Indirect Fick Method. The Fick method of determining CO is based on the principle that the total quantity of a gas entering or leaving the lungs is a product of the blood flow to the lungs and the net uptake or expulsion of the gas. In clinical practice, CO2 consumption is measured as the difference between inspired and expired levels of the gas, as represented in Eq. 5: CO ¼

v_ CO2 CvCO2  CaCO2

(5)

where CO = cardiac output, v_ CO2 ¼ CO2 excreted from the lungs, CvCO2 is the mixed venous CO2 content, and CaCO2 is arterial CO2 content. Arterial CO2 is taken from an arterial blood gas analysis or, more commonly, an end-tidal CO2 monitor. The need for the mixed venous CO2 measurement is eliminated by

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Fig. 10 An example of a partial CO2 rebreathing circuit in order to mathematically cancel out the need for direct measurement of mixed venous CO2, which allows for the measurement of CO using an adjusted Fick equation (Reproduced with permission (Haryadi et al. 2000))

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Differential Pressure Flow Sensor

Mainstream CO2 Sensor

Pneumatic Valve

obtaining two different samples, first under normal breathing conditions and second via a rebreathing circuit attached to the ventilator (which allows for the mathematical canceling out of the central venous CO2 terms) (Chaney and Derdak 2002). A graphical representation of a partial CO2 rebreathing circuit is shown in Fig. 10. Evidence suggests that the Fick method of determining CO is accurate in the right setting. The Fick method was compared with TD in patients with pulmonary disease and was found to perform similarly (Neviere et al. 1994). Other studies have shown comparable results (Odenstedt et al. 2002). However, this method has limitations in many patient populations (spontaneously breathing patients, those with abnormal gas exchange or oxygen consumption, hyperventilating patients, and patients with large pulmonary shunts). The Fick method performed poorly when compared with TD in patients with ARDS and was found to be inaccurate in patients who had low minute ventilation or who were spontaneously breathing (Allardet-Servent et al. 2009; Tachibana et al. 2003). Additionally, because of the small difference between arterial and venous CO2 (normally only 6 mmHg), small measurement errors can translate into large miscalculations of CO. The Fick method of estimating CO is not commonly used in clinical practice, but does share some common technology with nutrition science (specifically with indirect calorimetry). With further advancements and refinements in technology, this technique may become a more emphasized

Adjustable Airway Deadspace

practice, and concomitant use with indirect calorimetry may promote more familiarity and understanding of the Fick method.

Applications to Other Conditions Hemodynamic monitoring is not typically done outside of an intensive care unit. There are, however, a number of areas where the technology described herein does overlap with other fields of medicine. For example, echocardiography is used to describe any number of heart conditions, and TPTD and TEB have a role in describing extravascular lung water. In nutrition science, hemodynamic monitoring can assist with decisions of formulation, timing, and caloric need. In the hemodynamically unstable patient, the provision of enteral nutrition has been associated with mesenteric ischemia, small bowel necrosis, bowel wall edema, and abdominal compartment syndrome (Zaloga et al. 2003). Additionally, immunomodulating nutritional formulas have been touted as a way to improve outcomes in inflammatory conditions such as septic shock, burns, and trauma, all of which are characterized by hemodynamic instability. Supplementation with immuno-nutrition has been extensively explored, with equivocal results. Finally, indirect calorimetry is a method by which many clinicians avoid hypo- or hypercaloric feeding (which has been associated with increased morbidity and mortality in the critically ill) (da Rocha 2006). Indirect calorimetry can be calculated using the Fick method, as described above.

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Guidelines and Protocols

Summary

The 2012 Surviving Sepsis Guidelines (Dellinger et al. 2013) recommend:

CO and volume responsiveness can be assessed using a number of hemodynamic monitoring methods and devices available in the critical care setting. The potential to improve cardiac performance with volume challenge can be measured by static metrics (CVP, PAoP, and LVEDA) and dynamic tools (PCA, IVCd variation). Dynamic metrics outperform the static measures in determining volume responsiveness. Various bedside technologies are available to monitor volume status as well as cardiac performance measures (CO and SV) in the hemodynamically unstable patient. PA catheter TD remains the gold standard and is an accurate means of monitoring CO, though its popularity has waned in recent years due to shifting beliefs of risk versus benefit. Other less invasive monitoring systems continue to be validated in the clinical setting. Hemodynamic monitoring can assist in guiding nutrition strategies, including when to initiate enteral feeding. Ultimately, sound clinical judgment, correct interpretation of results, and thoughtful use of clinical tools can, in aggregate, improve hemodynamic management and end-organ perfusion as well as assist in devising nutrition strategy. A thorough understanding of crossover technology (as is the case with the Fick method of determining CO and indirect calorimetry) can assist the astute clinician with a global assessment of the patient. Advancements in technology, increased availability in ICU settings, and continued comparative research will further shape the landscape in hemodynamic monitoring and nutrition science.

• A target CVP of 8–12 mmHg as part of an initial resuscitation strategy • An initial fluid challenge in patient with sepsisinduced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 ml/kg of crystalloids • That the fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (e.g., change in pulse pressure or stroke volume variation) or static (e.g., arterial pressure, heart rate) variables • The administration of either oral or enteral feedings, as tolerated, rather than complete fasting within the first 48 h of diagnosis of severe sepsis/septic shock • Avoiding mandatory full caloric feeding in the first week, but rather suggest low-dose feeding (e.g., up to 500 cal per day), advancing only as tolerated • Nutrition with no specific immunomodulating supplementation in severe sepsis The 2009 ASPEN/SCCM (McClave et al. 2009) recommend:

guidelines

• That in patients with hemodynamic compromise (high-dose catecholamine agents alone or in combination with large-volume fluid resuscitation), enteral resuscitation be withheld until hemodynamic stability can be achieved • That immunomodulating formulations be used with caution in select patient populations • That the target goal of enteral nutrition (defined by energy requirements) can be calculated by predictive equations or indirect calorimetry, the latter of which is more accurate in the critical care setting • That efforts be made to provide >50–65 % of goal calories in order to achieve clinical benefit

Summary Points • The assessment of volume status in a critically ill patient can be challenging, and both underresuscitation and over-resuscitation can have grave consequences. • Hemodynamic monitoring can assist the critical care clinician in determining whether or not a patient is volume responsive, while the

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•

•

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ultimate goal is to ensure adequate end-organ perfusion and oxygen delivery to tissues. Static measurements of volume status, such as PAoP, CVP, and LVEDA, lack precision and accuracy. Dynamic parameters of cardiac performance, such as PPV and SVV, are valid predictors of volume responsiveness and are based on the principle of pulsus paradoxus. A multitude of tools have been developed to assist the clinician in determining volume status, with the gold standard remaining the PA catheter. Cardiac performance is evaluated at the bedside with judicious use of available technology, appropriate interpretation of values, and sound clinical judgment. Hemodynamic monitoring can assist the clinician in nutritional aspects of critical care, such as when to initiate enteral nutrition and which formulations to consider.

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17 Adv Chron Kidney Dis. 2013;20(1):21–9. doi: 10.1053/j.ackd.2012.10.006. Cannesson M, Musard H, Desebbe O, et al. The ability of stroke volume variations obtained with Vigileo/FloTrac system to monitor fluid responsiveness in mechanically ventilated patients. Anesth Analg. 2009;108(2):513–7. doi:10.1213/ane.0b013e318192a36b. Cariou A, Monchi M, Joly LM, et al. Noninvasive cardiac output monitoring by aortic blood flow determination: evaluation of the Sometec Dynemo-3000 system. Crit Care Med. 1998;26(12):2066–72. Chaney JC, Derdak S. Minimally invasive hemodynamic monitoring for the intensivist: current and emerging technology. Crit Care Med. 2002;30(10):2338–45. doi:10.1097/01.CCM.0000029186.57736.02. Connors Jr AF, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA. 1996;276(11):889–97. da Rocha EEM. Indirect calorimetry: methodology, instruments and clinical application. Curr Opin Clin Nutr Metab Care. 2006;9(3):247–56. Dahl MK, Vistisen ST, Koefoed-Nielsen J, Larsson A. Using an expiratory resistor, arterial pulse pressure variations predict fluid responsiveness during spontaneous breathing: an experimental porcine study. Crit Care. 2009;13(2):R39. doi:10.1186/cc7760. Dark PM, Singer M. The validity of trans-esophageal Doppler ultrasonography as a measure of cardiac output in critically ill adults. Intensive Care Med. 2004;30 (11):2060–6. doi:10.1007/s00134-004-2430-2. Davison D, Junker C. Advances in critical care for the nephrologist: hemodynamic monitoring and volume management. Clin J Am Soc Nephrol. 2008;3(2): 554–61. doi:10.2215/CJN.01440307. de Waal EE, Rex S, Kruitwagen CL, Kalkman CJ, Buhre WF. Dynamic preload indicators fail to predict fluid responsiveness in open-chest conditions. Crit Care Med. 2009a;37(2):510–5. doi:10.1097/CCM.0b013e3 181958bf7. de Waal EE, Wappler F, Buhre WF. Cardiac output monitoring. Curr Opin Anaesthesiol. 2009b;22(1):71–7. doi:10.1097/ACO.0b013e32831f44d0. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228. doi:10.1007/s00134-0122769-8. Dipti A, Soucy Z, Surana A, Chandra S. Role of inferior vena cava diameter in assessment of volume status: a meta-analysis. Am J Emerg Med. 2012;30(8): 1414–1419.e1. doi:10.1016/j.ajem.2011.10.017. Feissel M, Michard F, Faller JP, Teboul JL. The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med. 2004;30(9):1834–7. doi:10.1007/s00134-004-2233-5. Godje O, Hoke K, Goetz AE, et al. Reliability of a new algorithm for continuous cardiac output determination

18 by pulse-contour analysis during hemodynamic instability. Crit Care Med. 2002;30(1):52–8. Goepfert MS, Reuter DA, Akyol D, Lamm P, Kilger E, Goetz AE. Goal-directed fluid management reduces vasopressor and catecholamine use in cardiac surgery patients. Intensive Care Med. 2007;33(1):96–103. doi:10.1007/s00134-006-0404-2. Gujjar AR, Muralidhar K, Banakal S, Gupta R, Sathyaprabha TN, Jairaj PS. Non-invasive cardiac output by transthoracic electrical bioimpedence in post-cardiac surgery patients: comparison with thermodilution method. J Clin Monit Comput. 2008;22(3):175–80. doi:10.1007/s10877-008-9119-y. Gunn SR, Pinsky MR. Implications of arterial pressure variation in patients in the intensive care unit. Curr Opin Crit Care. 2001;7(3):212–7. Hadian M, Kim HK, Severyn DA, Pinsky MR. Crosscomparison of cardiac output trending accuracy of LiDCO, PiCCO, FloTrac and pulmonary artery catheters. Crit Care. 2010;14(6):R212. doi:10.1186/cc9335. Harvey S, Young D, Brampton W, et al. Pulmonary artery catheters for adult patients in intensive care. Cochrane Database Syst Rev. 2006;3(3):CD003408. doi:10.1002/14651858.CD003408.pub2. Haryadi DG, Orr JA, Kuck K, McJames S, Westenskow DR. Partial CO2 rebreathing indirect Fick technique for non-invasive measurement of cardiac output. J Clin Monit Comput. 2000;16(5–6):361–74. Hofer CK, Senn A, Weibel L, Zollinger A. Assessment of stroke volume variation for prediction of fluid responsiveness using the modified FloTrac and PiCCOplus system. Crit Care. 2008;12(3):R82. doi:10.1186/cc6933. Holmes CL. Vasoactive drugs in the intensive care unit. Curr Opin Crit Care. 2005;11(5):413–7. Jensen L, Yakimets J, Teo KK. A review of impedance cardiography. Heart Lung. 1995;24(3):183–93. Kay HR, Afshari M, Barash P, et al. Measurement of ejection fraction by thermal dilution techniques. J Surg Res. 1983;34(4):337–46. Koo KK, Sun JC, Zhou Q, et al. Pulmonary artery catheters: evolving rates and reasons for use. Crit Care Med. 2011;39(7):1613–8. doi:10.1097/CCM.0b013e31821 8a045. Kumar A, Anel R, Bunnell E, et al. Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects. Crit Care Med. 2004;32(3):691–9. Lahner D, Kabon B, Marschalek C, et al. Evaluation of stroke volume variation obtained by arterial pulse contour analysis to predict fluid responsiveness intraoperatively. Br J Anaesth. 2009;103(3):346–51. doi:10.1093/bja/aep200. Laupland KB, Bands CJ. Utility of esophageal Doppler as a minimally invasive hemodynamic monitor: a review. Can J Anaesth. 2002;49(4):393–401. doi:10.1007/ BF03017329. Machare-Delgado E, Decaro M, Marik PE. Inferior vena cava variation compared to pulse contour analysis as

L. Busse et al. predictors of fluid responsiveness: a prospective cohort study. J Intensive Care Med. 2011;26(2):116–24. Maizel J, Airapetian N, Lorne E, Tribouilloy C, Massy Z, Slama M. Diagnosis of central hypovolemia by using passive leg raising. Intensive Care Med. 2007;33 (7):1133–8. doi:10.1007/s00134-007-0642-y. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008;134(1):172–8. doi:10.1378/chest. 07-2331. Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: a systematic review of the literature. Crit Care Med. 2009;37(9):2642–7. doi:10.1097/ CCM.0b013e3181a590da. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009;33(3):277–316. doi:10.1177/0148607109335234. Michard F. Changes in arterial pressure during mechanical ventilation. Anesthesiology. 2005;103(2):419–28. quiz 449-5. Michard F, Teboul JL. Predicting fluid responsiveness in ICU patients: a critical analysis of the evidence. Chest. 2002;121(6):2000–8. Moreno FL, Hagan AD, Holmen JR, Pryor TA, Strickland RD, Castle CH. Evaluation of size and dynamics of the inferior vena cava as an index of right-sided cardiac function. Am J Cardiol. 1984;53(4):579–85. Moretti R, Pizzi B. Inferior vena cava distensibility as a predictor of fluid responsiveness in patients with subarachnoid hemorrhage. Neurocrit Care. 2010;13(1): 3–9. doi:10.1007/s12028-010-9356-z. Nakao S, Come PC, McKay RG, Ransil BJ. Effects of positional changes on inferior vena caval size and dynamics and correlations with right-sided cardiac pressure. Am J Cardiol. 1987;59(1):125–32. Neviere R, Mathieu D, Riou Y, et al. Carbon dioxide rebreathing method of cardiac output measurement during acute respiratory failure in patients with chronic obstructive pulmonary disease. Crit Care Med. 1994;22(1):81–5. Obritsch MD, Jung R, Fish DN, MacLaren R. Effects of continuous vasopressin infusion in patients with septic shock. Ann Pharmacother. 2004;38(7–8):1117–22. doi:10.1345/aph.1D513. Odenstedt H, Stenqvist O, Lundin S. Clinical evaluation of a partial CO2 rebreathing technique for cardiac output monitoring in critically ill patients. Acta Anaesthesiol Scand. 2002;46(2):152–9. Petter H, Erik A, Bjorn E, Goran R. Measurement of cardiac output with non-invasive Aesculon impedance versus thermodilution. Clin Physiol Funct Imaging. 2011;31(1):39–47. doi:10.1111/j.1475-097X.2010. 00977.x.

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Preau S, Saulnier F, Dewavrin F, Durocher A, Chagnon JL. Passive leg raising is predictive of fluid responsiveness in spontaneously breathing patients with severe sepsis or acute pancreatitis. Crit Care Med. 2010;38(3): 819–25. doi:10.1097/CCM.0b013e3181c8fe7a. Proulx F, Lemson J, Choker G, Tibby SM. Hemodynamic monitoring by transpulmonary thermodilution and pulse contour analysis in critically ill children. Pediatr Crit Care Med. 2011;12(4):459–66. doi:10.1097/ PCC.0b013e3182070959. Reisner AT, Xu D, Ryan KL, Convertino VA, Rickards CA, Mukkamala R. Monitoring non-invasive cardiac output and stroke volume during experimental human hypovolaemia and resuscitation. Br J Anaesth. 2011;106(1):23–30. doi:10.1093/bja/aeq295. Sageman WS, Riffenburgh RH, Spiess BD. Equivalence of bioimpedance and thermodilution in measuring cardiac index after cardiac surgery. J Cardiothorac Vasc Anesth. 2002;16(1):8–14. Sakka SG, Reinhart K, Wegscheider K, Meier-Hellmann A. Is the placement of a pulmonary artery catheter still justified solely for the measurement of cardiac output? J Cardiothorac Vasc Anesth. 2000;14(2): 119–24. Sandham JD, Hull RD, Brant RF, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med. 2003;348 (1):5–14. doi:10.1056/NEJMoa021108. Sandroni C, Cavallaro F, Marano C, Falcone C, De Santis P, Antonelli M. Accuracy of plethysmographic indices as predictors of fluid responsiveness in mechanically ventilated adults: a systematic review and

19 meta-analysis. Intensive Care Med. 2012;38(9): 1429–37. doi:10.1007/s00134-012-2621-1. Schefold JC, Storm C, Bercker S, et al. Inferior vena cava diameter correlates with invasive hemodynamic measures in mechanically ventilated intensive care unit patients with sepsis. J Emerg Med. 2010;38(5):632–7. doi:10.1016/j.jemermed.2007.11.027. Segal E, Katzenelson R, Berkenstadt H, Perel A. Transpulmonary thermodilution cardiac output measurement using the axillary artery in critically ill patients. J Clin Anesth. 2002;14(3):210–3. Tachibana K, Imanaka H, Takeuchi M, Takauchi Y, Miyano H, Nishimura M. Noninvasive cardiac output measurement using partial carbon dioxide rebreathing is less accurate at settings of reduced minute ventilation and when spontaneous breathing is present. Anesthesiology. 2003;98(4):830–7. Tang WH, Tong W. Measuring impedance in congestive heart failure: current options and clinical applications. Am Heart J. 2009;157(3):402–11. doi:10.1016/j. ahj.2008.10.016. Teboul JL, Monnet X. Prediction of volume responsiveness in critically ill patients with spontaneous breathing activity. Curr Opin Crit Care. 2008;14(3):334–9. doi:10.1097/MCC.0b013e3282fd6e1e. Urban P, Scheidegger D, Gabathuler J, Rutishauser W. Thermodilution determination of right ventricular volume and ejection fraction: a comparison with biplane angiography. Crit Care Med. 1987;15(7):652–5. Zaloga GP, Roberts PR, Marik P. Feeding the hemodynamically unstable patient: a critical evaluation of the evidence. Nutr Clin Pract. 2003;18(4):285–93.

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Acid-Base Balance in Context of Critical Care Phil Ayers, Carman Dixon, Andrew Mays, and D. Timothy Cannon

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Metabolic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Anion Gap Metabolic Acidosis . . . . . . . . . . . . . . . . . . . . . Diabetic Ketoacidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alcoholic Ketoacidosis (AKA) . . . . . . . . . . . . . . . . . . . . . . . Lactic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sodium Chloride-Responsive Metabolic Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sodium Chloride-Resistant Metabolic Alkalosis . . . . . Respiratory Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Respiratory Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Acid–Base Disorders . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Metabolic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Metabolic Acidosis and Metabolic Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Metabolic Acidosis and Respiratory Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Metabolic Alkalosis and Respiratory Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Metabolic Acidosis and Respiratory Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Metabolic Alkalosis and Respiratory Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23 23 24 24 25

Triple Acid–Base Disorders . . . . . . . . . . . . . . . . . . . . . . . . . Compensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutrition and Acid–Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications to Critical or Intensive Care . . . . . . . . . . . . Applications to Other Conditions . . . . . . . . . . . . . . . . . . . . . Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30 30 30 31 31 31

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

25 26 26 27 27 27 28 28 28 29 29

P. Ayers (*) Department of Pharmacy, Mississippi Baptist Medical Center, Jackson, MS, USA e-mail: [email protected] C. Dixon • A. Mays Mississippi Baptist Medical Center, Jackson, MS, USA e-mail: [email protected]; [email protected] D.T. Cannon Jackson Pulmonary Associates, Jackson, MS, USA e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_100

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Abstract

Acid–base homeostasis of the body requires the lungs, kidneys, and a complex system of buffers. The maintenance of a normal pH of 7.35–7.45 of arterial blood is ideal for optimal organ function. This chapter will describe the role of the lungs, kidneys, and complex buffers in acid–base balance. The chapter will review the diagnosis, sources, and treatment of metabolic and respiratory acidosis and alkalosis. Mixed disorders and compensatory mechanisms will be discussed in this text. The chapter will conclude with the influence of nutrition on acid–base balance (Roberts 2013; Ayers and Dixon 2012; Madias 2002). List of Abbreviations

ABG ADP AKA BDZ BE/BD Cl
CNS CPOD CVA D5NS DKA ECF HCO3 Kg L mEq Na+ NH4+ NM PaCO2 RTA

Arterial blood gas Adenosine triphosphate Alcoholic ketoacidosis Benzodiazepines Base excess/base deficit Chloride Central nervous system Chronic obstructive pulmonary diseases Cerebrovascular accident 5 % dextrose in 0.9 % sodium chloride Diabetic ketoacidosis Extracellular fluid Bicarbonate Kilogram Liter Milliequivalent Sodium Ammonia Neuromuscular Arterial pressure of carbon dioxide Renal tubular acidosis

Introduction Acute illness, chronic disease states, nutritional deficiencies, and subsequent replacement as well as numerous other factors all contribute to

acid–base abnormalities. The successful diagnosis and subsequent correction of these variations are dependent upon a complete history and physical examination, accurate arterial blood gas analysis, and correct interpretation of the results (Stewart 2007). This chapter will provide insight into the identification and management of acid–base disorders. The body’s ability to maintain acid–base homeostasis is imperative for optimal cellular function and is dependent upon a complex system of buffers and organ systems. Hydrogen ion (H+) is the primary indicator of acid–base status and is commonly expressed as pH (negative logarithm of H+ concentration). Normal arterial pH ranges from 7.35 to 7.45. Acidemia is defined as an arterial pH 7.45 is termed alkalemia. Disorders that lower or raise pH are termed an acidosis or alkalosis, respectively. It is important to note that a normal pH does not necessarily indicate an absence of acidosis or alkalosis. Mixed disorders and the normal physiology of compensatory mechanisms preclude the use of pH as the sole measure of acid–base status. Additional values used to evaluate arterial blood gases (ABG) include the arterial pressure of carbon dioxide (PaCO2), bicarbonate (HCO3
), and base excess/deficit (BE/BD) (Roberts 2013; Ayers and Dixon 2012). The lungs and kidneys together play the vital role in maintaining a normal arterial pH. Small alterations in pH stimulate minor changes to respiratory ventilation within minutes to hours of the disturbance. Conversely, changes in renal response to acid–base disorders occur over several days. The lungs regulate the excretion of carbon dioxide, considered the primary volatile acid in the body. Respiratory acidosis occurs in conditions that cause diminished carbon dioxide excretion and thus increased PaCO2. During hyperventilation, carbon dioxide removal occurs at an increased rate which lowers PaCO2 and leads to respiratory alkalosis. The kidneys primarily affect systemic pH by regulation of bicarbonate reabsorption in the proximal tubule. Additionally, the kidneys function to eliminate nonvolatile acids and ammonia (NH4+) in the urine. Disorders that lead to a deficit or an excess of HCO3
are called metabolic acidosis or metabolic alkalosis,

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respectively (Devlin and Matzke 2011). This balance of the metabolic and respiratory mechanisms to maintain a normal systemic pH is described by the Henderson–Hasselbalch equation: pH ¼ 6:1 þ log ð½HCO3
=ð0:03  pCO2 ÞÞ

Metabolic Acidosis Metabolic acidosis presents with an arterial pH 70 24 (22–30)
3 to +3

Venous blood 7.36 (7.31–7.41) 42–55 30–50 24–28
3 to +3

> 90

60–85

Ayers and Dixon (2012)

assist the clinician in determining the cause of acidosis and guide the clinician toward adequate treatment. The reference range for a calculated anion gap is 3–11 mEq/L. The following equation is used to calculate anion gap: Na+
(Cl
+ HCO3
) (Constable 2009). Table 2 shows the common causes of metabolic acidosis divided into anion and non-anion gap. The primary issue related to metabolic acidosis is loss of bicarbonate. The body will compensate within minutes for this decreased pH with an increase in alveolar ventilation (Kussmaul respiration) to eliminate carbon dioxide. Metabolic acidosis can depress intrinsic myocardial contractility, but catecholamine release can maintain normal inotropic function. Central venoconstriction and peripheral arterial vasodilation can be present, and this decrease in central and pulmonary vascular compliance can increase the risk for pulmonary edema in these patients. Patients do not require alkalinization therapy with sodium bicarbonate unless acidosis is severe (pH 7.45 and is due to a primary increase in plasma bicarbonate concentration. Normally, the gastric parietal cells produce hydrogen ions and bicarbonate from carbon dioxide and water. Hydrogen ions are secreted into gastric fluid while bicarbonate is retained in the extracellular fluid. The balance between bicarbonate and hydrogen ions is maintained as bicarbonate is eliminated in an amount equal to the amount produced in the stomach via alkaline pancreatic and small bowel secretions (Roberts 2013; Ayers and Dixon 2012). With excessive vomiting and nasogastric suctioning, loss of hydrogen ions from gastric fluid leads to metabolic alkalosis. Active vomiting can lead to a state in the proximal tubule where the reabsorptive capacity for HCO3
is exceeded due to an acute increase in the filtered load of bicarbonate (Devlin and Matzke 2011). The distal tubule is also affected as hydrogen ion secretion is enhanced by aldosterone. Secretory diarrhea, when the amount of fluid presented to the colon exceeds its maximal absorption capacity, can often result in an excess of gastrointestinal loss

25

of chloride-rich, bicarbonate-poor fluid also leading to metabolic alkalosis. Diuretic agents acting on the ascending loop of Henle (furosemide, bumetanide, and torsemide) and the distal convoluted tubule (thiazides) promote the excretion of sodium and potassium in association with chloride ions and no proportionate increase in bicarbonate excretion. The decrease in extracellular fluid volume from diuretics leads to an increase in serum bicarbonate concentrations without changes in total body bicarbonate content. Corticosteroid administration, particularly those with high mineralocorticoid activity, can stimulate collecting duct hydrogen ion secretion and cause renal sodium and fluid retention and hypokalemia. This concomitant hypokalemia can increase ammoniagenesis, which can further increase net acid excretion. High doses of penicillins such as ticarcillin can act as nonreabsorbable anions in the distal renal tubule and can produce metabolic alkalosis by enhancing secretion of potassium and hydrogen ions. Of note, patients with chronic administration of alkali (bicarbonate, parenteral nutrition with high acetate loads, transfusions due to citrate loads, and cation-exchange resins plus antacids) with normal renal function will rarely develop alkalosis, but those same patients who become hemodynamically unstable could develop alkalosis due to decreased excretion of bicarbonate or enhanced reabsorption of bicarbonate (Constable 2009; DuBose 2012; DuBose and Hamm 2002). Table 3 shows common causes of metabolic alkalosis divided into sodium chloride responsive and resistant.

Sodium Chloride-Responsive Metabolic Alkalosis Metabolic alkalosis is precipitated through intravascular volume depletion (volume-mediated processes) by a variety of mechanisms. Decreased intravascular volume leads to decreased glomerular filtration rate, which decreases the kidney’s ability to excrete excess bicarbonate. Also, decreased effective arterial blood volume enhances proximal and distal tubular sodium reabsorption, which must be coupled with

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Table 3 Causes of metabolic alkalosis Sodium chloride responsive Urine chloride 10 mEq/L Normotensive Potassium depletion Hypercalcemia Hypertensive Mineralocorticoids

Ayers and Dixon (2012) Reprinted with permission from Lee M, Basic Skills in Interpreting Laboratory Data, Fifth Edition. Copyright#2013, American Society of Health-System Pharmacists, Bethesda, Maryland, p. 200

reabsorption of an anion (chloride, bicarbonate) or exchange with a cation (potassium or hydrogen) to maintain charge neutrality. This increased sodium reabsorption leads to increased bicarbonate reabsorption in the proximal tubule and stimulation of hydrogen ion secretion during hypokalemia. As volume depletion presents, the body will increase secretion of aldosterone. This increased aldosterone, by way of mineralocorticoid activity, will stimulate collecting duct hydrogen ion secretion. This condition is responsive to volume resuscitation with sodium chloride and potassium replenishment to correct volume deficit (Constable 2009; Devlin and Matzke 2011).

Sodium Chloride-Resistant Metabolic Alkalosis Metabolic alkalosis can be precipitated in ways other than volume depletion. In sodium chlorideresistant metabolic alkalosis, the underlying cause of mineralocorticoid excess should be identified. Mineralocorticoid excess by way of increased aldosterone levels can be the result of autonomous primary adrenal overproduction or increased aldosterone secondary to renal overproduction of renin. Mineralocorticoid excess increases net acid

excretion, distal sodium absorption, and kaliuresis. Potassium excretion persists due to sodium retention causing increased extracellular fluid volume, continued potassium depletion due to polydipsia, inability to concentrate urine, and polyuria. Various pharmacologic agents can be used to treat conditions associated with syndromes of mineralocorticoid excess. Spironolactone is a mineralocorticoid receptor antagonist, and amiloride and triamterene are potassium-sparing diuretics that all inhibit aldosterone-stimulated sodium reabsorption in the nephron’s collecting duct (Ayers and Dixon 2012; Constable 2009; Devlin and Matzke 2011).

Respiratory Acidosis Respiratory acidosis is a chronic or acute state when the lungs fail to adequately excrete carbon dioxide leading to a decrease in arterial pH. Hypoventilation is commonly linked with respiratory acidosis because decreased respiratory rates do not allow proper elimination of carbon dioxide leading to hypercapnia. Partial pressure of arterial carbon dioxide (PaCO2) is a value on the arterial blood gas panel (ABG) that allows the clinician to identify respiratory acidosis as opposed to metabolic acidosis. Normal PaCO2 levels are 35–45 mmHg, and a PaCO2 greater than 45 mmHg is indicative of respiratory acidosis. Acute causes of depressed respiratory drive leading to respiratory acidosis are drug overdose, head trauma, cerebrovascular accident (CVA), spinal cord injury, acute airway diseases, pulmonary embolus, and pneumothorax. These acute causes of respiratory acidosis cause a more abrupt alteration in pH compared to chronic causes due to the body’s compensatory mechanisms in longstanding respiratory acidosis. Patients with acute respiratory acidosis can present with symptoms of anxiety, dyspnea, confusion, psychosis, and hallucinations. Acute increases in PaCO2 occur following upper airway occlusion from asthma-induced bronchospasm, anaphylaxis, and inhalation burns from heat or toxins. Depression of the respiratory center of the brain by drugs (general anesthetics, sedatives, narcotics), injury (head trauma and CVA), or disease (pulmonary embolus, seizures,

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Guillain–Barre syndrome) can also precipitate respiratory acidosis. Restrictive disorders involving both the chest wall and lungs can lead to respiratory acidosis because of the high metabolic cost of respiration leading to ventilatory muscle fatigue. End-stage obstructive lung disease or advanced stages of intrapulmonary and extrapulmonary restrictive defects can present as chronic respiratory acidosis. In patients with chronic respiratory acidosis, chronic hypercapnia blunts the usual respiratory stimulus caused by increased PaCO2. In these patients, hypoxemia drives the primary ventilatory stimulus in chronic respiratory acidosis (Roberts 2013; Barrett et al. 2012; Constable 2009; Devlin and Matzke 2011; DuBose 2012). Table 4 shows common causes of respiratory acidosis divided into acute and chronic.

Respiratory Alkalosis Respiratory alkalosis is a clinical condition when hyperventilation decreases PaCO2 and increases arterial pH. This is due to the loss of carbon dioxide by the lungs, which exceeds the body’s metabolic ability to excrete bicarbonate. Patients to who are acutely critically ill with cardiogenic, hypovolemic, or septic shock have a decreased PaCO2 due to a reduction in oxygen delivery to the carotid and aortic chemoreceptors. Also, the metabolic production of bicarbonate can be increased during periods of high stress or with excessive carbohydrate administration. Most patients are asymptomatic, but periods of decreased PaCO2 lead to a decrease in cerebral blood flow, which can lead to neurologic symptoms (confusion, syncope, seizures). Electrolyte abnormalities can occur with metabolic alkalosis, such as slight reduction in serum potassium and a slight increase in serum chloride. Symptoms of muscle cramps and tetany can occur due to reductions in the blood ionized calcium concentration because an increase in pH results in an increased binding of calcium to albumin. Serum phosphorus concentrations can also decrease due to the shift of inorganic phosphate into cells (Roberts 2013; Barrett et al. 2012; Constable 2009;

27 Table 4 Causes of respiratory acidosis Acute CNS depression Drug overdose (BDZs, narcotics, propofol) Head trauma CVA NM disease Guillain–Barre syndrome Spinal cord injury Botulism Acute airway disease Status asthmaticus Upper airway obstruction COPD exacerbation Parenchymal and vascular disease Massive pulmonary embolus Acute pleural or chest wall disease Pneumothorax Flail chest Seizures

Chronic Central sleep apnea Primary alveolar hypoventilation Obesity hypoventilation syndrome Spinal cord injury Diaphragmatic paralysis Amyotrophic lateral sclerosis Myasthenia gravis Muscular dystrophy Multiple sclerosis Poliomyelitis Hypothyroidism Kyphoscoliosis COPD Severe chronic interstitial lung disease

Ayers and Dixon (2012) Reprinted with permission from Lee M, Basic Skills in Interpreting Laboratory Data, Fifth Edition. Copyright#2013, American Society of Health-System Pharmacists, Bethesda, Maryland, p. 201 BZDs benzodiazepines, CNS central nervous system, CVA cerebrovascular accident, COPD chronic obstructive pulmonary disease, NM neuromuscular

Devlin and Matzke 2011; DuBose 2012; Laski and Wesson 2002). Table 5 shows common causes of respiratory alkalosis.

Mixed Acid–Base Disorders Mixed Metabolic Acidosis During the evolution of chronic renal failure, mixed hyperchloremic and anion gap metabolic acidosis can occur. The reduction in bicarbonate is partially compensated by an anion gap increase and partially by hyperchloremia. Hyperchloremic

28 Table 5 Causes of respiratory alkalosis Hypoxia Parenchymal lung disease Pneumonia Bronchial asthma Pulmonary embolus Pulmonary edema High altitudes Severe anemia Medications and mechanical ventilation Salicylates Nicotine Xanthine Progesterone CNS disorders Meningitis, encephalitis Head trauma Brain tumors Anxiety Pain Ayers and Dixon (2012) Reprinted with permission from Lee M, Basic Skills in Interpreting Laboratory Data, Fifth Edition. Copyright#2013, American Society of Health-System Pharmacists, Bethesda, Maryland, p. 201

metabolic acidosis is common during the early phase of renal failure due to the reduced renal excretion of ammonium chloride. As renal failure progresses, more typical uremic anion gap acidosis will develop. Mixed metabolic acidosis can also develop in patients with severe diarrhea due to volume depletion leading to lactic acidosis and alkali loss leading to hyperchloremic acidosis (Constable 2009; DuBose 2012).

Mixed Metabolic Acidosis and Metabolic Alkalosis Anion gap and bicarbonate relationship is an essential clue to determine the existence of mixed metabolic acidosis and metabolic alkalosis. When comparing anion gap changes with changes in bicarbonate concentration, one should see if the anion gap increases significantly more than the reduction in bicarbonate. If this is true, then mixed metabolic acidosis and metabolic alkalosis could exist.

P. Ayers et al.

A patient who develops uremic metabolic acidosis has a fall in serum bicarbonate and an increase in anion gap. This same patient could develop nausea and vomiting leading to a loss of gastric acid leading to an increase in bicarbonate and reduction of chloride levels. However, a patient with hyperchloremic metabolic acidosis has increased chloride concentration and reduced bicarbonate concentrations with no residual clue of an increased anion gap (Constable 2009; DuBose 2012).

Mixed Metabolic Acidosis and Respiratory Alkalosis Metabolic acidosis associated with a PaCO2 that is below the predicted compensatory level may indicate a mixed metabolic acidosis and respiratory alkalosis. Also, a mixed metabolic acidosis and respiratory alkalosis can occur if respiratory alkalosis occurs primarily with overcompensation of excessive bicarbonate reduction. Mixed metabolic acidosis and respiratory alkalosis is often seen in advanced liver disease, salicylate ingestion, and pulmonary–renal syndromes. Ingestion of toxic amounts of salicylates leads to hyperventilation and respiratory alkalosis due to direct stimulation of respiratory centers in the CNS. This toxic ingestion also leads to organic acid accumulation due to the uncoupling of mitochondrial oxidative phosphorylation. Respiratory alkalosis will decrease PaCO2 below the appropriate range normal for metabolic acidosis, and plasma bicarbonate concentration will decrease below the expected compensation for simple respiratory alkalosis. There is an enhanced compensation for each disorder. This leads to a normal or close to normal pH with a low PaCO2 and a low serum bicarbonate concentration (Constable 2009; DuBose 2012).

Mixed Metabolic Alkalosis and Respiratory Acidosis In patients with chronic respiratory acidosis, the body should compensate with an increase in serum bicarbonate. If the body’s compensatory metabolic response is greater than the normal

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Acid-Base Balance in Context of Critical Care

compensation, a mixed metabolic alkalosis and respiratory acidosis exists. Mixed metabolic alkalosis and respiratory acidosis occurs in patients with chronic obstructive pulmonary disease and chronic respiratory acidosis that are treated with salt restriction, diuretics, and/or glucocorticoids. The initiation of diuretics in these patients can lead to increased renal bicarbonate generation and reabsorption leading to the generation and maintenance of metabolic alkalosis. Overcompensation of increased serum bicarbonate levels elevates pH to a near “normal range” and can eliminate respiratory drive that would normally compensate for increased PaCO2. The pH of these patients may not differ significantly from normal, but the identification of this mixed disorder is necessary to maintain PaO2 and PaCO2 at acceptable levels. Patient response to therapies can help determine if a mixed disorder is present. The discontinuation of diuretics and administration of normal saline and potassium will precipitate a normalization of PaCO2 in a simple metabolic alkalosis, but the same interventions will minimally affect the PaCO2 in a mixed disorder. Patients with mixed metabolic alkalosis and respiratory acidosis should have therapy aimed at decreasing plasma bicarbonate with proper fluids to increase renal elimination of bicarbonate with caution in those with underlying congestive heart failure (Constable 2009; DuBose 2012).

Mixed Metabolic Acidosis and Respiratory Acidosis Metabolic acidosis significantly lowers the serum bicarbonate concentration to an acidotic level, but when the PaCO2 is not lowered sufficiently, then a mixed metabolic and respiratory acidosis can coexist. Mixed metabolic and respiratory acidosis can occur in respiratory failure, cardiopulmonary arrest, severe pulmonary edema, and those with chronic lung disease who develop shock and lactic acidosis. Patients with metabolic acidosis that is complicated with severe hypokalemia or hypophosphatemia can develop respiratory acidosis due to respiratory muscle weakness. Clinicians should address both sources of acidosis when

29

treating this mixed disorder. Proper oxygen delivery can improve hypercarbia and hypoxia with mechanical ventilation as a possibility to reduce PaCO2. These patients should be given appropriate amounts of alkali to reverse the metabolic acidosis as a part of initial treatment. Total bicarbonate dose can be calculated with the following formula: 0.5 (L/kg)  body weight (kg)  desired increase in serum bicarbonate (mEq/L). Initial replacement should be 50 % of the total bicarbonate dose over 3–4 h with the remaining dose over 8–24 h. When bicarbonate is administered as a bolus dose, the initial effects on systemic pH will be maximal due to the original dose of bicarbonate being distributed into the intracellular space as time passes (Constable 2009; DuBose 2012).

Mixed Metabolic Alkalosis and Respiratory Alkalosis When patients present with a low PaCO2 and elevated bicarbonate level, this combination is indicative of metabolic alkalosis and respiratory alkalosis. Mixed metabolic and respiratory alkalosis is the most common mixed acid–base disorder. It commonly occurs in critically ill surgical patients with respiratory alkalosis due to mechanical ventilation, hypoxia, sepsis, or hypotension and metabolic alkalosis caused by vomiting, nasogastric suctioning, or large blood transfusions. This disorder can also occur in patients with hepatic cirrhosis that develop hyperventilation, receive diuretics, or have excessive emesis. Mixed metabolic and respiratory alkalosis can also occur in patients with chronic respiratory acidosis with elevated plasma bicarbonate concentrations who are placed on mechanical ventilation leading to a rapid decrease in PaCO2. Renal compensation for respiratory alkalosis by way of the excretion of bicarbonate is prevented by metabolic alkalosis. Respiratory compensation for metabolic alkalosis by the decreasing of respiratory rate to retain PaCO2 is prevented by primary respiratory alkalosis. The failure of the body’s natural compensatory mechanisms can lead to a synergistic development of severe alkalemia. Severe alkalemia can produce cerebral

30

vasoconstriction, increased hemoglobin affinity for oxygen, hypokalemia, and cardiac arrhythmias. Proper fluid administration will help correct the metabolic component of this disorder, and adjustment of the ventilator or treatment of the underlying disorder causing hyperventilation can help correct the respiratory component of this mixed disorder (Constable 2009; DuBose 2012).

Triple Acid–Base Disorders A triple acid–base disorder occurs when metabolic acidosis and metabolic alkalosis combine with respiratory acidosis or respiratory alkalosis. Triple acid–base disorders commonly occur in patients with severe liver disease. Metabolic acidosis can be caused by uremia, lactic acidosis, renal tubular acidosis, or diarrhea. Then a patient could develop metabolic alkalosis from vomiting, diuretics, or nasogastric suction. High anion gap metabolic acidosis occurs when anion gap increase exceeds the reduction of bicarbonate concentration. These patients with liver failure will develop chronic hyperventilation and respiratory alkalosis due to stimulation of the respiratory center of the CNS by ammonia and accumulation of toxic compounds and high progesterone levels. Patients with liver failure also have hypoxia produced from increased pressure on the diaphragm from ascites and arteriovenous shunting (Constable 2009; DuBose 2012).

Compensation A summary of the expected results in the four simple acid–base disorders is demonstrated in Tables 6 and 7. In each disorder, you will note a primary occurrence followed by a compensatory response. For example, in respiratory alkalosis the primary issues are an elevated pH and a decreased PaCO2 by the lungs. The kidneys compensate by excreting bicarbonate to assist in lowering the pH toward normal. It is important to remember that the body never overcompensates and complete compensation may not occur. Complete respiratory compensation requires adequate lung capacity,

P. Ayers et al. Table 6 Levels of compensation in acid–base disorders Disorder Metabolic acidosis Metabolic alkalosis Respiratory acidosis (acute) Respiratory acidosis (chronic) Respiratory alkalosis (acute) Respiratory alkalosis (chronic)

Reference level of compensation # PaCO2 = 1.2  (normal HCO3
- measured HCO3
) " PaCO2 = 0.6  (measured HCO3

normal HCO3
) " HCO3
=0.1  (measured PaCO2
normal PaCO2) " HCO3
=0.4  (measured PaCO2
normal PaCO2) # HCO3
=0.2  (measured PaCO2
normal PaCO2) # HCO3
=0.4  (measured PaCO2
normal PaCO2)

The metabolic formulas tend to be less accurate than the respiratory formulas Ayers and Dixon (2012) Reprinted with permission from Lee M, Basic Skills in Interpreting Laboratory Data, Fifth Edition. Copyright#2013, American Society of Health-System Pharmacists, Bethesda, Maryland, p. 198

and complete renal compensation requires adequate volume status and normal renal function. In the case of the predicted level of compensation not occurring, this could be indicative of an additional underlying disorder. It is important to remember that respiratory compensation occurs in a matter of minutes to hours, whereas renal compensation may require 3–5 days. Formulas used for estimating the level of compensation can be found in Table 6. These are estimates only and generally changes within 10 % of the calculated values are seen with normal compensation. Changes greater than 10 % of the predicted value may be consistent with a mixed acid–base disorder (Roberts 2013; Constable 2009).

Nutrition and Acid–Base Acid–base disorders may occur in the overfeeding of patients. Excessive caloric delivery may result in an increase in the production of carbon dioxide, which drives up minute ventilation and results in failure to wean from mechanical ventilation (Wooley et al. 2012). In regard to parenteral nutrition, the removal of chloride salts and/or the addition of acetate salts in parenteral nutrition

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Acid-Base Balance in Context of Critical Care

31

Table 7 Physiological compensation Disorder Metabolic acidosis Metabolic alkalosis Respiratory alkalosis Respiratory acidosis

Initial presentation #pH and #HCO3
"pH and "HCO3 "pH and #PaCO2 #pH and "PaCO2

Compensation Lungs compensate Lungs compensate Kidneys compensate Kidneys compensate

Result "pH and #PaCO2 #pH and "PaCO2 #pH and #HCO3 "pH and "HCO3

Ayers and Dixon (2012) Reprinted with permission from Lee M, Basic Skills in Interpreting Laboratory Data, Fifth Edition. Copyright#2013, American Society of Health-System Pharmacists, Bethesda, Maryland, p. 198

admixture may be required. In patients with a metabolic acidosis, the clinician should consider maximizing the acetate salt. In metabolic alkalosis, the chloride salt should be maximized. Due to instability issues, sodium bicarbonate should not be directly added into parenteral nutrition solutions. Even with the ability to adjust acetate and chloride salts, parenteral nutrition should not be the singular treatment to correct a severe metabolic acidosis.

recently released a statement that multiple studies found that approximately one in every three patients in the United Sates is suffering from malnutrition and in many cases patients are becoming malnourished while hospitalized. Malnourished patients often have longer hospital stays, a greater chance of readmission, and higher rates of complications and death (White et al. 2012).

Guidelines and Protocols Applications to Critical or Intensive Care In order to provide optimal parenteral and enteral nutrition to the critically ill patient, it is imperative that the clinician have an understanding of acid–base balance. Chloride and acetate salts, used in parenteral nutrition, can influence the acid–base status of the patient. Parenteral nutrition salts should not be used to correct metabolic acidosis or alkalosis, but may be used for the maintenance of the normal metabolic status. Selection of an incorrect salt form may worsen the acid–base status of the patient. Overfeeding by the parenteral and enteral route has been associated with the accumulation of the carbon dioxide which may lead to a worsening of respiratory acidosis. Parenteral and enteral nutrition should not be initiated in patients with an unstable acid–base status.

Standard nutrition screening, assessment, and prescribing protocols should be utilized by the critical care clinician. Standard order forms and labels should be utilized for ordering parenteral nutrition (McClave et al. 2009). The order process, electronic or printed, should include: • • • • • • • • •

Applications to Other Conditions The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) (September 24, 2013)

• • • •

Appropriate patient identifiers Height, weight, and age of the patient Vascular access device Administration date and time Appropriate laboratory and monitoring Amino acids, dextrose, and IV fat emulsion in grams/day in adults Amino acids, dextrose, and IV fat emulsion in grams/kg/day in neonates and pediatrics Electrolytes in mEq/day and mmol/day for phosphate salts in adults Electrolytes in mEq/kg/day and mmol/kg/day for phosphate salts in neonates and pediatrics Vitamins, trace elements in ml/day Total volume of parenteral nutrition Rate of infusion, start and stop times Prescriber and contact information

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The critical care clinician should utilize a standard process for initiating and advancing enteral nutrition (McClave et al. 2009). The order process, electronic or printed, should include: • • • • •

Route of administration for enteral nutrition Name of enteral formulation Appropriate laboratory and monitoring Instructions for administration Instructions for advancement of enteral feedings and goal rate • Appropriate water flushes • Instructions for residuals checks and head of bed elevation • Prescriber and contact information

Summary • Acid–base homeostasis is dependent upon a complex system of buffers and organ systems. The kidneys, primarily through the regulation of bicarbonate, and the lungs, primarily through the regulation of carbon dioxide, play a vital role in maintaining normal arterial pH. • Laboratories set slightly different ranges for normal measures of acid–base markers. This chapter defines acidemia as a pH of 7.45. Normal systemic pH is described by the Henderson–Hasselbalch equation. • Metabolic acidosis is primarily related to a decrease in bicarbonate and metabolic alkalosis is primarily related to an increase in bicarbonate in the body. A calculated anion gap can help identify the cause of metabolic acidosis. • Respiratory acidosis is a chronic or an acute condition in which the lungs fail to adequately excrete carbon dioxide. Respiratory alkalosis occurs when hyperventilation decreases PaCO2 and increases arterial pH. • Each acid–base disorder is associated with an appropriate renal or respiratory compensatory response (Table 6). A normal response would indicate a simple acid–base disorder and an abnormal response may indicate a mixed disorder.

P. Ayers et al.

• Overfeeding patients and unbalanced parenteral anion solutions can both contribute to development of acid–base disorders. Parenteral anion salts should not be used to correct underlying acid–base disorders, but appropriate anion adjustment is used to help the body achieve normal metabolic status. • Nutritional deficiencies can contribute to acid–base abnormalities. Malnourished patients often have longer hospital stays, a greater chance of readmission, and higher rates of complications and death.

References Ayers P, Dixon C. Simple acid–base tutorial. J Parenter Enteral Nutr. 2012;36:18–23. Barrett KE, Barman SM, Boitano S, Brooks HL. Acidification of urine & bicarbonate excretion. In: Barrett KE, Barman SM, Boitano S, Brooks HL, editors. Ganong’s review of medical physiology. 24th ed. New York: McGraw-Hill; 2012. http://www.accesspharmacy.com/ content.aspx?aID=56266144. Accessed 16 May 2013. Constable P. Clinical acid–base chemistry. In: Ronco C, Bellomo R, Kellum J, editors. Critical care nephrology. 2nd ed. Philadelphia: Elsevier; 2009. p. 581–614. Devlin JW, Matzke GR. Acid–base disorders. In: Talbert RL, DiPiro JT, Matzke GR, Poser LM, Wells BG, Yee GC, editors. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York: McGraw-Hill; 2011. p. 923–42. DuBose TD. Acidosis and alkalosis. In: Fauci AS, Kasper DL, Jameson JL, Longo DL, Hauser SL, editors. Harrison’s principles of internal medicine. 18th ed. New York: McGraw-Hill; 2012. p. 363–73. DuBose TD, Hamm L. Diagnosis of simple and mixed disorders. In: Emmett M, editor. Acid base and electrolyte disorders: a companion to Brenner & Rector’s the kidney. 1st ed. Philadelphia: Elsevier; 2002. p. 41–53. Kamel KS, Davids MR, Lin SH, Halperin ML. Interpretation of electrolyte and acid–base parameters in blood and urine. In: Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu ASL, Brenner BM, editors. Brenner and Rector's the Kidney. 9th ed. Philadelphia: Saunders; 2011. p. 897–928. Laski ME, Wesson DE. Lactic acidosis. In: DuBose TD, Hamm LL, editors. Acid–base and electrolyte disorders-a companion to Brenner and Rector’s the kidney. Philadelphia: Saunders; 2002. p. 83–107. Madias NE. Respiratory alkalosis. In: DuBose TD, Hamm LL, editors. Acid–base and electrolyte disorders-a companion to Brenner and Rector’s the Kidney. Philadelphia: Saunders; 2002. p. 147–64. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support

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therapy in the adult critically Ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Neteral Nutr. 2009;33(3):277–316. Roberts AL. Arterial blood gases and acid base balance. In: Lee M, editor. Interpreting laboratory data. Bethesda: American Society of Health-System Pharmacists Inc; 2013. p. 193–205. Stewart PA. Goals, definitions and basic principles. In: Kellum JA, Ebers PWG, editors. Stewart’s textbook of acid–base. 2nd ed. Amsterdam: Elsevier; 2007. p. 36–62.

33 White JV, Guenter P, Jensen G, et al. Consensus statement: academy of nutrition and dietetics and american society for parenteral and enteral nutrition: characteristics recommended for the identification and documentation and adult malnutrition (undernutrition). J Parenter Enteral Nutr. 2012;36(3):275–83. Wooley JA, Frakenfield MS. In: Muller CM, editor. The A.S.P.E.N. Adult nutrition support core curriculum. 2nd ed. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition; 2012. p. 22–35.

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Liver Dysfunction in Critically Ill Patients Jennifer M. Newton, Andrew Aronsohn, and Donald M. Jensen

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Hypoxic Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis, Clinical Presentation, and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36 36 37

Liver Dysfunction in Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . The Liver as an Organ of Host Defense . . . . . . . . . . . . . . The Liver as a Target of Injury . . . . . . . . . . . . . . . . . . . . . . . Hyperbilirubinemia in Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis, Treatment, and Prognosis . . . . . . . . . . . . . . . . .

40 40 40 41 43

38

Patients with acute hepatobiliary dysfunction are frequently encountered in the intensive care unit. Therefore, it is important for intensivists to understand the various causes of hepatobiliary dysfunction and to have a thorough understanding of the pathophysiology, presentation, and management in each process. The aim of this chapter is to discuss the most common causes of acute hepatobiliary dysfunction encountered in the intensive care unit.

Drug-Induced Liver Injury (DILI) . . . . . . . . . . . . . . . . . 43

List of Abbreviations

Acute Acalculous Cholecystitis . . . . . . . . . . . . . . . . . . . . . 43 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Clinical Presentation, Diagnosis, and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

AAC ALP ALT AST BSEP CHF CO CT CVP DILI HH HIDA ICU IL INR LDH LPS MRP

Applications to Critical or Intensive Care . . . . . . . . . 45 Applications to Other Conditions . . . . . . . . . . . . . . . . . . . . . 45 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

J.M. Newton (*) • A. Aronsohn • D.M. Jensen Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago Medicine, Chicago, IL, USA e-mail: [email protected]; [email protected]; [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_47

NO

Acute acalculous cholecystitis Alkaline phosphatase Alanine aminotransferase Aspartate aminotransferase Bile salt export pump Congestive heart failure Cardiac output Computed tomography Central venous pressure Drug-induced liver injury Hypoxic hepatitis Hepatobiliary iminodiacetic acid Intensive care unit Interleukin International normalized ratio Lactate dehydrogenase Lipopolysaccharide Multidrug-resistance-associated protein Nitric oxide 35

36

J.M. Newton et al.

NTCP

Sodium-dependent taurocholate cotransporter OATPs Organic anion transport proteins PMH Polymorphonuclear cell PO2 Partial pressure of oxygen ROS Reactive oxygen species S-AT Serum aminotransferase SIRS Systemic inflammatory response syndrome SOFA Sequential organ failure assessment TB Total bilirubin TNF Tumor necrosis factor TPN Total parenteral nutrition US Ultrasound xULN Times the upper limit of normal

Introduction Liver dysfunction and its complications are frequently encountered in the intensive care unit (ICU). Critical illness may result in hepatic injury due to alterations in hemodynamics and oxygen delivery, metabolic derangements, and secondary effects of systemic inflammation and medical therapies. This may result in impairment of key liver functions including detoxification of the blood, participation in the immune response, and synthesis of proteins, inflammatory mediators, and bile. Lack of these important functions may further exacerbate the critical illness, creating a vicious cycle. The morbidity, mortality, and cost associated with liver dysfunction in the intensive care unit are high. The goal of this review is to describe the common causes and complications of acute hepatobiliary dysfunction encountered in the intensive care unit – from pathophysiology to management.

were proposed including infectious toxinmediated damage (Mallory 1901), congestive damage from heart failure (Lambert 1916), and ischemic damage from circulatory shock, the latter giving rise to the terms “shock liver” (Birgens et al. 1978) and “ischemic hepatitis” (Bynum et al. 1979). It was not until a series of studies were published in the 1990s that the term “hypoxic hepatitis” was coined due to new evidence suggesting that hypoperfusion (ischemia) was only one mechanism by which liver cells experienced hypoxia (Henrion et al. 2003; Birrer et al. 2007). It has now been demonstrated that liver cell hypoxia primarily develops in the setting of acute or chronic cardiac failure, respiratory failure, and sepsis, with or without shock states (Birrer et al. 2007). Hypoxic hepatitis (HH) is defined as an acute reversible elevation of serum aminotransferases (S-AT), excluding known causes of hepatitis or hepatocellular injury, in the appropriate clinical setting of decreased oxygenation of hepatocytes. The end result of this process is centrilobular liver cell necrosis. It is generally agreed upon that the aminotransferase elevation be at least 20 times the upper limit of normal (xULN). HH is relatively common, with a prevalence of one case per 100 ICU admissions (Henrion et al. 2003; Birrer et al. 2007; Henrion 2012) and one case per 1,000 hospital admissions (Henrion 2012). Some studies have shown higher frequencies, and it is thought that the prevalence is likely underestimated. Heart failure (chronic or acute), respiratory failure, and septic shock are the most common causes of HH, with heart failure representing approximately 70 % of cases (Henrion et al. 2003; Henrion 2012).

Pathophysiology

Hypoxic Hepatitis Centrilobular necrosis, a pattern of hepatic necrosis localized around the central vein, was first described in 1901 in a series of autopsies (Mallory 1901). Over the next century, many theories as to the etiology of this finding in critically ill patients

The liver has several mechanisms to protect against hypoxic events, and therefore, usually more than one insult to the system is required. Systemic oxygen delivery depends upon cardiac output (CO), hemoglobin concentration, and oxygen saturation. The liver receives approximately 20–25 % of the

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Liver Dysfunction in Critically Ill Patients

37

Table 1 Clinical profiles by mechanism of hypoxic hepatitis Presence of shock Central venous pressure Arterial oxygenation Cardiac index Delivery of oxygen

Chronic cardiac failure Occasional Elevated Low Low Low

Acute cardiac failure Frequent Elevated Normal Low Very low

CO via a dual delivery system, with 70–80 % of blood flow via the portal vein and the remainder of flow via the hepatic artery. The partial pressure of oxygen (PO2) in the hepatic artery is significantly higher than in the portal system, so the oxygen delivery is similar despite the large differential in blood flow (Henrion 2012; Lautt 2007; Giallourakis et al. 2002). Although portal blood flow varies in proportion to the CO, the “hepatic artery buffer response,” an adenosine-mediated dilation of hepatic arterioles in response to decreased portal flow, allows for large increases in oxygen delivery to the liver (Lautt et al. 1985; Lautt 1985; Lautt 2007). Lastly, the hepatic sinusoids are highly permeable which allows for rapid diffusion of oxygen to hepatocytes, allowing for more than 90 % of oxygen to be extracted from the blood (Henrion 2012). Although these mechanisms enable the hepatic blood flow to be significantly reduced without affecting hepatic oxygen consumption, major alterations in one or more of these parameters may lead to hypoxic hepatitis. It is important to note that several studies have shown that shock is not required to cause HH. In a series of 293 patients with hypoxic hepatitis, only 51 % had a hypotensive episode (Birrer et al. 2007). Additionally, reperfusion and thus reoxygenation injury is felt to play a role in the pathogenesis of hypoxic hepatitis as liver cell necrosis can occur at the time of reperfusion, rather than during periods of ischemia. This appears to be mediated by two phases: early Kupffer cells activation, followed by late polymorphonuclear cell (PMN) activation. These cells produce injury via oxidative stress, production of inflammatory cytokines, and disruption of microcirculation (Henrion 2012; Giallourakis et al. 2002).

Respiratory failure Occasional Elevated Very low Elevated Low

Septic shock Always Low Normal Elevated Normal

Mechanisms of Injury Chronic Cardiac Failure Heart failure is the etiology in approximately 70 % of cases of HH, the majority occurring in patients with chronic cardiac failure (congestive heart failure). In a large study published in 2003 (Henrion et al. 2003), 56 % of 142 cases of HH were attributed to decompensated congestive heart failure (CHF). In another study published in 1994 (Henrion et al. 1994), HH was diagnosed in 2.6 % of 766 patients admitted to the coronary care unit, which is more than double that found in intensive care units overall. Two distinct mechanisms appear to be involved in the pathogenesis of this disease: hepatic hypoperfusion and hepatic congestion (Table 1). Hepatic hypoperfusion, but not necessarily shock, was critical to the development of HH in cardiac failure. In a series with 80 episodes of HH related to cardiac failure, nearly 93 % of patients had clinical signs of systemic hypoperfusion, but shock was only present in approximately 40 %. Depressed CO, resulting in decreased oxygen delivery to the liver, appears to be the primary mechanism leading to injury (Henrion et al. 2003; Giallourakis et al. 2002). The addition of hepatic congestion from elevated right-sided filling pressures likely acts to prime the liver for injury, as it causes dilation of the hepatic sinusoids and impairs diffusion of oxygen. A study comparing cases of HH from cardiac failure to controls with circulatory shock demonstrated that systemic hypoperfusion alone did not cause hypoxic injury; the majority of patients who developed HH had right-sided heart disease leading to passive congestion of the liver (Henrion et al. 1994). Another study evaluating patients admitted for cardiogenic shock demonstrated that the degree of

38

hypotension and decrease in CO were similar between those who developed HH and those who did not, but those who developed HH had more significantly elevated central venous pressure (CVP) (Seeto et al. 2000). This likely explains why HH is infrequently seen in hemorrhagic or hypovolemic shock and why undetected transient decreases in perfusion may be sufficient to cause hypoxic injury in patients with cardiomyopathy. Lastly, it should be noted that the majority of patients who develop HH related to CHF had an acute event, such as arrhythmia, pulmonary edema, or myocardial infarction, preceding the development of liver injury.

Acute Cardiac Failure Acute cardiac failure, defined as an acute event causing cardiac failure in the absence of chronic heart failure, was found to cause approximately 14 % of 142 cases of hypoxic hepatitis (Henrion et al. 2003). The etiologies identified in this study were myocardial infarction, pulmonary embolism, pericardial tamponade, thoracic trauma, and sudden arrhythmia. In general, the hemodynamic profile of these patients is similar to that seen in patients with chronic cardiac failure, except shock is more common in acute cardiac failure (70 % versus 41 %). This suggests impaired hepatic oxygen delivery was primarily related to a sudden drop in CO (Table 1). Respiratory Failure Respiratory failure causes approximately 15 % of cases of hypoxic hepatitis (Henrion 2012). An acute exacerbation of chronic respiratory failure results in severe hypoxemia leading to decreased hepatic oxygen delivery (Table 1). In 1999, a prospective study of 142 patients with HH identified 17 cases related to acute or chronic respiratory failure, without concomitant left heart failure (Henrion et al. 1999). Eight of these patients had previously undergone pulmonary function testing, and all had a forced expiratory volume in 1 s 2, and a Sequential Organ Failure Assessment (SOFA) score >10 were independently predictive of overall mortality (Fuhrmann et al. 2009). The treatment of HH is directed at correction of the underlying disease and restoration of the hemodynamic abnormalities. While there are no specific therapies, support of hepatic oxygen

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delivery and avoidance of hepatic congestion are the goals. This is often achieved with the use of vasopressors, mechanical ventilation, and careful management of volume status.

Liver Dysfunction in Sepsis Sepsis is a clinical syndrome resulting from a dysregulated inflammatory response to an invading pathogen, resulting in excessive cytokine production, vasodilation, leukocyte migration, and increased microvascular permeability. The incidence of sepsis has been increasing, estimated at approximately 240 per 100,000 persons (Martin et al. 2003), and carries a substantial mortality rate, estimated between 20 % and 50 % (Blanco et al. 2008). In sepsis, the liver is an important mediator of host defense but is also at risk for injury itself in the setting of this exuberant inflammatory response. Moreover, early hepatic dysfunction, which occurs in approximately 11 % of critically ill patients, represents an independent risk factor for poor prognosis (Kramer et al. 2007).

The Liver as an Organ of Host Defense The liver is the home to the largest population of macrophages in the body, accounting for greater than 50 % of the monocytes released from the bone marrow (Crofton et al. 1978). These macrophages (Kupffer cells) are responsible for clearance of bacteria and endotoxin from the bloodstream, as well as antigen presentation, which is a critical step in the transition from innate to adaptive immunity. In a study of mice injected with viable E. coli, clearance of greater than 95 % of bacteria from the bloodstream was seen within 5 min; greater than 70 % of this clearance was attributable to the liver, with the spleen, lungs, and kidneys accounting for the remainder. Additionally, in mice with a surgically created portacaval shunts, the hepatic clearance of bacteria was significantly lower, at 45 %, suggesting a possible explanation for increased risk of infection in patients with hepatic dysfunction (Katz et al. 1991). Another study evaluated the hepatic

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clearance of a radiolabeled endotoxin lipopolysaccharide (LPS). Within 30 min, greater than 50 % of LPS was removed from the blood, with Kupffer cells accounting for approximately 40 % of the tissue bound endotoxin, which was four times that of any other tissue (Mathison and Ulevitch 1979). Over time, Kupffer cells redirect LPS to hepatocytes (Freudenberg et al. 1982) in lipoprotein micelles (Van Oosten et al. 2001), which are subsequently excreted into the bile (Mathison and Ulevitch 1979). Furthermore, Kupffer cells produce thousands of proteins, including many important cytokines, which mediate the host response. In turn, via cell surface receptors, hepatocytes respond by producing coagulant factors, complement proteins, and acute-phase proteins. Lastly, Kupffer cells help to limit the systemic inflammatory response by acting as scavengers for many inflammatory mediators and cytokines (Andus et al. 1991).

The Liver as a Target of Injury In sepsis and the systemic inflammatory response syndrome (SIRS), two distinct phases of liver injury have been described (Dhainaut et al. 2001). Primary hepatic dysfunction is believed to be the result of hepatic hypoperfusion, generally after an episode of shock has occurred. While sepsis can induce low cardiac output states contributing to a reduction in hepatic perfusion, mesenteric arterial vasoconstriction and the resultant decrease in portal blood flow likely plays a more important role (Navaratnam et al. 1990; Dhainaut et al. 2001). Additionally, the previously described hepatic artery buffer response may be impaired in severe inflammatory states. Since the reduction in portal flow is not met with a compensatory increase in hepatic arterial flow, the overall hepatic blood flow is reduced (Szabo et al. 2002). In addition, evidence suggests that endotoxin and tumor necrosis factor (TNF) perfusion may induce cellular dysfunction, even in the absence of hypoperfusion (Wang et al. 1993). The resultant hepatic dysfunction, in combination with circulating endotoxins and inflammatory mediators, triggers parenchymal cells to modify their metabolic activity.

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Although gluconeogenesis is initially increased due to the abundant lactate and amino acid substrates, LPS later inhibits gluconeogenesis, which is a poor prognostic sign (Szabo et al. 2002). Additional alterations are seen in amino acid uptake, ureagenesis, glycogenolysis, and increased synthesis and release of coagulant factors, complement factors, and antiproteolytic enzymes (acute-phase proteins). This primary hepatic dysfunction may lead to disseminated intravascular coagulation (Dhainaut et al. 2001). Fortunately, because this process is primarily mediated by hypoperfusion, proper resuscitation may reverse much of this injury. The cellular makeup of the liver is quite heterogeneous. Hepatocyte, Kupffer cell, endothelial cell, and recruited polymorphonuclear cell communication is vital to the immune function and metabolic responses of the liver. In response to infection and sepsis, these interactions lead to secondary hepatic dysfunction. Although Kupffer cells remove endotoxins and inflammatory mediators from circulation, once they are activated, they become a source of inflammatory mediators. Production of chemokines recruits additional inflammatory cells to the liver. Several pro-inflammatory mediators are synthesized including cytokines (primarily TNF-α and interleukins (IL) 1, 6, and 12), nitric oxide, eicosanoid mediators (such as leukotriene B4), and reactive oxygen species (ROS). As a result of the release of leukotriene B4 and TNF-α, PMNs are recruited to the liver and activated. Upregulation of adhesion molecules on both PMNs and sinusoidal endothelial cells promotes PMN migration and microvascular thrombi. Once they have migrated into the hepatic parenchyma, release of ROS and proteases leads to hepatocyte injury (Doi et al. 1993; Diehl 2000). This is the main mechanism of hepatocyte dysfunction in sepsis. Lastly, endothelial cells acquire procoagulant and pro-inflammatory activities, such as the production of IL-1, IL-6, nitric oxide, and carbon monoxide, which may be involved in regulating systemic and hepatic circulation. In the setting of hepatic dysfunction, spillover of TNF may promote or worsen multiorgan dysfunction (Szabo et al. 2002; Dhainaut et al. 2001).

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Hyperbilirubinemia in Sepsis Jaundice is a common complication in critically ill patients. Second only to malignant biliary obstruction, sepsis-associated cholestasis is the leading cause of jaundice in hospitalized patients (Whitehead et al. 2001). The degree of jaundice has been shown to correlate both with the number of failing organs and mortality (te Boekhorst et al. 1988). Gram-positive and gram-negative bacteria are equally culpable in this process. The major mechanisms of hyperbilirubinemia in sepsis are hemolysis and cholestasis, the latter being caused by both hepatocyte and bile duct dysfunction (Chand and Sanyal 2007).

Normal Physiology of Bilirubin and Bile Acid Processing In order to better understand cholestasis, it is important to first understand the normal processing of bilirubin and bile acids by the hepatocytes and bile flow (Fig. 2). With the breakdown of hemoglobin and other hemoproteins, unconjugated bilirubin is released into the blood and bound tightly but reversibly by albumin. In the hepatic sinusoids, the albumin-bilirubin complex dissociates, which allows for bilirubin to be transported across the basolateral membrane, likely via organic anion transport proteins (OATPs). Within the hepatocyte, bilirubin is bound by cytosolic proteins and undergoes conjugation, which allows for excretion into bile via the canalicular membrane transport protein multidrug-resistanceassociated protein (MRP) 2. Bile salts are synthesized in the hepatocytes or taken up into the hepatocytes as a part of the enterohepatic circulation. Conjugated bile salts are taken up into the hepatocyte on the basolateral membrane via the sodiumdependent taurocholate cotransporter (NTCP), which is dependent on a sodium-potassium ATPase. Unconjugated bile acids are taken up into hepatocytes via the sodium-independent OATPs. Internalized bile acids are bound by cytosolic transporter proteins and are directed to the canalicular membrane. There, bile salts are transported into the bile canaliculus via the bile salt export pump (BSEP) or MRP2. Organic cations are likewise transported across the membrane

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Fig. 2 Physiology of bilirubin and bile acid processing. OATPs organic anion transport proteins, MRP multidrugresistance-associated protein, NTCP sodium-dependent taurocholate cotransporter, BSEP bile salt export pump,

MDR1 multiple-drug-resistance-1, CFTR cystic fibrosis transmembrane regulator, AE2 chloride-bicarbonate anion exchanger isoform 2

via the multiple-drug-resistance-1 transporter. Due to the osmotic gradient created by bile salts and other solutes in the bile canaliculus, water and inorganic cations diffuse across tight junctions into the canaliculus, thus creating bile. The cyclic AMP activated cystic fibrosis transmembrane regulator is responsible for maintaining the fluidity of the bile by driving secretion of bicarbonate through the chloride-bicarbonate anion exchanger isoform 2. Lastly, bile salt efflux pumps, MRP3 and MRP4, which are normally expressed at low levels, are upregulated in the setting of cholestasis to pump bile salts back into the sinusoids (Trauner and Boyer 2003; Chand and Sanyal 2007; Geier et al. 2006).

excretion of bile salts leads to impaired bile flow, or cholestasis. In response to endotoxemia, particularly to LPS (as studied in animal models), Kupffer cells and endothelial cells release TNF-α, IL-6, and IL-1B, which then mediate hepatocellular and bile duct-related cholestasis. On the basolateral membrane, these inflammatory mediators lead to the reduced uptake of substrate by OATP family transporters and NTCP, thus reducing bilirubin and bile acid transport into hepatocytes. On the canalicular membrane, BSEP and MRP2 also have reduced activity and gene expression (Bolder et al. 1997; Roelofsen et al. 1994; Elferink et al. 2004). Additionally, the production of nitric oxide (NO) by inducible NO synthase alters tight junctions and gap junctions, disrupting the gradient between portal and canalicular spaces and ultimately impairing bile flow (Han et al. 2004). NO may also impair canalicular motility (Dufour et al. 1995). Through these mechanisms,

Hepatocellular Mechanisms of Cholestasis In sepsis and SIRS, decreased uptake and excretion of bilirubin into bile contributes to hyperbilirubinemia, while decreased uptake and

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infections and the resultant inflammatory response lead to hyperbilirubinemia and cholestasis.

Ductal Mechanisms of Cholestasis Pro-inflammatory cytokines and NO both induce changes in cholangiocytes and cause cholestasis at the level of the bile duct. As with the hepatocyte, tight junctions and barrier functions of the cholangiocytes are disturbed. Chloride, bicarbonate, and fluid secretion into the bile duct are impaired, altering the alkalinity and hydration of the bile, thus altering flow. Additionally, cholangiocytes produce interferon-gamma, TNF, and growth factors, leading to or perpetuating cholangitis (Strazzabosco et al. 2005; Spirlì et al. 2001, 2003). Progressive sclerosing cholangitis, which portends a poor prognosis, is a rare bile duct stricturing disease seen in critically ill patients with burns, septic shock, or trauma. Although not completely understood, bile duct ischemia is likely involved in the pathogenesis of this disease. A persistently elevated bilirubin with a rising alkaline phosphatase (ALP) and gamma-glutamyltransferase is typically seen. Bile duct strictures on endoscopic retrograde cholangiopancreatography confirm the diagnosis (Benninger et al. 2005). Histologically, bile duct proliferation, portal lymphocytic infiltrates, and portal and periductal fibrosis are seen (Engler et al. 2003). Some patients progress rapidly to cirrhosis after the critical illness has resolved, at which point orthotopic liver transplantation is the only therapy.

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despite adequate treatment of sepsis, then progressive sclerosing cholangitis should be considered (Moseley 2004). Treatment is supportive care for sepsis and identification and treatment of the underlying infection. Appropriate antibiotic coverage is paramount, but medications that are excreted primarily into the bile (i.e., ceftriaxone) should be avoided as they reduce excretion of bilirubin and bile acids. Early enteral feeding may improve cholestasis. Persistent hyperbilirubinemia and jaundice are associated with increased morbidity and mortality, primarily secondary to the extrahepatic complications of sepsis (Geier et al. 2006; Chand and Sanyal 2007).

Drug-Induced Liver Injury (DILI) The liver is the main site of drug metabolism and is therefore at risk for drug-induced injury. Additionally, in the intensive care unit, the liver is at even greater risk due to frequent liver dysfunction related to critical illness, polypharmacy, and the older age and comorbid conditions of this population. Drugs may cause a direct, dose-dependent, drug toxicity or a dose-independent idiosyncratic drug reaction. Three patterns of liver injury are seen: hepatocellular, cholestatic, or mixed. Table 3 outlines common drugs encountered in the ICU that may result in DILI.

Acute Acalculous Cholecystitis Diagnosis, Treatment, and Prognosis The diagnosis is generally made clinically, based on the appropriate clinical setting of infection, usually with sepsis, and characteristic laboratory findings. Bilirubin is usually elevated at 5–10 mg/dL, but can occasionally rise to 30–50 mg/dL, the majority of which is conjugated. ALP and S-ATs are typically only mildly elevated, and LDH is often normal. Liver biopsy is generally not needed but reveals intrahepatic cholestasis with Kupffer cell hyperplasia, hepatocyte dropout, and mononuclear cell portal infiltrates. If hyperbilirubinemia persists, especially in the setting of a rising ALP,

Acute acalculous cholecystitis (AAC) is the cause of approximately 10 % of all cases of acute cholecystitis and complicates courses in 0.2–0.4 % of all critically ill patients. AAC is a necroinflammatory disorder of the gallbladder, found in the absence of cholelithiasis, and is associated with significant mortality (approximately 30 %) (Huffman and Schenker 2010).

Pathophysiology AAC is believed to result from a combination of ischemia and bile stasis. Several risk factors for

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Table 3 Common drugs causing liver injury

Antimicrobials

Antiepileptics

Cardiac drugs

Other

Hepatocellular (elevated ALT) Ketoconazole Tetracyclines Isoniazid Rifampin HAART drugs Valproic acid

Amiodarone Statins Lisinopril Acetaminophen Propofol Halothane Diclofenac Trazodone Risperidone Venlafaxine

Mixed (elevated ALP and elevated ALT) Nitrofurantoin Clindamycin TMP-SMX

Phenytoin Carbamazepine Phenobarbital Verapamil

Cyclosporine Methimazole TPN

Cholestatic (elevated ALP or TB) Amoxicillin Clavulanate Macrolides

Irbesartan Clopidogrel Chlorpromazine TPN

HAART highly active antiretroviral therapy, TMP-SMX trimethoprim-sulfamethoxazole, TPN total parenteral nutrition, ALT alanine aminotransferase, AST aspartame aminotransferase, TB total bilirubin, ALP alkaline phosphatase

disease provide a clue to the underlying pathophysiology. The most commonly associated risk factors include trauma, recent surgery, shock, burns, sepsis, critical illness, total parenteral nutrition (TPN), and prolonged fasting (Huffman and Schenker 2010). The aforementioned disease states may lead to visceral hypoperfusion and gallbladder ischemia. Additionally, TPN, fasting states, systemic inflammation, mechanical ventilation, volume depletion, and narcotics (all frequently seen in critically ill patients) contribute to gallbladder stasis and thus gallbladder distension (McChesney et al. 2003; Barie and Eachempati 2003). In turn, distension may reduce blood flow and lymphatic drainage, which increases susceptibility to infection (McChesney et al. 2003). Histologically, leukocyte margination of blood vessels, lymphatic dilation, and extensive bile infiltration of the gallbladder wall are seen (Laurila et al. 2005). These findings support the proposed mechanisms of disease by providing histological evidence of disturbed microcirculation from ischemia and increased permeability of the gallbladder epithelium from bile stasis and distension.

Clinical Presentation, Diagnosis, and Management AAC remains an elusive disease, in large part because its clinical presentation is nonspecific. Patients may present with right-upper-quadrant pain, fever, leukocytosis, and abnormal liver function tests (elevated S-ATs, bilirubin, and ALP). AAC may be complicated by gallbladder gangrene, perforation, empyema, and death if not identified early. Therefore, a high index of suspicion in the appropriate clinical setting with prompt diagnostic evaluation and treatment is vital. Unfortunately, there is no gold standard diagnostic test. Ultrasound (US), computed tomography (CT), hepatobiliary iminodiacetic acid (HIDA) scan, and surgery are all used in practice. As most patients are in the intensive care unit, US is often the preferred method, as it can be done at the bedside and has excellent specificity (Huffman and Schenker 2010; Mirvis et al. 1986). The commonly considered “diagnostic triad” for AAC includes wall thickness, biliary sludge, and hydrops. Other findings may include

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pericholecystic fluid, subserous edema, intramural gas, and sloughed mucosa (Huffman and Schenker 2010). CT scan appears to be as accurate as US (Mirvis et al. 1986) and has similar diagnostic criteria. It is the preferred method if additional thoracic or abdominal imaging is required (i.e., to evaluate for intraabdominal abscess). HIDA scan is less commonly used to diagnose AAC in critically ill patients, as it requires transport to the nuclear medicine suite. Additionally, the reported sensitivity and specificity are quite variable among HIDA studies, ranging from 68–100 % to 38–100 %, respectively (Huffman and Schenker 2010). Nevertheless, it is considered a reasonable adjunctive diagnostic modality, especially when the diagnosis is not clear based on prior imaging studies. Lastly, diagnostic laparoscopy and laparotomy are occasionally used. Indeed, the Society of American Gastrointestinal and Endoscopic Surgeons recommends bedside diagnostic laparoscopy for critically ill patients with suspected AAC (Hori and SAGES Guidelines Committee 2008). However, noninvasive tests remain the preferred option by most, reserving surgery for therapeutic purposes. Treatment options for AAC are limited. All patients receive broad-spectrum antibiotics and, historically, proceed to cholecystectomy as the definitive treatment. However, due to the poor operative candidacy of many critically ill patients, cholecystostomy is often used as a bridge to cholecystectomy. Cholecystostomy is also gaining favor as the sole treatment, as complication rates are relatively low and outcomes are favorable (Barie and Eachempati 2003; Ginat and Saad 2008).

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is at increased risk for hepatic injury and biliary complications. Prompt diagnosis and treatment, including supportive care with restoration of normal hemodynamics is paramount, as morbidity and mortality related to hepatobiliary complications is high.

Applications to Other Conditions While the acute hepatobiliary complications are most frequently seen in patients in the intensive care unit, all patients admitted to the hospital with alterations in hemodynamics or infections leading to cytokine release are at risk for these processes. As in the intensive care patients, early recognition of these complications with prompt treatment is important for reducing length of stay and improving morbidity and mortality.

Conclusion Liver dysfunction and its complications are commonly encountered in the intensive care unit and portend an increased morbidity and mortality. As all patients in the ICU are at risk for liver injury, care should be taken to monitor for signs and symptoms of new or worsening liver dysfunction. Common acute hepatobiliary manifestations include hypoxic hepatitis, sepsis-induced liver dysfunction, drug-induced liver injury, and acute acalculous cholecystitis. In all of the diseases discussed, prompt diagnosis and treatment, including early and aggressive resuscitation, is key to avoid precipitating hepatobiliary injury and perpetuating a downward spiral.

Applications to Critical or Intensive Care

Guidelines and Protocols

Critically ill patients are vulnerable to hepatobiliary dysfunction, regardless of baseline liver functional status. Due to the changes in hemodynamic parameters and activation of inflammatory cascades that are frequently observed in intensive care patients, this population

As acute hepatobiliary dysfunction is common in critical illness, prompt evaluation and diagnosis is important in improving outcomes. Outlined below are recommendations for management once the etiology for liver dysfunction is determined.

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• When hypoxic hepatitis is suspected, other causes of acute hepatitis such as viral hepatitis and drug-induced liver injury should be excluded. Treatment is then directed at reversing the underlying illness and restoring hepatic oxygen delivery via the use of vasopressors, mechanical ventilation, and careful management of volume status. • In sepsis, liver dysfunction occurs in two distinct phases; primary hepatic dysfunction is primarily mediated by hypoperfusion whereas secondary hepatic dysfunction is related to activation of an inflammatory cascade. Therefore, treatment is primarily supportive, with aggressive volume resuscitation and treatment of the underlying infection. • While the mainstay of treatment in hyperbilirubinemia of sepsis is treatment of the underlying illness, it is important to avoid volume states or medications that may worsen or prolong jaundice, and early enteral feeding is recommended. • A septic patient with persistent hyperbilirubinemia and a rising ALP, despite appropriate treatment of sepsis, should be considered for diagnostic evaluation for progressive sclerosing cholangitis. • When possible, polypharmacy in the intensive care unit should be avoided to reduce the risk of DILI. • When AAC is suspected, prompt evaluation with US or CT, broad-spectrum antibiotics, and surgical consult are indicated. Cholecystostomy is often an appropriate alternative to cholecystectomy.

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•

•

•

•

•

proteins; and additionally limits the inflammatory response by scavenging many inflammatory mediators. The liver is a target of injury in sepsis and SIRS; several mechanisms lead to hepatocyte damage, including hypoperfusion, reduced oxygen extraction, alterations to metabolic functions, and recruitment of inflammatory cells with subsequent release of TNF-α, interleukins, leukotrienes, and ROS which lead to hepatocyte dysfunction. The liver is a target of injury in sepsis and SIRS. Primary dysfunction (caused by hypoperfusion, reduced oxygen extraction, and alterations to metabolic functions) and secondary dysfunction (caused by recruitment of inflammatory cells with subsequent release of TNF-α, interleukins, leukotrienes, and ROS) ultimately lead to liver dysfunction. Sepsis-associated cholestasis is a common cause of jaundice in the ICU. Endotoxins and cytokines act on hepatocyte transporters to reduce bilirubin and bile salt excretion into bile and on the cholangiocytes to reduce bile flow. Drug-induced liver injury can present with hepatocyte injury, cholestasis, or a mixed pattern. As ICU patients are critically ill, receiving multiple combinations of medications, and have an increased number of comorbid conditions, they are at an increased risk for DILI. The major risk factors for acute acalculous cholecystitis include trauma, surgery, shock, sepsis, burns, critical illness, TPN, and prolonged fasting. Cholecystectomy is the definitive treatment, but cholecystostomy is increasingly used as the sole treatment.

Summary Points • Hypoxic hepatitis is common in the ICU, manifesting as a sharp marked elevation in serum aminotransferases, in the setting of reduced oxygen delivery to or reduced oxygen uptake by the liver. Shock is often not seen. • The liver is an active organ of host defense; it hosts the largest population of macrophages in the body; produces cytokines, coagulant factors, complement proteins, and acute-phase

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48 Laurila JJ, Ala-Kokko TI, Laurila PA, Saarnio J, Koivukangas V, Syrj€al€a H, et al. Histopathology of acute acalculous cholecystitis in critically ill patients. Histopathology. 2005;47(5):485–92. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol. 1985;249(5 Pt 1):G549–56. Lautt WW. Regulatory processes interacting to maintain hepatic blood flow constancy: vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction. Hepatol Res. 2007;37(11):891–903. Lautt WW, Legare DJ, d’ Almeida MS. Adenosine as putative regulator of hepatic arterial flow (the buffer response). Am J Physiol. 1985;248(3 Pt 2):H331–8. Mallory FB. Necroses of the liver. J Med Res. 1901;6(1): 264–280.7. McChesney JA, Northup PG, Bickston SJ. Acute acalculous cholecystitis associated with systemic sepsis and visceral arterial hypoperfusion: a case series and review of pathophysiology. Dig Dis Sci. 2003;48 (10):1960–7. Mirvis SE, Vainright JR, Nelson AW, Johnston GS, Shorr R, Rodriguez A, et al. The diagnosis of acute acalculous cholecystitis: a comparison of sonography, scintigraphy, and CT. AJR Am J Roentgenol. 1986;147 (6):1171–5. Moseley RH. Sepsis and cholestasis. Clin Liver Dis. 2004;8(1):83–94. Navaratnam RL, Morris SE, Traber DL, Flynn J, Woodson L, Linares H, et al. Endotoxin (LPS) increases mesenteric vascular resistance (MVR) and bacterial translocation (BT). J Trauma. 1990;30 (9):1104–13; discussion 1113–1115. Raurich JM, Pérez O, Llompart-Pou JA, Ibáñez J, Ayestarán I, Pérez-Bárcena J. Incidence and outcome of ischemic hepatitis complicating septic shock. Hepatol Res. 2009;39(7):700–5. Raurich JM, Llompart-Pou JA, Ferreruela M, Colomar A, Molina M, Royo C, et al. Hypoxic hepatitis in critically ill patients: incidence, etiology and risk factors for mortality. J Anesth. 2011;25(1):50–6. Roelofsen H, van der Veere CN, Ottenhoff R, Schoemaker B, Jansen PL, Oude Elferink RP. Decreased bilirubin transport in the perfused liver of endotoxemic rats. Gastroenterology. 1994;107(4):1075–84.

J.M. Newton et al. Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation and pathogenesis. Am J Med. 2000;109(2):109–13. Spirlì C, Nathanson MH, Fiorotto R, Duner E, Denson LA, Sanz JM, et al. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology. 2001;121(1):156–69. Spirlì C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, et al. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology. 2003;124(3):737–53. Strazzabosco M, Fabris L, Spirli C. Pathophysiology of cholangiopathies. J Clin Gastroenterol. 2005;39 (4 Suppl 2):S90–102. Szabo G, Romics Jr L, Frendl G. Liver in sepsis and systemic inflammatory response syndrome. Clin Liver Dis. 2002;6(4):1045–66, x. Te Boekhorst T, Urlus M, Doesburg W, Yap SH, Goris RJ. Etiologic factors of jaundice in severely ill patients. A retrospective study in patients admitted to an intensive care unit with severe trauma or with septic intra-abdominal complications following surgery and without evidence of bile duct obstruction. J Hepatol. 1988;7(1):111–7. Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev. 2003;83(2):633–71. Ucgun I, Ozakyol A, Metintas M, Moral H, Orman A, Bal C, et al. Relationship between hypoxic hepatitis and cor pulmonale in patients treated in the respiratory ICU. Int J Clin Pract. 2005;59(11):1295–300. Van Oosten M, Rensen PC, Van Amersfoort ES, Van Eck M, Van Dam AM, Breve JJ, et al. Apolipoprotein E protects against bacterial lipopolysaccharideinduced lethality. A new therapeutic approach to treat gram-negative sepsis. J Biol Chem. 2001;276(12): 8820–4. Wang P, Ayala A, Ba ZF, Zhou M, Perrin MM, Chaudry IH. Tumor necrosis factor-alpha produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation. Am J Physiol. 1993;265 (1 Pt 1):G126–32. Whitehead MW, Hainsworth I, Kingham JG. The causes of obvious jaundice in South West Wales: perceptions versus reality. Gut. 2001;48(3):409–13.

4

Nutrition and Acute Lung Injury in Critical Care: Focus on Nutrition Care Process Corrine Hanson, Eric P. A. Rutten, Christina Rollins, and Stephanie Dobak

Contents

Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Nutrition Screening for ALI Patients . . . . . . . . . . . . . . 51

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Calculations for Nutrition Assessment of ALI Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Assessment of Energy Needs . . . . . . . . . . . . . . . . . . . . . . . . . 52 Assessment of Protein Needs . . . . . . . . . . . . . . . . . . . . . . . . . 52 Nutrition Interventions for ALI Patients . . . . . . . . . . 53 Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Nutrition Monitoring of ALI Patients . . . . . . . . . . . . . . Monitoring of Energy Balance . . . . . . . . . . . . . . . . . . . . . . . . Monitoring of Protein Status . . . . . . . . . . . . . . . . . . . . . . . . . . Monitoring of Micronutrient Status . . . . . . . . . . . . . . . . . . . Other Types of Patient Monitoring . . . . . . . . . . . . . . . . . . .

55 55 55 56 56

Applications to Critical or Intensive Care . . . . . . . . . 56 Applications to Other Conditions . . . . . . . . . . . . . . . . . . 58

C. Hanson (*) School of Allied Health Professions, University of Nebraska Medical Center, Omaha, NE, USA e-mail: [email protected] E.P.A. Rutten Program Development Center, Centre of Expertise for Chronic Organ Failure, Horn, The Netherlands e-mail: [email protected] C. Rollins Memorial Medical Center, Springfield, IL, USA e-mail: [email protected] S. Dobak Thomas Jefferson University Hospital, Willow Grove, PA, USA e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_34

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C. Hanson et al.

Abstract

Acute lung injury (ALI) remains a significant source of morbidity and mortality in patients hospitalized in critical care units. Nutrition therapy can play a critical role in the management of patients with ALI. The nutrition care process for ALI patients involves nutrition screening, nutrition assessments, nutrition interventions, and monitoring of nutritional parameters. Nutrition screening can help identify patients early in the hospitalization who have existing nutrition deficits, so timely assessment and intervention can take place. Consequences of nutrition-related issues such as malnutrition and catabolism can be profound in this population; therefore, nutrition assessments to estimate energy and protein requirements are an integral part of patient management. Nutrition interventions in this patient population are targeted at preventing cumulative calorie deficits; identifying, preventing, and treating malnutrition; avoiding loss of lean body mass and the resulting deterioration of respiratory muscle strength; and modulating the inflammatory response associated with ALI. The careful monitoring of nutritional parameters in ALI patients is critical in order to quantify the progress made toward meeting the goals of nutrition therapy. List of Abbreviations

ALI APACHE ASPEN/ SCCM BMI CO2 COPD DEXA EN EPA FIO2 GLA

Acute lung injury Acute Physiology and Chronic Health Evaluation American Society for Enteral and Parenteral Nutrition/Society of Critical Care Medicine Body mass index Carbon dioxide Chronic obstructive pulmonary disease Dual-energy X-ray absorptiometry Enteral nutrition Eicosapentaenoic acid Fraction of inspired oxygen γ-Linolenic acid

IC NPO REE RQ SEMICYUCSENPE

SNAQ SOFA VAP VO2

Indirect calorimetry Nil per os Resting energy expenditure Respiratory quotient Spanish Society of Intensive Care Medicine and Coronary Units and Spanish Society of Parenteral and Enteral Nutrition Short nutritional assessment questionnaire Sequential organ failure assessment Ventilator-acquired pneumonia Maximal oxygen consumption

Introduction Acute lung injury (ALI) remains a significant source of morbidity and mortality in critically ill patients. ALI may be associated with a direct injury to the lung, such as aspiration, pneumonia, pulmonary contusion, smoke, or toxic gas inhalation, or indirect lung injury resulting from conditions inciting an inflammatory cascade, such as sepsis, traumatic shock, or pancreatitis (Turner et al. 2011). ALI is characterized by persistent production of oxygen-free radicals combined with inflammatory mediators that cause a disruption of the lung endothelial and epithelial barriers (Johnson and Matthay 2010). Nutrition therapy plays a critical role in the management of patients with ALI and is necessary to prevent cumulative calorie deficits, malnutrition, loss of lean body mass, and deterioration of respiratory muscle strength and to modulate the inflammatory response associated with ALI. Studies have shown that the inclusion of trained nutrition professionals in the management of intensive care patients is associated with improvements in nutrition delivery to patients (Soguel et al. 2012). This chapter, therefore, will focus on the nutrition care process in a population of patients with ALI as a mechanism for the delivery of nutrition screening, assessment, intervention, and monitoring.

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Nutrition and Acute Lung Injury in Critical Care: Focus on Nutrition Care Process

Nutrition Screening for ALI Patients Nutrition screening is the process through which it is determined that a patient may benefit from nutrition care. Identifying patients at nutritional risk is a core competency of nutrition practitioners, recommended by clinical practice guidelines and mandated by many credentialing agencies. Most patients admitted to a critical care unit will likely meet the criteria for nutritional risk; however, screening patients with preexisting lung conditions, such as chronic obstructive pulmonary disease (COPD), may help identify patients early in the critical care stay who have existing nutrition deficits. The large groups of patients entering critical care units with ALI are comprised of patients with preexisting COPD who are now suffering from acute worsening of their disease. It is known from patients with COPD that a low body mass index (BMI, body weight/height2) or in particular a low fat-free mass index (as an indirect marker of skeletal muscle mass or lean body mass) is an independent determinant of mortality, even in clinically stable patients. The ANTADIR study showed that among patients treated with long-term oxygen therapy, low BMI was associated with increased duration of hospitalization and mortality (Chailleux et al. 2003). Subsequently, measuring fat-free mass index seemed to be of additional value since it was independent of BMI and other confounders, inversely associated with all-cause mortality in a sample of moderate to severe COPD patients (Schols et al. 2005). The prevalence of low body weight and/or low skeletal muscle mass is dependent on the severity of the disease and increases with worsening disease and with the presence of emphysema. Overall, about 20–40 % of the patients with COPD are undernourished (Vestbo 2006). On the other hand, overweight to obese patients’ (defined as patients with a BMI >25 kg/m2) BMI seems to have a protective effect on both all-cause and respiratory mortality (Landbo et al. 1999). Recent involuntary weight loss has been identified as another prognostic marker in COPD, particularly in patients with

51

low body weight (Prescott et al. 2002). Determination of the nutritional status in patients with preexisting COPD is thus of relevance, even in the stable phase. In patients with ALI, it is even more difficult to collect data on nutritional state. Apart from the critical condition of these patients, hydration state is often disrupted, making reliable assessment of body composition by current devices extremely difficult. Nevertheless, knowledge of a patient’s nutritional state is of importance to be able to evaluate energy requirements. For this, insight into the nutritional state during a patient’s clinically stable phase can be helpful. There have been several questionnaires, e.g., short nutritional assessment questionnaire (SNAQ), developed to record recent involuntary weight loss or to determine patients at risk for undernutrition (Wijnhoven et al. 2012). Interestingly, one study recently showed a technique to derive body cell mass (as a marker of skeletal muscle mass) from anthropometric data and weight change (Savalle et al. 2012). This technique was validated with dual-energy X-ray absorptiometry (DEXA) scanning, showed an error of less than 20 %, and was found to be useful in identifying undernutrition in critical care. The effect of nutrition in patients with ALI does not simply depend on nutritional state but on several other factors. These may include a complex interaction of prior nutritional reserves, the effects of any initial or evolving nutritional deficiency, the extent and severity of the underlying illnesses, the processes of recovery interacting with the metabolic signaling from nutrients, and the burdens imposed by the complications of providing nutrition therapy. These factors suggest that not all patients may benefit equally. An important challenge is identifying patients at increased nutritional risk. In order to identify critically ill patients at risk for undernutrition, a new scoring algorithm has been formulated, which may be helpful (Heyland et al. 2011). Based on the statistical significance in multivariate regressions models, this score included baseline Acute Physiology and Chronic Health Evaluation (APACHE) II scores, baseline Sequential Organ Failure Assessment (SOFA) scores, number of

52

comorbidities, days from hospital admission to critical care unit admission, and serum interleukin-6. As the score increased, so did the days of mechanical ventilation and mortality; however, nutrition adequacy modified the association between the score and 28-day mortality ( p = 0.01). Therefore, this tool may help discriminate which patients will benefit from aggressive protein-energy provision.

Calculations for Nutrition Assessment of ALI Patients

C. Hanson et al. Table 1 Consequences of caloric underfeeding and overfeeding Underfeeding Impaired immune function Delays in wound healing Wasting of respiratory muscles

Overfeeding Hypercapnea Delayed ventilator weaning Hepatic dysfunction Hyperlipidemia Azotemia Hyperglycemia Increased ventilatordependent days Increased ICU length of stay

Assessment of Energy Needs Most patients with ALI are hypermetabolic, and precise calculation of energy requirements is vital to avoid complications and improve health outcomes. The consequences of both overfeeding and underfeeding can be profound in this patient population and are summarized in Table 1. Indirect calorimetry (IC) is considered the gold standard for calculating the energy needs of critically ill patients (Doley et al. 2011; Haugen et al. 2007). IC provides a measure of resting energy expenditure (REE) and respiratory quotient (RQ) by measuring whole body oxygen (VO2) and carbon dioxide (VCO2) exchange using the abbreviated Weir equation as shown below (WEIR 1949; Wooley and Sax 2003): Modified Weir equation: REE ¼ ð3:94  VO2 Þ þ ð1:11  VCO2 Þ To obtain an accurate REE using IC, the test should be conducted at rest, avoiding bed movements and disruptions such as bathing or dressing change for at least 30 min prior to testing. Contraindications to performing IC on mechanical ventilator-dependent patients include fraction of inspired oxygen (FIO2) > 60 % as well as air leaks from chest tubes, around endotracheal tube cuff, or anywhere in the ventilator circuit (Nutrition care manual). For situations when IC is not available or inaccurate, numerous mathematical equations are available and are given in Table 2. The Academy of Nutrition and Dietetics’ evidence-based

guideline for critical illness recommends using the Penn State and modified Penn State equations as the most accurate option for determining needs in both obese and nonobese critically ill patients (Nutrition care manual). The American Society for Enteral and Parenteral Nutrition and the Society of Critical Care Medicine (ASPEN/SCCM) suggest using mathematical equations with caution as they are less accurate than results obtained using IC (McClave et al. 2009).

Assessment of Protein Needs ALI is characterized by a pro-inflammatory state as well as protein catabolism (Turner et al. 2011). Protein catabolism, due to an increase in protein turnover rates, breakdown, and oxygenation of protein, can lead to a loss of lean body mass, especially when combined with underlying diseases such as sepsis or trauma/burn (Mizock 2001). Protein requirements in normal or underweight patients are increased to 1–1.5 g/kg/day (Doley et al. 2011; Grau Carmona et al. 2011), with needs as high as 1.8 g/kg/day in critically ill patients with chronic respiratory failure (Grau Carmona et al. 2011). For obese patients (BMI 30–40 kg/m2), the ASPEN/SCCM recommends at least 2 g/kg/day protein ideal body weight (IBW). For patients with a BMI >40 kg/m2, needs are further increased to at least 2.5 g/kg/day IBW (Doley et al. 2011; McClave et al. 2009).

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Nutrition and Acute Lung Injury in Critical Care: Focus on Nutrition Care Process

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Table 2 Mathematical equations for calculating calorie need during critical illness Equation Mifflin St. Jeor (10)

Penn State (2003b) (10)

Male, 9.99(W) + 6.25 (H)  4.92(A) + 5; female, 9.99(W) + 6.25(H)  4.92 (A)  161 Mifflin (0.96) + VE (31) + Tmax (167)  6,212

Adjustment factor Multiply by 1.25 (5) for injury factor; may need to add an activity factor

Indication Non-vented

None

Any age with BMI < 30 or age 30; ventilator dependent BMI > 30 and age > 60 years; mechanical ventilator support; ventilator dependent Trauma/burn; ventilator dependent BMI > 30

Penn State (2010) (10)

Mifflin (0.71) + VE (64) + Tmax (85)  3,085

None

Ireton-Jones 1992 equation (10) Calories per kilogram (11)

1925  10(A) + 5(W) + 281 (S) + 292(T) + 851(B) 11–14 kcal/kg actual weight or 22–25 kcal/kg ideal body weight

May need to add an activity factor None

BMI body mass index, A age in years, H height in cm, W weight in kg, T temperature in degrees Celsius, Tmax maximum body temperature in degrees Celsius over the last 24 h, VE minute ventilation in L/min, S sex (male = 1, female = 0), T diagnosis of trauma (present = 1, absent = 0), B diagnosis of burn (present = 1, absent = 0)

Nutrition Interventions for ALI Patients Enteral Nutrition Many patients experiencing ALI require mechanical ventilation and therefore are dependent on alternate forms of nutrient delivery for nutrition support. Enteral nutrition is a common mechanism for providing nutrition to this patient population. Early initiation of enteral nutrition in critically ill patients is associated with numerous benefits, including the attenuation of hypercatabolism, reduced activation and release of inflammatory cytokines, and decreased infections and mortality (Krzak et al. 2011). The ASPEN/SCCM recommends that enteral feedings be initiated within the first 24–48 h following admission and advanced toward the goal over the next 48–72 h whenever possible (McClave et al. 2009). Historically, it was believed that carbohydrates should be restricted in ALI patients because of concerns regarding increased carbon dioxide. This led to the manufacture of commercial enteral formulas with high fat content, primarily omega-6 and omega-9 fatty acids (Lev and Singer 2013).

Later, researchers clarified that avoidance of excessive energy intake is more important than excessive carbohydrate intake (DeMichele et al. 2006). It also now appears that exposure to high levels of omega-6 and omega-9 fatty acids, which can be metabolized into inflammatory mediators, may be undesirable in this population, and attention has focused on the anti-inflammatory properties of other fatty acids, such as omega-3’s. Several independent studies and meta-analyses have shown the use of inflammation-modulating formulations to be associated with significant reductions in duration of mechanical ventilation, among other pulmonary benefits, including gas exchange and respiratory dynamics (Pontes-Arruda et al. 2006; Pontes-Arruda et al. 2008; Singer et al. 2006). Enteral products enriched with eicosapentaenoic acid (EPA or fish oil), γ-linolenic acid (GLA or borage oil), and enhanced levels of antioxidants have been used in an attempt to manipulate the inflammatory response associated with ALI. These products should not be confused with “immune-enhancing diets” containing other active nutritional ingredients, including arginine, nucleotides, and glutamine, that have also been evaluated regarding their role in critical care. Many pro-inflammatory mediators are metabolites

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of omega-6 fatty acids, and substitution of omega3 fatty acids for the more inflammatory omega-6 fatty acids is thought to possibly have a beneficial effect. This concept was first recognized in 1999 by Gadek et al., who attempted to translate bench findings in this area into bedside care. Patients were randomly assigned to receive enteral nutrition with similar calorie and protein content: a high-fat, low-carbohydrate product or a product enriched with fish oil, borage oil, and antioxidants. Patients receiving the enriched formula had more ventilator-free days, more critical care unit-free days, and a shorter hospital stay (Gadek et al. 1999). It has been speculated, however, that the exposure to the high fat content and therefore high exposure to omega-6 and omega-9 fatty acids led to a decline in status in the control group, as opposed to an improvement in the intervention group. However, two more recent studies published in 2006 and a 2008 meta-analysis have found similar results (Pontes-Arruda et al. 2006; Pontes-Arruda et al. 2008; Singer et al. 2006). These results, however, remain controversial. Studies that have evaluated the effect of fish oil supplementation (Stapleton et al. 2011), as well as enteral products containing fish oil (Pacht et al. 2003), on biomarkers of inflammation have conflicting results. In one of the most recent studies to evaluate the effect of omega-3 fatty acids on ventilator-free days in ALI, the OMEGA study provided twice-daily supplementation of omega3 fatty acids, γ-linolenic acid, and antioxidants separately from enteral nutrition. In contrast to previous studies, the study was stopped for futility after 143 patients in the intervention group and 129 controls were enrolled. Subjects who received the omega-3 supplements had fewer ventilator-free days, fewer organ failure-free days, and more days with diarrhea (Rice et al. 2011). Based on this data, continued investigation into the optimal amounts and delivery of enteral nutrition components is needed, and caution is recommended when considering supplementation of these substances. Currently, however, the ASPEN/SCCM recommendation is that ALI patients “be placed on an enteral formulation characterized by an antiinflammatory lipid profile (omega 3 fish oils, borage oil)” (McClave et al. 2009).

C. Hanson et al.

Parenteral Nutrition ALI itself is not an indication for parenteral nutrition. The very nature of ALI patients may make reaching enteral nutrition goals difficult. Gastrointestinal dysmotility has been reported in up to 70 % of ventilator-dependent patients (Turner et al. 2011). Current guidelines support the use of supplemental parenteral nutrition when nutrient needs cannot be met by the enteral route. Indeed, the ASPEN/SCCM guideline for nutrition support therapy in the critically ill adult patient endorses initiating supplemental parenteral nutrition if unable to meet 100 % of the target goal calories after 7–10 days by the enteral route alone (McClave et al. 2009). In this context, successful administration of enteral nutrition may be a sign of improvement, and the need for supplemental parenteral nutrition may be a marker of ALI disease severity (Turner et al. 2011). Parenteral nutrition administration in this population is not without concerns. Administration of parenteral nutrition has been associated with lateonset respiratory distress syndrome (Plurad et al. 2009) and a case reports of onset of rejections and ALI in a transplant patient after lipid administration (Kostopanagiotou et al. 2008). There are several possible mechanisms for such findings, including the inflammatory properties of lipids. The type of fatty acids that comprise the cell membrane, including alveolar macrophages, is influenced by fatty acid intake, which can, in turn, impact the types of inflammatory mediators produced (Mizock 2001). Although lipids are often a mainstay in the parenteral nutrition therapy regimens of critically ill patients, their role in this population remains undefined. No controversy exists regarding the need to prevent essential fatty acid deficiency and provide adequate substrate for cellular oxidation for energy; however, the makeup of lipid formulations being used is under scrutiny. Current US formulations of lipids are soy based, providing high amounts of omega-6 fatty acids which may possibly enhance the pro-inflammatory response during critical illness (Calder et al. 2010; Fasano et al. 2010). Parenteral lipid formulations containing fish oils are not available at this time in the United States.

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Nutrition and Acute Lung Injury in Critical Care: Focus on Nutrition Care Process

Other countries have the option of using several different formulations of parenteral lipids containing fish oils, olive oils, medium-chain triglycerides, and even structured lipids (Calder et al. 2010).

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potential energy sources (lipid-emulsified medications, dextrose solutions) must be made as well. If overfeeding is verified, calories (total macronutrient provision) must be reduced.

Monitoring of Protein Status

Nutrition Monitoring of ALI Patients Monitoring of Energy Balance Careful attention must be given to patients previously identified as malnourished. These patients are at risk for refeeding syndrome, a condition characterized by the metabolic and physiologic shifts of fluid and electrolytes (phosphate, magnesium, and potassium) when calories, particularly carbohydrates, are introduced to a malnourished patient (Solomon and Kirby 1990). In these patients, electrolytes must be supplemented prior to initiating nutrition therapy, and calories initiated and advanced conservatively (Solomon and Kirby 1990). Guidelines from SEMICYUCSENPE speak about the need to monitor electrolyte, trace element, and antioxidant status in this patient population (Grau Carmona et al. 2011). It is of utmost importance that clinicians be attuned to the symptoms of potential underfeeding or overfeeding. A caloric debt of greater than 10,000 cal has been noted to increase ICU stay and prolong weaning of mechanical ventilator support (Villet et al. 2005). If a patient exhibits signs of underfeeding, reassessment of energy requirements is indicated. Once the appropriate enteral nutrition (EN) prescription is determined, barriers to optimal nutrition delivery must be identified. Having identified obstacles to EN delivery, strives must be made to compensate for inadequate EN delivery, such as implementing compensatory feeding rates, 24-h volume-based feeding schedules, or limiting the time a patient is made nil per os (NPO) for procedures. If weaning trials remain unsuccessful despite adequate EN provision, a recalculation of energy needs (using indirect calorimetry or the Penn State equations) is recommended. Likewise, if overfeeding is suspected, energy requirements should again be recalculated. A thorough assessment of other

Strong emphasis must be placed on preserving lean body mass and optimizing respiratory muscle strength in order to support mechanical ventilation weaning trials. Low fat-free mass index is correlated with airway obstruction, lung hyperinflation, and higher inspiratory load (Budweiser et al. 2008). Even a short period of suboptimal nutrition results in decreased respiratory muscle strength, though hypocaloric feeding for the obese patient may be beneficial (Frankenfield et al. 2003; McClave et al. 2009). However, monitoring the adequacy of nutrition therapy can be difficult. Acute-phase proteins, such as albumin and prealbumin, do not reliably reflect nutritional status but instead are limited to indicating illness severity and inflammation (Raguso et al. 2003). Measuring nitrogen balance is tedious, as it is challenging to quantify protein losses from stool, wounds, drains, etc. Though not necessarily markers of nutritional status, markers of inflammation are often used as measures of the severity of illness, which is an important consideration in the nutrition therapy of the patient. Increased markers of inflammation, including tumor necrosis factor-α (Meduri et al. 1995), interleukin-6 (Meduri et al. 1995; Parsons et al. 2005), and interleukin8 (McClintock et al. 2008; Parsons et al. 2005), and disordered markers of coagulation and fibrinolysis (protein C and plasminogen activator inhibitor-1) are associated with worse outcomes in patients with ALI (Prabhakaran et al. 2003; Ware et al. Matthay 2003; Ware et al. 2007). Interestingly, increased BMI has been associated with decreased plasma inflammatory biomarkers (Stapleton et al. 2010). A trial determining the impact of trophic feeds versus full-energy feeds on markers of inflammation and coagulation failed to note significant differences in outcomes (Bastarache et al. 2012).

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Monitoring of Micronutrient Status Altered levels of trace elements have been identified in ALI animal models, with significant decreases in serum levels of zinc, selenium, and manganese (Wang et al. 2012). Careful monitoring of serum phosphorus levels is also warranted in ALI. Normal diaphragmatic contractility is dependent upon adensosine50 -triphosphate, and hypophosphatemic patients may experience prolonged ventilator dependence (McClave et al. 2009). Selenium is an important compound which protects against free radical injury, and it has been speculated, although not proven, that selenium could be important in the pathogenesis of lung disorders in other populations, such as bronchopulmonary dysplasia in preterm infants (Falciglia et al. 2003). Monitoring of these micronutrients and appropriate repletion are warranted. Monitoring 25(OH)D levels for assessment of vitamin D status may also be of benefit in this population, as alterations in vitamin D status with associated alterations in antimicrobial peptide levels have also been reported in critically ill patients (Jeng et al. 2009).

C. Hanson et al. Table 3 Nutrition monitoring of ALI patients Monitoring domain Energy and protein status

Refeeding syndrome

Micronutrients

Others

Monitoring indicator Nutrient intake Results of indirect calorimetry Weight changes 24-h feeding volumes compared against goal Ventilator weaning Other potential energy sources (i.e., lipid-emulsified medications) Disease severity Comorbid conditions GI function Fluid changes Serum phosphate Serum magnesium Serum potassium Zinc Selenium Manganese Phosphorus Antioxidants Vitamin D (25(OH)D) Abdominal pain, distention, and abnormal bowel movements (especially during enteral nutrition) Dysphagia post-extubation

Other Types of Patient Monitoring For all patients receiving enteral nutrition, physical assessments evaluating the presence of abdominal pain, distention, and abnormal bowel movements must be performed routinely to ascertain feeding tolerance (McClave et al. 2009). Once the patient is extubated, he/she must be monitored for signs and symptoms of dysphagia. Tracheal intubation interferes with swallowing function. Patients intubated for greater than 48 h are at high risk for aspiration shortly after extubation (Ajemian et al. 2001; Leder et al. 1998). Though dysphagia generally improves over time, some patients may benefit from supplemental EN and working with a speech language pathologist until safe and adequate per os intake is achieved. A summary of nutrition monitoring for ALI patients is given in Table 3.

Applications to Critical or Intensive Care Nutrition therapy in this patient population is necessary to prevent cumulative calorie deficits, malnutrition, loss of lean body mass, and deterioration of respiratory muscle strength and to modulate the inflammatory response associated with ALI. In critical care settings, differences in opinion exist regarding the amount of time necessary to withhold enteral nutrition prior to such events as surgery or mechanical ventilation extubation. Many facilities continue to hold enteral nutrition after midnight for morning surgical procedures or weaning attempts due to the fear of potential aspiration. No current literature supports this common practice. In fact, studies show perioperative continuation of post-pyloric feeds, which are feedings provided through a

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Nutrition and Acute Lung Injury in Critical Care: Focus on Nutrition Care Process

57

Decision tree for EN tolerance Nutrition Assessment: NPO expected >24-48 hrs

Is GI tract functional?

Defer PN unitl NPO > 7days

Initiate Enternal Nutrition (EN)

No

No

Yes Assessment parameters include, but are not limited to, abdomen soft/nontender, positive bowel sounds, passing flatus, and bowel movement.

Is the patient malnourished? Yes Initiate Parenteral Nutrition (PN) Possible reasons include, but are not limited to, paralytic ileus, mesenteric ischemia, small bowel obstruction, and high dose vasopressor support.

Gastric Residual Volume (GRV) >500mL? No Continue EN Yes Head of Bed >30 degrees?

No Reposition and recheck GRV Yes Troubleshoot EN intolerance •

Clinically assess for abdominal distention, bloating/fullness, nausea/vomitimg.

•

Consider post-pyloric feeding tube access.

•

Switch to more calorically dense EN product

•

Minimize narcotics

•

Switch from bolus to continuous infusion

•

Initiate prokinetic therapy

•

Consider proton pump inhibitor

No Confirmed Enteral Intolerance?

Continue EN Yes

Fig. 1 A sample algorithm for enteral tolerance and initiation of enteral feeding (McClave and Parrish 2008; Montejo et al. 2010)

tube which has been advanced through the stomach into the duodenum or jejunum, to be feasible in some critically ill surgical patients and result in the provision of additional calories (McElroy et al. 2012). Other studies have

shown that providing post-pyloric feeds during ventilator weaning and tracheal extubation is safe and results in the provision of more optimal nutrition (Lyons et al. 2002). Whereas practice guidelines for preoperative fasting exist

58

for healthy patients undergoing elective procedures (American Society of Anesthesiologists Committee 2011), there is a great need to develop similar practice guidelines for critically ill patients.

Applications to Other Conditions Although this chapter targets the nutrition care process as it specifically applies to lung disease, many patients in critical care units, such as trauma and septic patients, also suffer from the hypermetabolism and catabolism present in ALI. As such, nutrition assessment and interventions described in this chapter, such as avoidance of under- and overfeeding, early enteral feedings, and careful monitoring of nutritional parameters, have the potential to provide benefits to other critically ill patients.

Guidelines and Protocols The use of nutrition support protocols in the intensive care setting has been shown to increase the proportion of mechanically ventilated patients who reach enteral nutrition targets. Such protocols usually provide guidelines on the initiation and advancement of enteral feedings. In one study, the percentage of ventilated patients who received 80 % of their estimated energy requirements increased from 20 % before protocol implementation to 80 % after implementation. ( p = 0.001). Parenteral nutrition use was reduced in the postimplementation group as well (1.6 % vs. 13 %, p = 0.02) (Mackenzie et al. 2005; Soguel et al. 2012). The beneficial impact of nutrition support protocols on lung outcomes has been shown in other populations as well. Indeed, the use of enteral feeding protocols is supported in evidence-based guidelines, as their use to increase delivery of enteral nutrition has been shown to improve outcomes (McClave et al. 2009). A sample decision tree for assessing tolerance to enteral nutrition is given in Fig. 1. Additional guidelines from the ASPEN/SCCM that are relevant to ALI are given in Table 4.

C. Hanson et al. Table 4 Summary of the ASPEN/SCCM evidence-based guidelines specific to nutrition and ALI: recommendation for clinicians Patients placed on enteral nutrition should be monitored for aspiration. Steps to reduce the risk of aspiration should be employed Immune-modulating enteral formulations (supplemented with agents such as arginine, glutamine, nucleic acid, omega-3 fatty acid, and antioxidants) would be used for the appropriate population (including crucially ill patients on mechanical ventilation), with caution in patients with severe sepsis Patients with ARDS and severe acute lung injury should be placed on an enteral formulation characterized by an anti-inflammatory lipid profile (i.e., omega-3 fish oils, borage oil) and antioxidants Specialty high-lipid, low-carbohydrate formulas to manipulate the respiratory quotient and reduce CO2 production are not recommended for routine use in ICU patients with acute respiratory failure Fluid-restricted calorically dense formulations should be considered for patients with acute respiratory failure Serum phosphate levels should be monitored closely and replaced appropriately when needed McClave, S; Martindale, R; Vanek V; McCarthy, M; Roberts, P; Taylor, B; Ochoa, J; Napolitano L; Cresci, G; the A. S.P.E.N. Board of Directors, the American College of Critical Care Medicine. Journal of Parenteral and Enteral Nutrition, 33(3) pp. 277–316, #2009 by the Journal of Parenteral and Enteral Nutrition and Sage Publications. Reprinted with permission of Sage Publications

Summary Points • ALI is a hypermetabolic and inflammatory state, leading to catabolism and nutritional depletion. • Nutrition therapy is required to prevent malnutrition, loss of lean body mass, and respiratory muscle deterioration. • Enteral nutrition is associated with modulation of stress and attenuation of disease severity. • The ASPEN/SCCM guidelines recommend the administration of enteral formulas characterized by an anti-inflammatory lipid profile. • Monitoring and repletion of antioxidants and phosphorus are warranted in ALI.

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References Ajemian MS, Nirmul GB, Anderson MT, Zirlen DM, Kwasnik EM. Routine fiberoptic endoscopic evaluation of swallowing following prolonged intubation: implications for management. Arch Surg. 2001;136(4):434–7. American Society of Anesthesiologists Committee. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: an updated report by the american society of anesthesiologists committee on standards and practice parameters. Anesthesiology. 2011;114(3):495–511. Bastarache JA, Ware LB, Girard TD, Wheeler AP, Rice TW. Markers of inflammation and coagulation may be modulated by enteral feeding strategy. JPEN J Parenter Enteral Nutr. 2012;36(6):732–40. Budweiser S, Meyer K, Jorres RA, Heinemann F, Wild PJ, Pfeifer M. Nutritional depletion and its relationship to respiratory impairment in patients with chronic respiratory failure due to COPD or restrictive thoracic diseases. Eur J Clin Nutr. 2008;62(3):436–43. Calder PC, Jensen GL, Koletzko BV, Singer P, Wanten GJ. Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions. Intensive Care Med. 2010;36(5):735–49. Chailleux E, Laaban JP, Veale D. Prognostic value of nutritional depletion in patients with COPD treated by long-term oxygen therapy: data from the ANTADIR observatory. Chest. 2003;123(5):1460–6. DeMichele SJ, Wood SM, Wennberg AK. A nutritional strategy to improve oxygenation and decrease morbidity in patients who have acute respiratory distress syndrome. Respir Care Clin N Am. 2006;12(4):547–66, vi. Doley J, Mallampalli A, Sandberg M. Nutrition management for the patient requiring prolonged mechanical ventilation. Nutr Clin Pract. 2011;26(3):232–41. Falciglia HS, Johnson JR, Sullivan J, Hall CF, Miller JD, Riechmann GC, et al. Role of antioxidant nutrients and lipid peroxidation in premature infants with respiratory distress syndrome and bronchopulmonary dysplasia. Am J Perinatol. 2003;20(2):97–107. Fasano E, Serini S, Piccioni E, Innocenti I, Calviello G. Chemoprevention of lung pathologies by dietary n-3 polyunsaturated fatty acids. Curr Med Chem. 2010;17(29):3358–76. Frankenfield DC, Rowe WA, Smith JS, Cooney RN. Validation of several established equations for resting metabolic rate in obese and nonobese people. J Am Diet Assoc. 2003;103(9):1152–9. Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. enteral nutrition in ARDS study group. Crit Care Med. 1999;27(8):1409–20.

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Grau Carmona T, Lopez Martinez J, Vila Garcia B, Spanish Society of Intensive Care Medicine and Coronary UnitsSpanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE). Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the spanish society of intensive care medicine and coronary units-spanish society of parenteral and enteral nutrition (SEMICYUC-SENPE): respiratory failure. [Recomendaciones para el soporte nutricional y metabolico especializado del paciente critico. Actualizacion. Consenso SEMICYUC-SENPE: insuficiencia respiratoria]. Med Intens/Sociedad Espanola De Medicina Intensiva y Unidades Coronarias. 2011;35 Suppl 1:38–41. Haugen HA, Chan LN, Li F. Indirect calorimetry: a practical guide for clinicians. Nutr Clin Pract. 2007;22(4):377–88. Heyland DK, Dhaliwal R, Jiang X, Day AG. Identifying critically ill patients who benefit the most from nutrition therapy: the development and initial validation of a novel risk assessment tool. Crit Care. 2011;15(6):R268. Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009;7(1):28. Johnson ER, Matthay MA. Acute lung injury: epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv. 2010;23(4):243–52. Kostopanagiotou G, Kalimeris K, Arkadopoulos N, Karakitsos P, Smyrniotis V, Pandazi A. Role of lipid emulsion administration in acute lung injury during liver transplant rejection: a case report. Transplant Proc. 2008;40(10):3823–5. Krzak A, Pleva M, Napolitano LM. Nutrition therapy for ALI and ARDS. Crit Care Clin. 2011;27(3):647–59. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(6):1856–61. Leder SB, Cohn SM, Moller BA. Fiberoptic endoscopic documentation of the high incidence of aspiration following extubation in critically ill trauma patients. Dysphagia. 1998;13(4):208–12. Lev S, Singer P. N-3 fatty acids and gamma-linolenic acid supplementation in the nutritional support of ventilated patients with acute lung injury or acute respiratory distress syndrome. World Rev Nutr Diet. 2013;105:136–43. Lyons KA, Brilli RJ, Wieman RA, Jacobs BR. Continuation of transpyloric feeding during weaning of mechanical ventilation and tracheal extubation in children: a randomized controlled trial. JPEN J Parenter Enteral Nutr. 2002;26(3):209–13. Mackenzie S, Zygun D, Whitmore B, Doig CJ, Hameed SM. Implementation of a nutrition support protocol increases the proportion of mechanically ventilated patients reaching enteral nutrition targets in the adult intensive care unit. J Parenter Enteral Nutr. 2005;29(2):74–80.

60 McClave S, Parrish C. Checking gastric residuals volumes. Nutr Iss Gastroenterol. 2008;67:46. McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009;33(3):277–316. McClintock D, Zhuo H, Wickersham N, Matthay MA, Ware LB. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care. 2008;12(2):R41. McElroy LM, Codner PA, Brasel KJ. A pilot study to explore the safety of perioperative postpyloric enteral nutrition. Nutr Clin Pract. 2012;27(6):777–80. Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, et al. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest. 1995;107(4):1062–73. Mizock B. Nutritional support in acute lung injury and acute respiratory distress syndrome. Nutr Clin Pract. 2001;16(6):319–28. Montejo JC et al. Gastric residual volume during the enteral nutrition in ICU patients: the REGANE study. Intensive Care Med. 2010;36:1386–93. Nutrition care manual. Retrieved 23 April 2013 from www. nutritioncaremanual.org Pacht ER, DeMichele SJ, Nelson JL, Hart J, Wennberg AK, Gadek JE. Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants reduces alveolar inflammatory mediators and protein influx in patients with acute respiratory distress syndrome. Crit Care Med. 2003;31(2):491–500. Parsons PE, Eisner MD, Thompson BT, Matthay MA, Ancukiewicz M, Bernard GR, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med. 2005;33(1):1–6. discussion 230–2. Plurad D, Green D, Inaba K, Belzberg H, Demetriades D, Rhee P. A 6-year review of total parenteral nutrition use and association with late-onset acute respiratory distress syndrome among ventilated trauma victims. Injury. 2009;40(5):511–15. Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gammalinolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006;34(9):2325–33. Pontes-Arruda A, Demichele S, Seth A, Singer P. The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr. 2008;32(6):596–605. Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are

C. Hanson et al. associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003;285(1):L20–8. Prescott E, Almdal T, Mikkelsen KL, Tofteng CL, Vestbo J, Lange P. Prognostic value of weight change in chronic obstructive pulmonary disease: results from the copenhagen city heart study. Euro Respir J. 2002;20(3):539–44. Raguso CA, Dupertuis YM, Pichard C. The role of visceral proteins in the nutritional assessment of intensive care unit patients. Curr Opin Clin Nutr Metab Care. 2003;6(2):211–16. Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, Steingrub J, Rock P. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574–81. Savalle M, Gillaizeau F, Maruani G, Puymirat E, Bellenfant F, Houillier P, et al. Assessment of body cell mass at bedside in critically ill patients. Am J Physiol Endocrinol Metab. 2012;303(3):E389–96. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr. 2005;82(1):53–9. Singer P, Theilla M, Fisher H, Gibstein L, Grozovski E, Cohen J. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med. 2006;34(4):1033–8. Soguel L, Revelly JP, Schaller MD, Longchamp C, Berger MM. Energy deficit and length of hospital stay can be reduced by a two-step quality improvement of nutrition therapy: the intensive care unit dietitian can make the difference. Crit Care Med. 2012;40(2):412–19. Solomon SM, Kirby DF. The refeeding syndrome: a review. JPEN J Parenter Enteral Nutr. 1990;14(1):90–7. Stapleton RD, Dixon AE, Parsons PE, Ware LB, Suratt BT. The association between BMI and plasma cytokine levels in patients with acute lung injury. Chest. 2010;138(3):568–77. Stapleton RD, Martin TR, Weiss NS, Crowley JJ, Gundel SJ, Nathens AB, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Crit Care Med. 2011;39(7):1655–62. Turner KL, Moore FA, Martindale R. Nutrition support for the acute lung injury/adult respiratory distress syndrome patient: a review. Nutr Clin Pract. 2011;26(1):14–25. Vestbo J. Clinical assessment, staging, and epidemiology of chronic obstructive pulmonary disease exacerbations. Proc Am Thorac Soc. 2006;3(3):252–6. Villet S, Chiolero RL, Bollmann MD, Revelly JP, Cayeux RNMC, Delarue J. Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin Nutr. 2005;24(4):502–9. Wang G, Lai X, Yu X, Wang D, Xu X. Altered levels of trace elements in acute lung injury after severe trauma. Biol Trace Elem Res. 2012;147(1–3):28–35. Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003;285(3):L514–21.

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Ware LB, Matthay MA, Parsons PE, Thompson BT, Januzzi JL, Eisner MD, et al. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med. 2007;35(8):1821–8. Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1949;109(1–2):1–9.

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Wijnhoven HA, Schilp J, van Bokhorst-de van der Schueren MA, de Vet HC, Kruizenga HM, Deeg DJ, et al. Development and validation of criteria for determining undernutrition in community-dwelling older men and women: the short nutritional assessment questionnaire 65+. Clin Nutr. 2012;31(3):351–8. Wooley JA, Sax HC. Indirect calorimetry: applications to practice. Nutr Clin Pract. 2003;18(5):434–9.

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Eicosanoid Synthesis and Respiratory Distress Syndrome in Intensive Medicine Abelardo Garcia-de-Lorenzo y Mateos, Juan Carlos Montejo González, and Manuel Quintana Diaz

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Eicosanoids: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Applications to Critical Medicine/Intensive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ALI and RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eicosanoids as Mediators and Prognostic Markers in ALI/RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dietary Lipids, Eicosanoids, and RDS . . . . . . . . . . . . . . .

67 67 68 69

Manipulating Eicosanoid Synthesis in Patients with ALI/RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Applications to Other Conditions . . . . . . . . . . . . . . . . . . 73 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

A. Garcia-de-Lorenzo y Mateos (*) • M. Quintana Diaz Servicio de Medicina Intensiva, Hospital Universitario La Paz, Madrid, Spain e-mail: [email protected]; abelardo.garcia@salud. madrid.org; [email protected] J.C. Montejo González Intensive Care Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_1

Eicosanoids are signaling molecules made by oxidation of 20 carbon fatty acids. They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system. Eicosanoids control both proinflammatory and anti-inflammatory effectors that are particularly relevant for inflammation. The networks of controls that depend upon eicosanoids are among the most complex in the human body. Lipid mediators are synthesized via cyclooxygenase, lipoxygenase, and cytochrome P450 pathways with fatty acids such as arachidonic acid used as substrate. These mediators include prostaglandins, thromboxanes, leukotrienes, lipoxins, and hydroxyl and epoxy fatty acids – all grouped as eicosanoids – and platelet-activating factor, acting as intercellular signaling molecules. They have an impact on the secretion of immunoregulatory cytokines, on secondary mediators like reactive oxygen species or proteases, and on autocrine eicosanoid regulation loops. Numerous experimental studies suggest that the generation of arachidonate metabolites can play a role in the development of ALI/RDS. In normal conditions, arachidonate is bound to the phospholipids of cell membranes. Following injury and in response to various mediators, free arachidonic acids are released from membrane phospholipids by the action of phospholipases. This arachidonic acid can serve as a substrate for 63

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the production of prostaglandins and thromboxanes through a cyclooxygenase enzyme and as a substrate for the production of several hydroxyl fatty acids and leukotrienes through the action of lipoxygenase enzymes. The lung is an important organ in the arachidonate cascade since it possesses the enzymatic capacity to synthesize all the arachidonate derivatives and also responsible in large part for selective catabolism of circulating eicosanoids. The use of diets high in w-3 fatty acids is a means to decrease levels of arachidonic acid in cells, thereby reducing the production of proinflammatory eicosanoids. Clinical investigation with enteral diets enriched in EPA/GLA and antioxidants shows beneficial effect in patients with ALI/ARDS.

List of Abbreviations

ALI BAL DGLA EPA GLA ICAM-1 IL LT MODS PAI-1 PEEP PG PUFAs RDS SIRS TBX TNF

Acute lung injury Bronchoalveolar lavage Dihomo-gamma-linoleic acid Eicosapentaenoic acid Gamma-linolenic acid Intercellular adhesion molecule-1 Interleukin Leukotriene Multiple organ dysfunction syndrome Plasminogen activator inhibitor-1 Positive end-expiratory pressure Prostaglandin Polyunsaturated fatty acids Respiratory distress syndrome Systemic inflammatory response syndrome Thromboxane Tumor necrosis factor

Introduction The body’s response to illness and injury is extremely complex. The following description is a simplistic description of the inflammatory response to injury and illness (Brun-Buisson 2000).

Table 1 Mediators in the inflammatory response Proinflammatory mediators Eicosanoids TBXA2 LTB2 Prostaglandins PGE2 Cytokines IL-1 IL-6 IL-8 TNF

Anti-inflammatory mediators Eicosanoids TBXA3 TBA5 Prostaglandins PGE2 PGE3 Cytokines IL-1 IL-4 IL-10 TNF receptor

In response to an injury or insult (trauma, burns, surgery, pancreatitis, infection, etc.), the body attempts to restore homeostasis, and a balance between proinflammatory and antiinflammatory mediators (various eicosanoids, prostaglandins, and cytokines) occurs. These anti- and proinflammatory mediators play an important role in initiating the healing process by limiting new damage and ameliorating damage that has already occurred. They destroy damaged tissue, promote new tissue growth, and overcome pathogenic organisms, neoplastic cells, and foreign antigens. The localized response can result in a spillover of anti-inflammatory and proinflammatory mediators into the systemic circulation (Table 1). Ideally, the pro- and anti-inflammatory mediators are in balance. However, when the anti-inflammatory mediators dominate, the immune system is suppressed, creating an increased risk of infection. Conversely, when proinflammatory mediators dominate, a state of uncontrolled inflammation develops, as seen in the systemic inflammatory response syndrome (SIRS), sepsis, or septic shock. In SIRS, the proinflammatory response is overreactive, and the inflammatory mediators are elevated in the systemic circulation, placing all organs of the body at risk. The risk of organ failure, multiple organ dysfunction syndrome (MODS), and death increases dramatically.

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Eicosanoid Synthesis and Respiratory Distress Syndrome in Intensive Medicine

Eicosanoids: An Overview The term eicosanoid is used to embrace biologically active lipid mediators (C20 fatty acids and their metabolites), including prostaglandins, thromboxanes, leukotrienes, and other oxygenated derivatives, which are produced primarily by three classes of enzymes, cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases. The key precursor fatty acids are 8c,11c,14c-eicosatrienoic (dihomogamma-linolenic or 20:3(w-6)), 5c,8c,11c,14ceicosatetraenoic (arachidonic or 20:4(w-6)), and 5c,8c,11c,14c,17c-eicosapentaenoic (20:5(w-3) or EPA) acids. However, it is now impossible to discuss these compounds and their biological activities properly without also considering the docosanoids (resolvins and protectins) derived from 4c,7c,10c,13c,16c,19c-docosahexaenoic acid (22:6(w-3) or DHA) and related products formed by nonenzymatic means (isoprostanes). Similarly plant products such as the jasmonates and other oxylipins derived from 9c,12c,15c-octadecatrienoic (alpha-linolenic or 18:3(w-3)) acid have analogous structures and functions. It is noteworthy that the precursor fatty acids for all of these

Fig. 1 Biosynthesis of eicosanoids from arachidonic acid

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belong to both the omega-6 and omega-3 families (Heller et al. 1998). Arachidonic acid has been by far the most studied, and it is special in many ways (Fig. 1). It is an essential fatty acid in that it cannot be synthesized de novo in animals, and linoleic acid from the diet is required as the primary precursor. As a major component of phospholipids, and especially of phosphatidylinositol, it is important for the integrity of cellular membranes. The four cis-double bonds mean that the molecule is highly flexible, and this helps to confer the correct degree of fluidity in membranes. Diacylglycerols enriched in arachidonic acid and derived from phosphatidylinositol are important cellular messengers. Anandamide or N-arachidonoylethanolamine is an endogenous cannabinoid or endocannabinoid, which produces neurobehavioral effects similar to those induced by cannabis and may have important signaling roles in the central nervous system, especially in the perception of pain and in the control of appetite. 2-Arachidonoylglycerol has similar properties. There are suggestions that arachidonic acid per se may have some biological importance in animal tissues; for example, the cellular level of unesterified arachidonic

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Fig. 2 Generation of arachidonic acid [w-6]- and eicosapentaenoic acid [w-3]-derived lipid mediators

Arachidonic acid

LTB5 LTC5

TXA3 PGI3

LTB4 TTC4

TXA2 PGI2

lipoxins

resolvins

Eicosapentaenoic acid

acid may be a mechanism by which apoptosis is regulated. The oxygenated metabolites derived from arachidonic and related fatty acids are rapidly biosynthesized within seconds to minutes of acute challenge by leukocyte from membrane-derived arachidonic acid, using either cyclooxygenase or lipoxygenase, and are produced through a series of complex interrelated biosynthetic pathways sometimes termed the “arachidonate or eicosanoid cascade.” They are so numerous and have such a range of biological activities that they must provide a substantial component of the reason for the essentiality of the latter to the survival and well-being of animals. The prostanoids (prostaglandins, thromboxanes, and prostacyclins) have distinctive ring structures in the center of the molecule. The hydroxyeicosatetraenes are apparently simpler in structure, but are precursors for families of more complex molecules, such as the leukotrienes and lipoxins. The eicosanoids are considered local hormones. They have specific effects on target cells close to their site of formation. They are rapidly degraded, so they are not transported to distal sites within the body. But in addition to participating in intercellular signaling, there is evidence for involvement of eicosanoids in intracellular signal cascades. Examples of eicosanoids are prostaglandins, prostacyclins, thromboxanes, leukotrienes, and epoxyeicosatrienoic acids. For each, there are two or three separate series, derived

either from a w-3 or w-6 EFA. These series of different activities largely explain the health effects of w-3 and w-6 fats. They have various roles in inflammation, fever, regulation of blood pressure, blood clotting, immune system modulation, control of reproductive processes and tissue growth, and regulation of the sleep/wake cycle (Calder 2003). The w-6 eicosanoids are generally proinflammatory; w-3 are much less so. Cyclooxygenase metabolizes arachidonic acid to 2-series and eicosapentaenoic acid to 3-series prostaglandins. After oxidation by 5-lipoxygenase, 4-series leukotrienes and 5-series leukotrienes are derived from arachidonic acid or eicosapentaenoic acid, respectively. Lipoxins are double-oxygenated mediators from arachidonic acid, whereas the new class of resolvins stems from eicosapentaenoic acid (Fig. 2; Mayer et al. 2006). The amounts and balance of these fats in a person’s diet will affect the body’s eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis. But with the discovery of lipid mediators that possess both anti-inflammatory and pro-resolution activities (dual action mediators) (Bannenberg et al. 2005), these new families of resolvins and protectins and class of eicosanoids, e.g., lipoxins, constitute a novel genus of pro-resolution mediators (Serhan 2008). Anti-inflammatory drugs such as aspirin and other NSAIDs act by downregulating eicosanoid synthesis.

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Applications to Critical Medicine/ Intensive Care ALI and RDS SIRS is a syndrome caused by increasing amounts of proinflammatory mediators. In this environment, instead of producing a positive healing response, the proinflammatory mediators become destructive and the risk for acute lung injury (ALI), respiratory distress syndrome (RDS), MODS, and death increases dramatically. The lungs are often the first organ affected. Due to the high number of inflammatory cells, they are particularly susceptible to the effects of an overreactive inflammatory response, which results in ALI which may later lead to RDS. ALI is characterized by pulmonary infiltrates, gas exchange disturbances, poor lung compliance, and hypoxemia. Research suggests that SIRS, triggered by a predisposing condition, accompanies most forms of ALI. Sepsis (SIRS with infection) and pneumonia are the primary predisposing conditions for the development of ALI. As a result of direct or indirect injury to the lung, pulmonary edema and hypoxemia develop,

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leading to a condition known as respiratory failure and, ultimately, to RDS. ALI is a milder, earlier, and more reversible stage of lung injury, and early interventions after the initial injury to the lung may diminish the likelihood of developing the more severe RDS. The inflammatory response is regulated by a complex system of endogenous mediators of inflammation capable of having single and multiple functions. The mechanisms that create the inflammatory edema of the lung epithelium are extremely complex. Although a number of triggering factors have been proposed, many of the inflammatory events appear to follow the activation of the complement system. This inflammatory response cascade is illustrated in Fig. 3. The initial stage of the inflammatory response is characterized by the release of vasoactive mediators from tissue mast cells, platelets, and plasma components, resulting in pulmonary vasodilation. Because of increased vascular permeability, water, salts, and some small proteins from the plasma pass into the damaged area, causing alveolar edema. This initial stage is followed by the activation of the coagulation system and the complement system and by the generation of plasma- and cell-derived chemotactic factors for inflammatory

Clinical catastrophe Inflammatory response initiated

Inflammatory cells produce metabolites, causing tissue damage and leading to MOF (the lungs fail first because of the high number of resident inflammatory cells)

Fig. 3 Injuryinflammatory cycle

Inflammatory mediators produced

Inflammatory mediators act on target cells and perpetuate the inflammatory response

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cells (mainly neutrophils) (Anas et al. 2010). Leukocyte chemotaxis causes white blood cells to gather at the site of injury. Activation of the complement system, in turn, promotes the recruitment and activation of cells such as neutrophils within the lung vasculature. The adhesion of these cells to lung endothelium causes them to aggregate along vessel walls in a process known as leukocyte margination. The neutrophils then migrate through the vessel membrane and pass into the area of tissue damage in a process known as emigration (Lorente and Esteban 2012). Later in the process, other cells such as macrophages also migrate to the damaged area (Serhan 2005).

Eicosanoids as Mediators and Prognostic Markers in ALI/RDS Experimental studies suggest that the generation of arachidonate metabolites can play a role in the development of ALI/RDS. In normal conditions, arachidonate is bound to the phospholipids of cell membranes. Following injury and in response to various mediators, free arachidonic acids are released from membrane phospholipids by the action of phospholipases. This arachidonic acid can serve as a substrate for the production of prostaglandins and thromboxanes through a cyclooxygenase enzyme and as a substrate for the production of several hydroxyl fatty acids and leukotrienes through the action of lipoxygenase enzymes. The lung is an important organ in the arachidonate cascade since it possesses the enzymatic capacity to synthesize all the arachidonate derivatives and also responsible in large part for selective catabolism of circulating eicosanoids (Leeman and Boeynaems 1984). Rivkind et al. (1989) studied multiply injured blunt trauma patients at high risk for development of RDS (multisystem trauma including more than one organ or extremity, Injury Severity Score of 26 or more, hypotension and need for 1,500 mL or more blood within the first hour after admission, and PaO2 less than or equal to 70 torr). Mixed venous blood samples were obtained for eicosanoids PGE2, PGF2 alpha, thromboxane B2, PGI2 (6-ketoPGF1 alpha), and leukotriene B4 (LTB4).

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Platelet and neutrophil counts were also done and plasma elastase was measured. These data were correlated with physiologic measurements of the respiratory index (RI), percent pulmonary shunt (QS/QT), and respiratory compliance measures. Seven patients developed a fulminant posttraumatic RDS within 96 h after injury. Twelve patients without RDS developed sepsis (TS) 4 or more days after injury, and 11 had uncomplicated post-injury courses (TR). Compared to both TR and TS, ARDS had a significant ( p < .01) rise in neutrophil superoxide production beginning on day 2 through day 4 after injury. This was preceded by rises in PGE2 and LTB4, which were significantly correlated with subsequent falls in PLAT and WBC and rises in TXB2, PGF1, and superoxide production and followed by increases in RI and QS/QT and a fall in compliance. The significant difference in the pattern and sequence of events in RDS compared to TR and TS patients suggests that in RDS the earliest event may be related to peripheral release of PGE2 and LTB4 due to platelet activation and lung sequestration with release of PGF2 alpha and by aggregation and leukocyte adherence with release of elastase. However, fulminant RDS mortality appears to be related to the subsequent amplification of the LTB4 leukocyte activation with superoxide production that does not achieve significance before the second day after injury and rises to a maximum by day 4 after injury. These data suggest that posttraumatic ARDS follows a different evolutionary pattern than that reported in animal models and is also different from that seen in human TS or TR patients. Other investigators refer that plasma level of eicosanoids in the RDS patients was higher than reference subjects ( p < .05), and no differences were observed between systemic arterial and pulmonary arterial values. The authors’ conclusion was that from all the eicosanoids studied (TXB2, PGF1 alpha, and LTB4), only LTB4 (in both systemic arterial and pulmonary blood) was correlated with the Lung Injury Score (r = 0.49, p < .05, and r = 0.45, p < .05, respectively). Patients who did not survive presented a lower LTB4 systemic-pulmonary arterial gradient than survivors (Masclan et al. 1999).

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Eicosanoid Synthesis and Respiratory Distress Syndrome in Intensive Medicine

More recently Amat et al. (2000) described that in both patients at risk of RDS and with RDS, leukotrienes (LTB4, LTC4, LTD4) are elevated during the early phases of RDS, whereas IL-8 increases throughout the study period. The conclusion was that the evaluation of LTB4 and IL-8 may be useful prognostic indexes in patients with early RDS after admission to the intensive care unit.

Dietary Lipids, Eicosanoids, and RDS Many critically ill patients are admitted with conditions that are associated with an inflammatory response, leading to SIRS. Because the mortality rate increases along the continuum from SIRS to MODS, early and effective intervention is imperative. However, effectively correcting the imbalance of proinflammatory mediators and attenuating the inflammatory response that leads to SIRS have been elusive. Since inflammation, through the release of arachidonic acid and its proinflammatory metabolites, is considered the key feature of RDS, the use of lipids, as a strategy to modulate the inflammatory response, is gaining acceptance as an important improvement in the daily management of patients with ALI and RDS. The literature suggests that providing specific dietary nutrients may downregulate the overactive inflammatory response and improve cardiopulmonary function in patients with pneumonia or SIRS, ALI, and RDS. These nutrients include gamma-linolenic acid (GLA), found in oil from seeds of the borage plant, and eicosapentaenoic acid (EPA), found in fish oil, as well as specific dietary antioxidants. These components have been shown to have important metabolic effects by altering the phospholipid content of alveolar macrophages, leading to the production of less proinflammatory mediators and improved pulmonary function while providing general nutrition support (Pontes-Arruda and DeMichele 2009). Dietary lipids have several important functions, including as source of energy (calories), carrier of fat-soluble vitamins, source of essential

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fatty acids, and precursors of eicosanoids (prostanoids and leukotrienes), and the relationship between essential fatty acids in nutrition, dietary supplementation, and the biosynthesis of resolvins and protectins is an area of active interest (El Kebir et al. 2012). The polyunsaturated fatty acids (PUFAs) can be divided into three major families – omega (w)-3, omega(w)-6, and omega(w)-9 fatty acids – based on the location of double bonds. The essential fatty acids consist of the w-6 fatty acids formed from linoleic acid and the w-3 fatty acids formed from alpha-linolenic acid. The intake of PUFAs is especially important for patients with ARDS because fats of the n-6 and n-3 group affect specific and nonspecific immune and inflammatory functions via products from arachidonic acid metabolism. The two families of dietary PUFAs (w-6 and w-3) are desaturated and elongated by the same enzymes. The ratelimiting factor in the conversion of linoleic acid to arachidonic acid is the enzyme delta-6desaturase. This enzyme is sensitive to feedback inhibition and to competitive inhibition by other PUFAs such as the n-3 fatty acids. Delta-6desaturase, with the aid of delta-5-desaturase, regulates the metabolism of linoleic acid to GLA and arachidonic acid and of alpha-linolenic acid to EPA, with each having metabolites that cause different immune responses. Therefore, delta-6desaturase is of major importance in the regulation of immune and inflammatory function. Arachidonic acid is the major precursor of the eicosanoids (prostanoids and leukotrienes). Eicosanoids are fatty acid metabolites that are synthesized via either a cyclooxygenase or 5-lipoxygenase enzyme system. Arachidonic acid metabolism via the cyclooxygenase pathway leads to the production of the proinflammatory mediators such as thromboxane A2, prostaglandin E2, and prostacyclin I2. Arachidonic acid metabolism via the 5-lipoxygenase pathway mediates the release of leukotrienes (LT). Leukotrienes, specifically LTB4, are potent neutrophil chemotactic factors and also potentiate the respiratory burst and increase cell adhesion processes. The use of diets high in n-3 fatty acids is a means to decrease levels of arachidonic acid in

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cells, thereby reducing the production of proinflammatory eicosanoids. For example, the incorporation of n-3 fatty acids (EPA) into cell phospholipids could lead to the production of metabolites with less inflammatory activity than those formed from arachidonic acid. The n-3 fatty acids could compete directly with arachidonic acid as substrates or for enzymes (e.g., delta-6desaturase) that catalyze the lipoxygenase and cyclooxygenase pathways. Another way to manipulate the inflammatory response by diet is by supplementation with GLA. A common misconception is that the n-6 fatty acid linoleic acid is rapidly converted to intermediates GLA, dihomo-gamma-linolenic acid (DGLA), and arachidonic acid. In fact, desaturation by delta-6desaturase occurs with difficulty and seems to be rate limited by precursor or product inhibition. Furthermore, metabolic stress, major surgery, and medical disorders also inhibit conversion. GLA is elongated to DGLA, which competes with arachidonic acid for cyclooxygenase binding sites and serves as the precursor of prostaglandins such as PGE1, which have anti-inflammatory properties. DGLA also can be converted to a 15-hydroperoxy derivative that inhibits the conversion of arachidonic acid to the undesirable 4-series of leukotrienes. The supplementation with both GLA and DGLA suppresses acute and chronic inflammation. Thus, dietary supplementation with GLA modulates inflammatory status like the n-3 fatty acids because of its ability to reduce the synthesis of the proinflammatory mediators derived from arachidonic acid metabolism. Patients with ALI and ARDS have lower circulating antioxidant levels than healthy individuals. During ALI/RDS, the oxidative stress produced from mechanical ventilation and free radical production formed by infiltrating neutrophils can overwhelm circulating antioxidant levels and allow oxygen free radicals to directly damage cellular and tissue structures. Thus, in cases of increased oxidative stress, patients must be supplemented with antioxidants at levels above those recommended to meet the needs of healthy adults because these levels do not reflect nutrient needs in disease.

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Manipulating Eicosanoid Synthesis in Patients with ALI/RDS As has been indicated, ALI/RDS is an inflammatory process with alveolar and vascular endothelial injury in the lung. Neutrophil activation plays a crucial role in the pathogenesis. When activated, it releases harmful mediators including proteases, cytokines, and others that lead to progressive lung damage. An intense inflammatory response within the alveolar spaces, with the accumulation of proinflammatory and anti-inflammatory cytokines, characterizes the ALI/ARDS. The fact that inflammatory mediator production can be modified by lipids has been the basis for investigation about dietary manipulation in ALI/RDS. Animal models have been investigated to analyze the relation between fat intake and inflammation in lung injury. In an experimental model of ARDS, rats treated with a diet rich in EPA and GLA can modulate the production of inflammatory mediators and improve lung function (Palombo et al. 1996). Another rat model of lung injury (Mancuso et al. 1997) investigated the production of several inflammatory mediators after a diet enriched in fish oil, fish, and borage oil or control diet. Animals that receive fish oil diets have a lower pulmonary synthesis of proinflammatory eicosanoids and cytokines after endotoxin injection as demonstrated in lower levels of leukotriene B4, leukotriene C4/D4, and thromboxane B2 in bronchoalveolar lavage fluid. Lung myeloperoxidase activity, a marker for neutrophil accumulation, was significantly lower with fish oil diets. Recent investigations are directed to analyze the importance of the resolvin pathway in healing of lung injury and the possible effect of dietary lipids in this mechanism. Resolvin E1 (RvE1), an endogenous lipid mediator derived from EPA, has been shown to promote lung healing via neutrophil apoptosis and their removal by macrophages in “in vitro” or “in vivo” animal models (El Kebir et al. 2012). Resolvin-mediated resolution of inflammation seems to be an important mechanism in lung tissue healing after ALI/ARDS. The clinical relevance of dietary manipulation of RvE1 by increasing EPA in the diet is, at present, not known.

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The release of pro- and anti-inflammatory cytokines from human alveolar cells after endotoxin challenge in several w3/w6 conditions has been investigated (Cotogni et al. 2011). These authors demonstrate that omega-3 PUFAs are associated with a decrease in the release of proinflammatory mediators in the cellular culture model. In the clinical scenario, several authors have investigated the effect of w3–w6 administration in patients with ALI/ARDS. Investigations have been done mainly by increasing EPA and GLA in the enteral formula administered to these patients. In general, these investigations indicate that an increase in the EPA/GLA administration with enteral nutrition results in better outcomes; a decrease in infectious complications and a lower mortality have been described in these studies. As a result of these investigations, dietary manipulation to increase EPA/GLA administration to critically ill patients with ALI/ARDS has been considered beneficial in these patients. Gadek et al. (1999) recruited 146 patients with ARDS in a randomized, multicenter, prospective, and double-blind study. Compared with control, patients treated with a low-carbohydrate/highlipid diet enriched in EPA/GLA had a significant improvement in oxygenation parameters and also in mechanical ventilation needs during the study (FiO2, positive end-expiratory pressure (PEEP), minute ventilation, and days on mechanical ventilation). The number of patients who developed a new organ failure during the study was also lesser in the study group. It is interesting to note that, to confirm the hypothesis that EPA/GLA can modulate inflammation, the authors investigate total cell count and neutrophils in bronchoalveolar lavage (BAL) fluid; the number of cells was significantly decreased in patients that received the study diet. This group of investigators published later more information (Pacht et al. 2003) about inflammatory mediators in BAL fluid in a group of 43 patients included in their previous study. Mediators like IL-8 and ceruloplasmin and markers of alveolar protein permeability were reduced in patients treated with the EPA/GLA diet. Another similar one-center study also compares an EPA-GLA-enriched diet with an isocaloric and

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isonitrogenous control diet in 95 patients with ALI (Singer et al. 2006). Their results indicate also a significant improvement in oxygenation and pulmonary compliance and a decrease in length of mechanical ventilation in patients treated with EPA-GLA diet. Authors speculate that the cause of the appreciated beneficial effects must be related with an EPA-GLA-induced decrease in the synthesis of interleukin-8 and leukotriene B4, thereby reducing the inflammatory process in the lung. Nevertheless, no investigation about inflammatory components in BAL fluid or in blood was performed in the study. Various inflammatory mediators that reflect lung injury in ALI/RDS have been investigated as potential biomarkers to diagnosis and outcome prediction. These include IL-6, IL-8, tumor necrosis factor receptor-1 (TNFR-1), von Willebrand factor (VWF), surfactant protein D (SP-D), intercellular adhesion molecule-1 (ICAM-1), protein C, and plasminogen activator inhibitor-1 (PAI-1). As indicated, only few studies with enteral feeding diets enriched in EPA/GLA have been done to analyze the effect of this dietary fat modification on these mediators. The effect of EPA-GLA-enriched diet has also been investigated in another clinical scenario: patients with sepsis and ALI/ARDS. In this situation, the enriched diet with an isonitrogenous and isocaloric diet in a group of 165 patients was compared (Pontes-Arruda et al. 2006). As in previous works, their results indicate also an increase in oxygenation parameters and in the ventilatorfree days in the study group. Mortality and development of new organ failures were also decreased in the group of patients that receive the EPA-GLAenriched diet. The authors did not investigate inflammatory mediators in their patients. In their opinion, the clinical benefit must be related with diet components. Also in patients with sepsis and ALI/RDS, a group of Spanish investigators performed a study comparing enteral nutrition with a modified diet (enriched in EPA/GLA) with a control diet. They performed a multicenter study that includes 198 patients. In the “per protocol” analysis (Moran et al. 2006), results indicate a decrease in infectious complications and in ICU stay in the

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patient that receives the study diet. Nevertheless, in the “intention to treat” analysis for the same study (Grau-Carmona et al. 2011) the effect on length of stay was the unique statistically significant result. Inflammatory mediators were not investigated in this study. Beneficial effect was attributed to the physiological hypothesis that relates EPA-GLA with less proinflammatory eicosanoids. The abovementioned studies have used EPA/GLA administration in the setting of full nutrition provision. The positive results that, in general, have been appreciated in these studies are in contrast with the negative results appreciated in other recent trials when the fatty acid supplements were administered independently of complete nutrition provision. In 2011 the OMEGA study was published, a multicenter and randomized study that compares omega-3, GLA, and antioxidant supplement with an isocaloric control diet in 272 ALI patients (Rice et al. 2011). Diet supplements were administered twice daily separately from the enteral nutrition. The main outcome of the study, ventilator-free days to study day 28, was better for patients in the control group. Also, other clinical variables (intensive care unit-free days and non-pulmonary organ failure-free days) were better in the control group. The authors conclude that w-3, GLA, and antioxidant supplements could be harmful in ALI patients. Nevertheless, as indicated by the authors, the study design (twice-daily bolus administration of fat supplement independently of nutrition administration) was selected to facilitate inclusion of patients unable to tolerate full feeding. This is in contrast with clinical practice and would have conditioned the study results. It is of note that the authors investigate the plasma levels of fatty acids and inflammatory mediators in some patients. Levels of EPA were significantly increased in the study group but levels of w-6 (arachidonic acid, leukotriene E4)- or w-3 (leukotriene E5)-derived mediators or IL-6 and IL-8 were similar in both groups during the study. The authors did not report an explanation for this finding. Also a new controlled study in patients with ALI was performed, evaluating the effect of the

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administration of enteral omega-3 supplements also dissociated from the enteral feeding (Stapleton et al. 2011). The primary end point was the modification of IL-8 levels in bronchoalveolar lavage fluid. Results indicate that levels of IL-8 in alveolar fluid were similar in the study and control groups. Clinical variables (organ failure score, ventilatorfree days, intensive care unit-free days, and 60-day mortality) were similar in both groups. The authors conclude that a fish oil supplement does not reduce biomarkers of inflammation in ALI patients. Some studies have been done with parenteral fish oil supplementation in patients with ALI/ARDS. Nevertheless, in contrast to enteral EPA/GLA administration, no randomized controlled clinical trials using w-3-enriched parenteral lipid emulsions have shown clear evidence of beneficial effects on clinical end points in ALI/RDS patients. Sabater et al. (2011), in a small number of critically ill patients with ARDS and indication for parenteral nutrition, compared the effect of an omega-3-enriched lipid infusion with a soybeanbased emulsion. Inflammatory mediators LTB4, TXB2, and 6-keto prostaglandin F1a were reduced in patients treated with omega-3 lipid infusion. In a previous publication, authors reported that there were no effects on pulmonary variables in the study patients. Finally a randomized study comparing control enteral diet versus diet supplemented with parenteral fish oil emulsion during 14 days was also published. According to their results there were no effects of w-3 infusion on oxygenation or outcome variables. The authors speculate about the causes of the absence of positive effect (low w-3 dose, need for combination with other lipids, or inadequacy of parenteral administration). No investigation about inflammatory mediators was done in the study (Gupta et al. 2011). Investigations about inflammatory mediators in BAL fluid are a good support for the hypothesis that implies EPA/GLA intake with inflammatory regulation in patients with ALI/RDS. Nevertheless, investigations in this field are very limited. Modification of plasma levels of inflammatory biomarkers after diet manipulation has been investigated also in a very few works.

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Clinical investigations have been the main argument favoring the use of EPA-GLA-modified diets in patients with ALI/RDS. Measurement of various proinflammatory and anti-inflammatory bioactive molecules would have given an indication of the products generated during the different stages of the illness and how supplementation of EPA/GLA altered their concentrations and influenced the outcome. These investigations will be of great value to better indicate EPA/GLA supplementation in patients with ALI/RDS in the future.

• •

• •

Applications to Other Conditions The potential benefit of adding w-3 to enteral nutrition in critically ill septic patients shows non-conclusive results because it is based on studies with diets of different compositions from other substrates, different amounts and percentages of w-3, and different comparative agents. Beneficial effects have been reported in terms of mortality, days on mechanical ventilation, and days of stay at ICUs with the administration of a diet rich in EPA, GLA, and antioxidants, while in other studies, with the same diet, these results could not be confirmed and only reported a reduction in the incidence of nosocomial pneumonia and organ dysfunction (Ortiz et al. 2011).

Guidelines and Protocols Current guidelines from different scientific societies (ESPEN, SCCM-ASPEN, SEMICYUC-SENPE, etc.) strongly recommend the use of enteral diets rich in EPA, GLA, and antioxidants in the management of RDS.

Summary Points • Eicosanoids control both proinflammatory and anti-inflammatory effectors that are particularly relevant for inflammation. • The lung is an important organ in the arachidonate cascade since it possesses the enzymatic capacity to synthesize all the arachidonate

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derivatives and also responsible in large part for selective catabolism of circulating eicosanoids. The generation of arachidonate metabolites can play a role in the development of ALI/RDS. The use of diets high in w-3 fatty acids is a means to decrease levels of arachidonic acid in cells, thereby reducing the production of proinflammatory eicosanoids. Clinical investigation with enteral diets enriched in EPA/GLA and antioxidants shows beneficial effect in patients with ALI/ARDS. Investigation with bolus omega-3 supplements dissociated from the nutritional regimen does not report beneficial effects in patients with ALI/ARDS.

References Amat B, Barcons M, Mancebo J, et al. Evolution of leukotriene B4, peptide leukotrienes, and interleukin-8plasma concentrations in patients at risk of acute respiratory distress syndrome and with acute respiratory distress syndrome: mortality prognostic study. Crit Care Med. 2000;28:57–62. Anas A, van der Poll T, de Vos AE. Role of CD14 in lung inflammation and infection. In: Vincent JL, editor. Annual update in intensive care and emergency medicine. Berlin: Springer; 2010. p. 129–40. Bannenberg GL, Chiang N, Ariel A, et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;174:4345–55. Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive Care Med. 2000;26:S64–74. Calder PN. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids. 2003;38:343–52. Cotogni P, Muzio G, Trombetta A, et al. Impact of the omega-3to omega-6 polyunsaturated fatty acid ratio on cytokine release in human alveolar cells. J Parenter Enteral Nutr. 2011;35:114–21. El Kebir D, Gjorstrup P, Filep JG. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc Natl Acad Sci U S A. 2012;109:14983–8. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gammalinolenic acid and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med. 1999;27:1409–20. Grau-Carmona T, Morán-García V, García-de-Lorenzo A, et al. Effect of an enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid and antioxidants on the outcome of mechanically ventilated, critically ill, septic patients. Clin Nutr. 2011;30:578–84.

74 Gupta A, Govil D, Bhatnagar S, et al. Efficacy and safety of parenteral omega 3 fatty acids in ventilated patients with acute lung injury. Indian J Crit Care Med. 2011;15:108–13. Heller A, Koch T, Schmeck J, van Ackern K. Lipid mediators in inflammatory disorders. Drugs. 1998;55:487–96. Leeman M, Boeynaems JM. Role of eicosanoids in the development of ARDS. In: Vincent JL, editor. Intensive care and emergency medicine. Berlin: Springer; 1984. p. 14–6. Lorente JA, Esteban A. Biomarkers of acute lung injury. In: Vincent JL, editor. Annual update in intensive care and emergency medicine. Berlin: Springer; 2012. p. 160–70. 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;25:1198–206. Masclan JR, Bermejo B, Picó M, et al. Prognostic value of eocosanoids in the acute respiratory distress syndrome. Med Clin (Barc). 1999;112:81–4. Mayer K, Schafer MB, Seeger W. Fish oil in the critically ill: from experimental to clinical data. Curr Opin Clin Nutr Metab Care. 2006;9:140–8. Moran V, Grau T, García de Lorenzo A, et al. Effect of an enteral feeding with eicosapentaenoic and gammalinoleic acids on the outcome of mechanically ventilated critically ill septic patients. Crit Care Med. 2006;34(12 Abstract Supplement):A70. Ortiz C, Montejo JC, Vaquerizo C. Guidelines for specialized nutritional and metabolic support in the criticallyill patient. Update. Consensus SEMICYUC-SENPE: Septic patient. Nutr Hosp. 2011;26(S2):67–71. Pacht ER, DeMichele SJ, Nelson JL, et al. Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid and antioxidants reduces alveolar inflammatory mediators and protein influx in patients with acute respiratory distress syndrome. Crit Care Med. 2003;31:491–500. Palombo JD, DeMichele SJ, Lydon E, et al. Rapid modulation of lung and liver macrophage phospholipids fatty acids in endotoxemic rats by continuous enteral feeding

A. Garcia-de-Lorenzo y Mateos et al. with n-3 and gamma-linolenic fatty acids. Am J Clin Nutr. 1996;63:208–19. Pontes-Arruda A, DeMichele SJ. Enteral nutrition with anti-inflammatory lipids in ALI/ARDS. In: Vincent JL, editor. Annual update in intensive care and emergency medicine. Berlin: Springer; 2009. p. 695–704. Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gammalinolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006;34:2325–33. Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306:1574–81. Rivkind AI, Siegel JH, Guadalupi P, Littleton M. Sequential patterns of eicosanoid, platelet, and neutrophil interaction in the evolution of the fulminant post-traumatic adult respiratory distress syndrome. Ann Surg. 1989;210:355–72. Sabater J, Masclans JR, Sacanell J, et al. Effects of anomega-3 fatty acid-enriched lipid emulsion on eicosanoid synthesis in acute respiratory distress syndrome (ARDS): a prospective, randomized, double-blind, parallel group study. Nutr Metab (Lond). 2011;8:22. Serhan CN. Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins. Curr Opin Clin Nutr Metab Care. 2005;8:115–21. Serhan CN, Chiang N, van Dyke E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8:349–61. Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and gammalinolenic acid in ventilated patients with acute lung injury. Crit Care Med. 2006;34:1033–8. Stapleton RD, Martin TR, Weiss NS, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Crit Care Med. 2011;39:1655–62.

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Muscle Weakness, Molecular Mechanism and Nutrition During Critical Illness Ilse Vanhorebeek

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Pathways of Muscle Breakdown . . . . . . . . . . . . . . . . . . . . Muscle Architecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Ubiquitin-Proteasome Pathway . . . . . . . . . . . . . . . . . . Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Applications to Critical or Intensive Care . . . . . . . . . Muscle Atrophy and Classical Proteolytic Systems During Critical Illness . . . . . . . . . . . . . . . . . . . . . . . Quality Control and Autophagy in the Muscle During Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . Nutrition and Mechanisms of Muscle Weakness During Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Applications to Other Conditions . . . . . . . . . . . . . . . . . . 86 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

I. Vanhorebeek (*) Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_29

Muscle weakness develops in a substantial proportion of critically ill patients. The consequences are severe, as illustrated by a prolonged dependency on mechanical ventilation and intensive care, impaired rehabilitation, and increased risk of death. Muscle weakness may originate from neurogenic disturbances, myogenic disturbances, or a combination of both. Regarding the myogenic component of muscle weakness, loss of muscle mass or atrophy has classically been put forward as culprit, whereas the importance of muscle quality has long been underappreciated and only recently has gained attention. Muscle atrophy of critical illness develops due to a decreased synthesis and accelerated breakdown of myofibrillar proteins. Several proteolytic systems are activated, including the ubiquitin-proteasome pathway, calpains, and lysosomal proteases. Also excessive activation of autophagy, which is a highly specialized lysosomal degradation pathway with a crucial role in intracellular quality control, has been implicated in the aggravation of muscle loss. Nevertheless, recent studies suggest that impairment of autophagy jeopardizes muscle quality and function and that autophagy may be insufficiently activated during critical illness. Illness-associated anorexia and gastrointestinal dysfunction often lead to a severe caloric deficit, which contributes to muscle atrophy. This raised the hypothesis that preventing the 75

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caloric deficit with intravenous nutrition would attenuate muscle atrophy and weakness. However, such nutritional interventions failed to prevent severe muscle atrophy. Recent studies pinpoint two potential explanations for the lack of success. First, aggravation of hyperglycemia as catabolic factor by intravenous nutrition may counteract any potential benefit of the artificial feeding. Second, preservation of muscle mass with forced nutrition may come at the expense of suppressed autophagy and compromised muscle quality and function. List of Abbreviations

Atg BNIP3

Autophagy-related gene Bcl-2/adenovirus E1B nineteen kilodalton-interacting protein-3 ICU Intensive care unit LAMP-2A Lysosome-associated membrane protein 2A LC3 Microtubule-associated protein light chain-3 mTOR Mammalian target of rapamycin MuRF-1 Muscle-Ring-Finger-1 PE Phosphatidylethanolamine PI3K Phosphatidylinositol-3-kinase ULK1 Unc-51-like kinase VPS Vesicular protein sorting

Introduction Critical illness is hallmarked by the failing of multiple vital organs. Thus, patients need intensive medical care to support organ functions with mechanical and/or pharmacological means. Without such support death would be imminent. The majority of the patients sufficiently recover to be discharged from the intensive care unit within a few days. However, about 30 % of the patients remain dependent on intensive care and enter a phase of prolonged critical illness. They are at high risk of dying. Apart from vital organs such as the kidney and liver, also muscle function is compromised in a substantial fraction of the patients. Such muscle weakness affects respiratory and peripheral muscles and has been associated with prolonged dependency on intensive care, impaired rehabilitation,

and increased risk of death (Latronico and Bolton 2011; De Jonghe et al. 2007). The origin of the muscle weakness may lie in a neurogenic disturbance with axonal degeneration of sensory and motor neurons (critical illness polyneuropathy), a myogenic disturbance that may involve impaired muscle membrane excitability and muscle atrophy (critical illness myopathy), or a combination of both (Latronico and Guarneri 2008). This chapter will focus on molecular alterations at the level of the muscle in relation to muscle weakness and on how this condition is affected by nutritional aspects. The chapter will start from the classical viewpoint that the pronounced loss of muscle mass evoked by the hypercatabolic state that develops in critical illness, especially when prolonged and at least related to inadequate nutrition, is an important culprit. Next, more recent evidence that highlights the importance of maintaining muscle quality versus muscle mass will be discussed.

Pathways of Muscle Breakdown Muscle protein turnover is a continuous process that serves important homeostatic functions in adaptation to changing physiologic conditions and quality control. Overall protein breakdown in muscle is increased in conditions such as starvation as well as several diseases to provide free amino acids for protein synthesis and energy metabolism (Wolfe 2006). Degradation of abnormally folded proteins, irreversibly damaged and potentially toxic proteins, which are prone to form aggregates, protects cellular components from further damage. Two major systems are involved. The ubiquitinproteasome pathway is responsible for the selective degradation of myofibrils and short-lived proteins (Mitch and Goldberg 1996; Glickman and Ciechanover 2002). Autophagy regulates the breakdown of long-lived proteins and organelles (Yang and Klionsky 2010; Kroemer et al. 2010).

Muscle Architecture Muscles contain bundles of fibers, which are composed of myofibrils. Myofibrils are organized

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Fig. 1 Organization of myofibrils in sarcomeres. Sarcomeres are composed of thick and thin filaments. The thick filaments contain myosin and myosin-binding Table 1 Properties of type I and type II myofibers

Contraction velocity Mitochondrial density Oxidative capacity Abundance of glycogen Glycolytic capacity Metabolism Myoglobin Color Force production Resistance to fatigue

in chains of sarcomeres, which contain thick filaments composed of myosin and myosin-binding proteins and thin filaments of actin and regulatory proteins (Fig. 1; Apkon 2003). The myofibrillar proteins myosin and actin form the contractile elements and mediate muscle contraction and relaxation by sliding of the actin filaments over the myosin filaments. Myosin consists of multiple subunits, including 2 myosin-heavy-chain and 4 myosin-light-chain subunits. The functional properties of the myosin-heavy-chain isoforms determine the classification of myofibers in different types. Type I myofibers have a slow contraction velocity (slow-twitch fibers). They are rich in myoglobin and mitochondria, thus allowing a high oxidative metabolism, higher resistance to fatigue, and longer endurance. Type II myofibers have a fast contraction velocity (fast twitch) but contain less myoglobin and mitochondria, which makes them more susceptible to fatigue, especially the glycolytic type IIb myofibers (Table 1).

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proteins and the thin filaments contain actin and the regulatory proteins troponin and tropomyosin. Also shown are the actin-binding proteins nebulin and titin

Type I Slow twitch High High Low Low Oxidative High Red Low High

Type IIa Fast twitch High High High High Oxidative/glycolytic High Red Intermediate Intermediate

Type IIb Fast twitch Low Low High High Glycolytic Low White High Low

The Ubiquitin-Proteasome Pathway Proteins to be degraded by the ubiquitinproteasome system are first marked for degradation by a multistep process in which a chain of several ubiquitin molecules is attached to the protein before they can be recognized by the proteasome (Fig. 2; Mitch and Goldberg 1996; Glickman and Ciechanover 2002). Ubiquitin is a strongly conserved polypeptide of 76 amino acids. Attachment of an ubiquitin molecule to the target protein requires a three-step enzymatic process. First, the ubiquitin-activating enzyme E1 activates ubiquitin. In the second step, the ubiquitin molecule is transferred to the active site of a ubiquitinconjugating E2 enzyme. In the third step, the target protein is recognized by an E3 ubiquitin ligase that also binds the E2 enzyme, after which the activated ubiquitin is transferred to the target protein. There is only one E1 enzyme, there are a few dozens of E2 enzymes, but there are more than 1,000 E3 enzymes.

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Fig. 2 The ubiquitin-proteasome pathway. A chain of at least four ubiquitin molecules needs to be attached to the target protein before the 26S proteasome can recognize it. This requires repeated cycles of a three-step process involving the ubiquitin-activating E1 enzyme, a ubiquitin-conjugating E2 enzyme, and an E3 ubiquitin ligase. The tagged protein is recognized and cleaved into short peptides by the 20S proteasome. ub ubiquitin

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The latter are determinant for the selectivity of the system. For instance, Muscle-Ring-Finger-1 (MuRF-1) and atrogin-1 are muscle-specific E3 ligases (Lecker 2003). The myosin heavy chains and actin are substrates of MuRF-1. MyoD and IF3-f, both involved in the control of protein synthesis, are the only atrogin-1 substrates known so far (Attaix and Baracos 2010). This suggests that atrogin-1 affects protein synthesis, rather than proteolysis. The three-step process is repeated several times. This elongation process may require a fourth enzyme or ubiquitin-ubiquitin ligase E4 (Glickman and Ciechanover 2002). A chain of at least four ubiquitin molecules needs to be attached before the 26S proteasome can recognize and degrade the target protein. The two 19S complexes of the 26S proteasome recognize and bind the polyubiquitinated proteins, after which they are unfolded and deubiquitinated (Glickman and Ciechanover 2002). The released ubiquitin molecules are recycled. The unfolded protein is cleaved into short peptides by the 20S proteasome. This barrel-shaped multi-subunit structure contains several proteolytic activities (Kisselev et al. 1999). Proteins containing only one or two ubiquitin molecules are degraded in the lysosomes, which harbor several cathepsin proteases in an acidic environment, each with their own substrate specificity (Mason 1996). Skeletal muscle cells contain very few lysosomes under normal circumstances. However, lysosomal proteolytic activity is enhanced in a wide array of pathological conditions, and cathepsin L in particular is recognized as a general marker of muscle atrophy (Deval et al. 2001). Also other proteases have been implicated in muscle breakdown. Moreover, the ubiquitinproteasome pathway cannot degrade intact myofibrils. Indeed, myosin and actin first need to be released from the sarcomere, for which several candidate proteases have been put forward (Williams et al. 1999; Du et al. 2004). Some studies support the importance of the non-lysosomal, Ca2+-dependent calpains (Bartoli and Richard 2005). These proteases disrupt the structural integrity of the sarcomere by degradation of titin and nebulin, whereby myosin and actin are passively released (Williams et al. 1999). Other

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Initiation

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organelle, cytoplasm

phagophore (isolation membrane) Atg3

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Atg12 Atg5

Atg16 Atg16

Atg7 Atg12

Atg12

Atg12

Atg10

Atg7

Atg7

Atg5

Atg10

Fig. 3 The different phases of autophagy. Autophagy starts with the formation of a phagophore or isolation membrane in the initiation phase, which grows in the elongation phase. Two ubiquitin-like conjugation systems, responsible for lipidation of LC3 and formation of an Atg5-Atg12-Atg16 multimeric complex, are involved in the elongation of the phagophore. This phase ends with the formation of an autophagosome which completely

sequesters the material to be degraded. In the last phase or maturation phase, the autophagosome fuses with a lysosome with formation of an autolysosome, which contains all the enzymes needed to degrade the sequestered content. Atg autophagy-related gene, LC3 microtubule-associated protein light chain-3, PI3K phosphatidylinositol-3-kinase, PE phosphatidylethanolamine

studies rather highlight a role for caspase-3 as initiator of protein degradation, via cleavage of actomyosin and actin (Du et al. 2004). Also, the calpains and caspases may interact and as such affect each other’s activity.

lysosome. In macroautophagy, further referred to as autophagy, the substrates are encircled by a double-membrane structure that subsequently fuses with a lysosome. Although autophagy was first discovered in mammals, the different steps in this pathway were largely unraveled via studies in yeast, which identified several autophagy-related genes (Yang and Klionsky 2010). In yeast, these are denoted as “Atg” genes. Several homologues have been found in mammals. Induction of autophagy is mediated via activation of Atg1, which is called Unc-51-like kinase (ULK1) in mammals. This triggers a cascade of reactions needed for initiation, elongation, and maturation of autophagic vacuoles (Fig. 3; Kroemer et al. 2010). In the initiation phase, a so-called phagophore or isolation membrane is formed nearby the substrates that are to be degraded. This requires activation of the class 3 phosphatidylinositol-3-kinase “vesicular protein sorting 34” (VPS34). The activation of VPS34 is mediated by a complex of several autophagy-related

Autophagy Autophagy is a process in which cells degrade parts of their own cytosol and organelles in lysosomes and is strongly conserved throughout evolution. Based on how the cytoplasmic content is delivered to the lysosomes, three types of autophagy can be discerned (Martinet et al. 2009). In microautophagy, cytosolic components are taken up into the lysosome directly, through invagination of the lysosomal membrane. In chaperonemediated autophagy, the substrate contains a specific amino acid motif that is recognized by chaperones. The chaperones bind to the lysosome-associated membrane protein 2A (LAMP-2A) and hereby deliver the protein to the

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proteins, including Atg6 (Beclin-1 in mammals), Atg14, and VPS15. In the elongation phase, the phagophore grows, ending with the formation of a double-membrane vesicular structure called autophagosome. Two ubiquitin-like conjugation systems are involved in this elongation process (Fig. 3). In the first system, the E1-like protein Atg7 activates the ubiquitin-like Atg12. Atg12 is transferred to the E2-like protein Atg10 and then covalently bound to Atg5. This is followed by interaction of Atg16 with the Atg12-Atg5 complex and formation of a multimeric complex. In the second system, Atg4 cleaves the carboxyterminus from Atg8 (microtubule-associated protein light chain-3 or LC3 in mammals). Atg7 and the E2-like enzyme Atg3 add a phosphatidylethanolamine group onto LC3. This lipidated form of LC3 (LC3-II) is translocated to and supports growth of the autophagosomal membranes until closure and complete sequestration of the cytoplasmic content to be degraded in the autophagosome. In the maturation phase, the autophagosome fuses with a lysosome to form an autolysosome. This compartment contains all the enzymes needed for the degradation of the sequestered content. Also the inner membrane of the autophagosome is degraded, together with the incorporated LC3-II. For a long time, it was thought that autophagy is nonselective and primarily an adaptive response to starvation, as bulk degradation of cytoplasmic material provides essential substrates in times of nutrient deprivation (Singh and Cuervo 2011; Sachdeva and Thompson 2008). Indeed, the released amino acids can be used for energy provision and synthesis of new proteins. It is becoming increasingly clear, however, that autophagy is involved in a plethora of other physiological and pathophysiological processes (Sachdeva and Thompson 2008; Eskelinen and Saftig 2009). This is underscored by the severe phenotypes that develop after genetic inactivation of autophagy in mice, which leads to cellular accumulation of abnormal ubiquitinated proteins, protein aggregates, and damaged organelles (Komatsu et al. 2005; Masiero et al. 2009). Hence, autophagy serves a crucial housekeeping function in safeguarding cellular homeostasis via

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intracellular quality control and constitutive turnover of cytoplasmic content. This also points to the existence of selective autophagy to remove such toxic protein aggregates and damaged organelles (Fig. 4). The mechanisms of selective recognition of autophagic substrates are complex. Increasing evidence pinpoints ubiquitin and p62 as key players (Komatsu and Ichimura 2010). The cytoplasmic protein p62 can bind ubiquitin and LC3, enabling recruitment to the autophagosome of ubiquitin-tagged substrates such as proteins, organelles, or invaded bacteria. As p62 is degraded in this process, it is frequently used as marker of autophagic activity. As such, p62 accumulates with inadequate functioning of autophagy, which can directly induce cellular stress and disease (Komatsu et al. 2007). For mitochondrial autophagy or “mitophagy” in particular, the proteins Parkin and Bcl-2/adenovirus E1B nineteen kilodalton-interacting protein-3 (BNIP3) are important (Youle and Narendra 2011). As pointed out, autophagy is activated in response to nutrient deprivation (Singh and Cuervo 2011; Sachdeva and Thompson 2008). In fact, fasting is the most powerful physiological activator of the pathway. This implies that the administration of nutrients is a powerful physiological suppressor of autophagy (He and Klionsky 2009). Also insulin and other growth factors powerfully inhibit autophagy (He and Klionsky 2009). A central downstream signaling control point is the kinase mammalian target of rapamycin (mTOR).

Applications to Critical or Intensive Care When reviewing the literature on muscle weakness during critical illness, the emphasis on muscle atrophy as culprit is remarkable. As such, it has been described that critically ill patients can lose even more than 10 % of their muscle mass within one week (Hasselgren and Fischer 2001). At the histological level, the loss of muscle mass is reflected in a shift toward smaller myofibers as compared with elective surgery patients or healthy volunteers (Derde et al. 2012a). Sequential biopsies of critically ill patients showed a 3–4 % reduction per day

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Fig. 4 Nonselective and selective autophagy. Although autophagy was originally thought to be a nonselective pathway for bulk degradation of cytoplasmic material during starvation, it is becoming increasingly clear that the process can be highly selective to fulfill intracellular quality control and safeguard cellular homeostasis by removal of toxic protein aggregates and damaged organelles. The proteins Parkin and Bcl-2/ adenovirus E1B nineteen kilodalton-interacting protein-3 (BNIP3) are involved in mitochondrial autophagy. The cytoplasmic protein p62, which contains a binding site for ubiquitin and microtubule-associated protein light chain-3 (LC3), is involved in the recruitment of ubiquitintagged substrates (proteins, organelles, or invaded bacteria) to the autophagosome

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µb µb µb µb

s

p62

Parkin

BNIP3 ?

µb µb µb µb

s

p62 LC3

LC3

S p62 IC3

S p62 IC3

Selective autophagy

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LC3-II Atg5-Atg12-Atg16 µb µb µb µb

s ubiquitinated substrate

in ICU in the cross-sectional area of type I and type II myofibers (Helliwell et al. 1998). The quality aspect of the muscle tissue received much less attention. Though, recent data stress its

importance. Indeed, severe morphological abnormalities develop at the level of the muscle of critically ill patients. As compared with noncritically ill volunteers, a substantially higher

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Fig. 5 Severe morphological abnormalities in the skeletal muscle of critically ill patients. Illustrative images are shown for signs of inflammation and necrosis, for

remarkable presence of adipocytes and connective tissue, and for myofiber vacuolization after hematoxylin-eosin staining

proportion of the critically ill patients shows signs of inflammation or necrosis (Derde et al. 2012a), a remarkable presence of adipocytes and connective tissue (Derde et al. 2012a), as well as myofiber vacuolization (Vanhorebeek et al. 2011; Fig. 5).

Muscle Atrophy and Classical Proteolytic Systems During Critical Illness When the muscle atrophies, this is due to an imbalance between the synthesis and degradation

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of muscle proteins. During critical illness both processes contribute. A decreased myofibrillar protein synthesis capacity is suggested by the strongly reduced levels of the mRNAs encoding these proteins, even more pronounced for myosin than for actin (Larsson 2008). In a large cohort of more than 200 patients who had a muscle biopsy taken on median day 10–15 of critical illness, transcript levels for the myosin heavy chains and actin were 70–95 % lower than in demographically matched healthy volunteers (Derde et al. 2012a). During critical illness, protein breakdown is enhanced in multiple organs to ensure the supply of essential amino acids for synthesis of specific proteins and to support energy metabolism (Reid et al. 2004). The muscle, as the largest protein reservoir in the body, is the most strongly affected. Most studies that showed an activation of proteolytic systems during critical illness focused on the ubiquitin-proteasome pathway, calpains, and lysosomal proteases. The expression of several enzymes involved in protein ubiquitination and several subunits of the proteasome is induced in critical illness, with the most consistent increases in E214k, atrogin-1, MuRF-1, and proteasome subunit C2 (Reid et al. 2004; Lang et al. 2007; Mansoor et al. 1996). As increased gene expression of MuRF-1 and atrogin-1 has been shown to correlate with activity of the ubiquitin-proteasome pathway and rate of muscle breakdown, both are widely used as specific markers of ubiquitinproteasome pathway activity during muscle atrophy (Mansoor et al. 1996; Voisin et al. 1996). However, such increases in gene expression appear to be transient, as shown in burn-injured rats and immobilized healthy human individuals (Lang et al. 2007; de Boer et al. 2007). On median day 10–15 of critical illness, patients also had mRNA levels of MuRF-1 and atrogin-1 that were comparable with noncritically ill volunteers (Derde et al. 2012a). However, the activity of the 20S proteasome as catalytic core of the 26S proteasome is clearly elevated in the early and prolonged phase of critical illness (Derde et al. 2012a; Klaude et al. 2007). The calpains show different responses in conditions of muscle atrophy, with increased expression of calpain-1

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and calpain-2 and decreased expression of calpain-3 (Fareed et al. 2006). In an animal model of sepsis, muscle protein breakdown was attenuated when a calpain inhibitor was administered (Bartoli and Richard 2005). This supports the involvement of calpains in the muscle wasting of critical illness. Likewise, several lysosomal cathepsins increase in critical illness, but a consistent response has only been observed for cathepsin L, with increased expression and activity as well as attenuation of protein breakdown upon inhibition of the enzyme (Deval et al. 2001; Derde et al. 2012a). Overall, it appears that the disturbed balance between synthesis and degradation appears to more strongly affect myosin than actin, which is illustrated by a decrease in the myosin/actin protein ratio (Derde et al. 2012a). Consequently, the optimal stoichiometry for the force-generating interaction between myosin and actin is disturbed (Ochala and Larsson 2008). Actually, a pronounced drop in the myosin/actin ratio has been suggested as a valuable diagnostic tool in the identification of critical illness myopathy (Larsson et al. 2000).

Quality Control and Autophagy in the Muscle During Critical Illness Whereas the role of the ubiquitin-proteasome pathway in muscle atrophy is well established, any potential involvement of the autophagic pathway is much less clear and actually has been considered only recently. The first in vivo studies on this subject were performed in mouse models and suggested that excessive activation of autophagy amplifies muscle loss (Zhao et al. 2007). However, the same team subsequently showed a spontaneous induction of atrophy as well as a phenotype of myopathy upon genetic inactivation of autophagy in skeletal muscle of healthy mice (Masiero et al. 2009). Myofibers decreased in size, showed degenerative changes such as vacuolization and the presence of centrally located nuclei, and accumulated p62 protein and p62-positive aggregates. These abnormalities coincided with a remarkable reduction in muscle force.

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Thus, basal autophagic flux is crucially important for preservation of muscle mass and myofiber integrity. Interestingly, in catabolic models of fasting and denervation, loss of muscle mass and signs of myofiber degeneration were exacerbated in autophagy-deficient as compared with wild-type mice (Masiero et al. 2009), unlike what would have been expected from the initial observations. Data on autophagy in skeletal muscle during critical illness are scarce, but interest is increasing. In the diaphragm of mechanically ventilated patients, an increase in the number of autophagosomes was observed, together with an elevated expression of several autophagy-related genes (Hussain et al. 2010). This was interpreted as a disuse-induced increase in autophagy. Nevertheless, with the investigated markers the study did not assess whether autophagy was sufficiently activated to clear the illness-evoked damage. A subsequent report on skeletal muscle biopsies from a heterogeneous cohort of prolonged critically ill patients was strongly suggestive of insufficient activation of autophagy (Vanhorebeek et al. 2011). Despite increased expression of proteins involved in the initiation and elongation phases of autophagy, the biopsies showed a phenotype as observed in the muscle of autophagydeficient mice. In particular, specific autophagic substrates (especially p62) strongly accumulated and the percentage of vacuolated myofibers was doubled. Several animal studies observed signs of impaired autophagy in muscle several days after severe insults such as sepsis and denervation (Banduseela et al. 2013; Quy et al. 2013), whereas there may be an acute upregulation of autophagy in the first 12–24 h after lipopolysaccharide administration or in the first few days after severe burn injury (Schakman et al. 2012; Hosokawa et al. 2013).

Nutrition and Mechanisms of Muscle Weakness During Critical Illness Critically ill patients develop a state of hypercatabolism irrespective of the primary reason for which they had been admitted to the ICU. Especially when prolonged, the hypercatabolism

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will lead to pronounced loss of muscle mass. Several factors may contribute, including inflammation (which can also directly impair muscle function (Reid and Moylan 2011)), endocrine stress responses (Vanhorebeek and Van den Berghe 2004), and inadequate nutrition (Debaveye and Van den Berghe 2006). The latter is classically considered an important culprit. Due to the frequent gastrointestinal tract dysfunction, enteral nutrition most often cannot fulfill the nutritional requirements, hence leading to a nutritional deficit and negative nitrogen balance that rapidly accumulate early in the disease course (Debaveye and Van den Berghe 2006). Ensuring uptake of the administered nutrients via intravenous nutrition emerged as promising strategy to counteract the hypercatabolism and to improve patient outcome. However, aggressive nutritional support that was assumed to be adequate was not able to prevent the loss of substantial amounts of body protein during critical illness (Wilmore 1991). In that regard, mechanically ventilated patients recovering from septic shock still lost about 12.5 % of body protein but gained fat mass with such aggressive nutritional support (Streat et al. 1987). Patients with sepsis appear particularly vulnerable to high protein breakdown (Shaw and Holdaway 1988). Furthermore, intravenous nutrition may also carry risk. Chronic parenteral nutrition has been associated with liver steatosis and fibrosis and liver dysfunction in patients with a failing gastrointestinal tract, which may be explained not only by lack of enteral nutrition-stimulated intestinal hormone secretion and biliary disturbances but also by an excessive caloric intake (Kelly 2006; Grau and Bonet 2009). In critical illness, parenteral nutrition increases the risk of infection and metabolic disturbances and has been associated with hepatobiliary complications and even liver failure, though it does not appear to increase the risk of death (Debaveye and Van den Berghe 2006; Grau and Bonet 2009). Although such risks may largely be ascribed to excessive nutrition (McCowen et al. 2001), they are an important concern and thus contributed to the lack of universal consensus about whether and when intravenous nutrition should be started in conditions of

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insufficient enteral nutrition (Singer et al. 2009; Martindale et al. 2009; Heyland et al. 2003). Hence, nutritional guidelines are largely based on expert opinion. The guidelines by the European Society for Parenteral and Enteral Nutrition recommend to initiate parenteral nutrition early, within 2 days, when enteral nutrition is insufficient (Singer et al. 2009), whereas the American and Canadian guidelines recommend the toleration of hypocaloric nutrition during the first week, provided the patients were not malnourished upon admission (Martindale et al. 2009; Heyland et al. 2003). An important factor in the lack of efficacy to prevent muscle atrophy with parenteral nutrition may be the aggravation of hyperglycemia, a common complication of critical illness (McCowen et al. 2001), with intravenous nutrition (Debaveye and Van den Berghe 2006). Such hyperglycemia increases risk of organ failure and death (Van den Berghe et al. 2001, 2006; Vlasselaers et al. 2009) and also enhances catabolism (Gore et al. 2002; Flakoll et al. 1993). Interestingly, in patients with severe burn injury, the rate of protein loss correlated with the severity of hyperglycemia (Gore et al. 2002). Since hyperglycemia had not been treated in the studies on intravenous nutrition, any protection by the nutritional support may have been overruled by the aggravated hyperglycemia. In that regard, intravenous administration of nutrition with a small amount of amino acids and lipids and increasing amounts of glucose to critically ill animals dosedependently attenuated the proteolytic response of the ubiquitin-proteasome pathway, calpain-1, and cathepsin L, provided hyperglycemia was prevented (Derde et al. 2010). A large multicenter randomized controlled study (Casaer et al. 2011) compared the parenteral nutrition management advised by the European (Singer et al. 2009) versus the American/Canadian guidelines (Martindale et al. 2009; Heyland et al. 2003), meaning early versus late supplementation of inadequate enteral nutrition with parenteral nutrition, while maintaining strict normoglycemia. Against expectations, late initiation of parenteral nutrition with toleration of a severe caloric deficit during the first week in

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ICU reduced morbidity of the patients, with fewer patients acquiring a new infection or liver dysfunction, and accelerated recovery as illustrated by a shorter dependency on mechanical ventilation and dialysis as well as a shorter ICU and hospital stay. Functional status of the patients, assessed by the 6 min walking distance at ICU discharge and activities of daily living, was not compromised by such caloric deficit. A few other randomized studies on early versus late initiation of parenteral nutrition in heterogeneous cohorts of critically ill patients have been published since, although comparing somewhat different approaches (Heidegger et al. 2013; Doig et al. 2013). Another study compared initial trophic versus full enteral feeding in patients with acute lung injury (Rice et al. 2012). None of these studies found clear benefits with more intensive nutritional support early in critical illness. Data on the impact of early versus late parenteral nutrition on development of muscle weakness in a randomized setting are not available at this time point but will yield further important information. The impact on the muscle of parenteral nutrition under maintenance of normoglycemia versus fasting has been investigated in an animal model of critical illness (Derde et al. 2012b). Simultaneously, the impact of macronutrient composition was evaluated, by enriching isocaloric nutrition either in glucose, lipids, or amino acids. Weight loss and activation of the ubiquitin-proteasome pathway were attenuated with feeding versus fasting, most pronounced with amino acid-enriched nutrition. The latter also best preserved myofiber size. However, amino acid-enriched and, to a lesser extent, lipid-enriched nutrition evoked signs of compromised autophagy activation in muscle, with accumulation of p62 and ubiquitinated proteins and more severe myofiber vacuolization, whereas autophagy was activated in the fasted animals. Furthermore, such a phenotype of autophagy deficiency also developed in the liver with nutrition enriched in amino acids or lipids, with fewer autophagosomes, fewer intact mitochondria, suppressed respiratory chain activity, and increased liver damage. These data

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suggest that intravenous nutrition may preserve muscle mass at the expense of muscle quality and severe vital organ damage. Thus, the search for the optimal nutrition of critically ill patients is not only about optimal timing but also about optimal composition and is far from over. Enriching nutrition with certain amino acids (e.g., glutamine), with certain unsaturated fatty acids or with antioxidants, may be beneficial in selected patient populations (Debaveye and Van den Berghe 2006). However, at this moment there is insufficient evidence to support a universal application of these strategies to all critically ill patients and the interventions even may be harmful (Heyland et al. 2013). The suppressive effect of feeding on autophagy may also explain why experimental studies suggest an acute upregulation of autophagy, which implicates a fasting state, whereas longer-term-fed models rather support insufficient activation of autophagy.

Applications to Other Conditions Muscle weakness is not only a problem of critically ill patients but has been described in a wide range of other conditions, including starvation, limb casting, prolonged bed rest, cancer, chronic pulmonary disease, acquired immunodeficiency syndrome, heart failure, uremia, and muscular dystrophies, and also in normal aging (Glover and Phillips 2010; Man et al. 2009). A detailed description is beyond the scope of this review, but also in these conditions, most attention has been paid to the component of muscle atrophy. Interestingly, an inverse relationship has been found between autophagy and aging (Terman 2006). The accumulation of damaged proteins and organelles observed in aged cells suggests that autophagic capacity may be a critical factor in determining the life span of cells and organisms. Deficient autophagy has been observed in a collagen VI muscular dystrophy model, where myofiber degeneration could be rescued by forced reactivation of autophagy with genetic, dietary, or pharmacological interventions (Grumati et al. 2010).

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Guidelines and Protocols As explained above, guidelines for the nutritional management of critically ill patients are based on expert opinion and widely diverging around the world (Singer et al. 2009; Martindale et al. 2009; Heyland et al. 2003). Early aggressive nutritional support has been recommended to counteract the hypercatabolic state and muscle weakness of critically ill patients. However, recently published randomized controlled studies challenged the benefits of such intensive nutritional support as compared with tolerating hypocaloric nutrition in the first days or week of critical illness (Casaer et al. 2011; Rice et al. 2012; Heidegger et al. 2013; Doig et al. 2013). Further high-quality randomized controlled clinical studies are required that further address the optimal timing and nutritional composition to support new evidence-based guidelines. In particular the impact of such interventions on muscle weakness and underlying mechanisms need to be studied to design optimal guidelines and protocols to safeguard the muscle compartment during critical illness, which at present are lacking.

Conclusions Loss of muscle mass, at least in part due to underfeeding of the patients, has long been considered a major culprit contributing to ICUacquired muscle weakness. Randomized animal studies suggested that enhancing nutrition during critical illness under maintenance of normoglycemia may counteract the proteolytic systems involved in muscle breakdown but simultaneously suppresses crucial quality control by autophagy. Hence, nutrition may play a dual role as preservation of muscle mass may come at the expense of a loss in muscle quality and inferentially function. Data on the impact of such intervention in human patients are so far lacking. The presented mechanistic insight may be important in view of the development of new strategies to simultaneously preserve muscle mass and quality.

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In this regard, pharmacological activation of autophagy may open perspectives.

Summary Points • Muscle weakness frequently complicates critical illness and has been associated with delayed weaning from mechanical ventilation, prolonged intensive care unit stay, impaired rehabilitation, as well as increased mortality risk. • Muscle atrophy has long been considered the major myogenic component contributing to muscle weakness. • Muscle atrophy is a consequence of an imbalance between synthesis and degradation of myofibrillar proteins. • Classical pathways of muscle protein breakdown include the ubiquitin-proteasome system, calcium-dependent calpains, and lysosomal cathepsins. • Excessive autophagy may contribute to muscle atrophy, but impaired autophagy leads to poor control of muscle quality and compromises muscle function. • Both reduced synthesis and accelerated breakdown of myofibrillar proteins contribute to muscle atrophy in critical illness. • Classical proteolytic systems are all upregulated in the muscle during critical illness. • Supplementing failing enteral nutrition with parenteral nutrition to prevent the accumulation of a severe caloric deficit during critical illness failed to protect the muscle compartment. • Aggravation of critical illness-induced hyperglycemia by parenteral nutrition may be pro-catabolic and counteract the anti-catabolic actions of nutrient provision. • Administration of parenteral nutrition, while maintaining normoglycemia, may counteract muscle catabolism and atrophy at the expense of compromised muscle quality and severe vital organ damage related to its suppressive effect on autophagy activation.

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Thyroid Function in Critical Illness Foteini Economidou, Evangelia Douka, Marinella Tzanela, Stylianos Orfanos, and Anastasia Kotanidou

Contents

Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Thyroid Axis in Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Thyroid Axis in Critical Illness . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Thyroid Hormones in Critical Illness . . . . . . . . . . . . . Triiodothyronine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serum Reverse Triiodothyronine . . . . . . . . . . . . . . . . . . . . Thyroxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyrotropin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Assessment of Thyroid Function in ICU . . . . . . . . . .

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Drugs in ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Thyroid Dysfunction and Outcome . . . . . . . . . . . . . . .

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Thyroid Hormone Treatment During Nonthyroidal Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Applications to Critical or Intensive Care . . . . . . . . 101 Application to Other Conditions . . . . . . . . . . . . . . . . . . 101

F. Economidou (*) • E. Douka • A. Kotanidou First Critical Care Department, Medical School, National and Kapodistrian University of Athens, Evangelismos General Hospital, Athens, Greece e-mail: [email protected]; [email protected]; [email protected] M. Tzanela Department of Endocrinology, Evangelismos General Hospital, Athens, Greece e-mail: [email protected] S. Orfanos Second Critical Care Department, Medical School, National and Kapodistrian University of Athens, Attikon General Hospital, Athens, Greece e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_2

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Abstract

The metabolic support of a critically ill patient is a relatively new topic of active research and discussion, and little is known about the effects of critical illness on metabolic physiology and activity. The nonthyroidal illness syndrome, also known as the low T3 syndrome or euthyroid sick syndrome, is characterized by abnormal thyroid function tests encountered in patients with acute or chronic systemic illnesses. The laboratory parameters of this syndrome include low serum levels of triiodothyronine (T3) and high levels of reverse T3, with normal or low levels of thyroxine (T4) and normal or low levels of thyroid-stimulating hormone (TSH). This condition may affect 70 % of critically ill patients. The changes in serum thyroid hormone levels in the critically ill patient are the result of alterations in TSH regulation, in the peripheral metabolism of the thyroid hormones, in the binding of thyroid hormone to transport protein, in receptor binding, and in intracellular uptake. Medications have also a very important role in these mechanisms. Hormonal changes can be seen within the first hours of critical illness, and interestingly, these changes correlate with the final outcome. Data of a beneficial effect on outcome with thyroid hormone treatment in critically ill patient are so far controversial. Thyroid function generally returns to normal in survivors as the acute illness resolves. List of Abbreviations

D1 D2 D3 HPT ICU LT3 NTIS rT3 T3 TBG TBPA TFTs TRH

Deiodinases type 1 Deiodinases type 2 Deiodinases type 3 Hypothalamic-pituitary-thyroid Intensive care unit Liothyronine Nonthyroid illness syndrome Reverse T3 3,5,30 -triiodothyronine Thyroxine-binding globulin Thyroxine-binding prealbumin Thyroid function tests Thyrotropin-releasing hormone

TR TSH T4

Thyroid hormone receptors Thyroid-stimulating hormone Thyroxine

Introduction Critical illness can be defined as any lifethreatening condition requiring the support of failing vital organ function. During critical illnesses, hypermetabolism, increased energy expenditure, hyperglycemia, and muscle loss are noted, with concomitant changes in circulating hormone levels (Van den Berghe 2001). As a result of the acute stress response, activation of pituitaryadrenal axis occurs, and serum cortisol concentration rises rapidly. Thyroid hormones play a key role in body homeostasis by modulating metabolism and immune system function. Alterations of the hypothalamic-pituitary-thyroid (HPT) axis are a common finding in critical illness, mainly expressed as low levels of total 3,5,30 -triiodothyronine (T3) and termed as “low T3 syndrome.” Sick patients with low serum T3 are often regarded as being clinically euthyroid, and as a consequence, the alternative term “euthyroid sick syndrome” was widely used in the past. “Nonthyroid illness syndrome (NTIS)” is now more commonly used to describe the typical changes in the thyroidrelated hormone concentrations that can arise in the serum following any acute or chronic illness that is not caused by an intrinsic abnormality in thyroid function (Chopra 1997). NTIS affects about 70 % of patients hospitalized with various diseases (Bermundez et al. 1975; Kaplan et al. 1982), and it is often associated with alterations in other endocrine axis, such as decrease in serum gonadotropin and sex hormone concentrations and increase in serum adrenocorticotropic hormone (corticotropin) and free cortisol levels. Thus, the NTIS should not be viewed as an isolated abnormal metabolic event but as part of a generalized systemic endocrine reaction to critical illness. It has been demonstrated that these changes in thyroid hormone levels are associated with the duration and severity of the disease. Subsequent studies confirmed the association between NTIS

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and adverse outcomes in patients with sepsis, multiple trauma, acute respiratory distress syndrome, respiratory failure, and mechanical ventilation, as well as in the general intensive care unit (ICU) population (Chinga-Alayo et al. 2005; Inglesias et al. 2009; Giuseppe et al. 2009; Sharshar et al. 2011). Low T3 levels are also indentified as an independent predictor of short- and long-term survival in patients with myocardial infarction, heart failure, or acute stroke outside the ICU setting (Inglesias et al. 2009). Even though NTIS has been studied for several decades now, it is still unclear whether these changes in the HPT axis during critical illness are representative of an associated pathology requiring thyroid hormone replacement therapy or are indeed an adaptive response to stress to decrease metabolic rate, which in turn may be beneficial to the sick patient. In this chapter, the current knowledge on the adaptation mechanisms of thyroid gland during the development of critical illness is summarized. In order to correctly interpret thyroid function tests (TFTs) in the critically ill patient, the clinician should be familiar with the changes that occur during critical illness in the regulation of the hypothalamic-pituitary-thyroid axis and in thyroid hormone metabolism and the effects of commonly used medications on thyroid physiology.

Thyroid Axis in Health In healthy subjects, the hypothalamus-pituitarythyroid axis functions as a classical feedback system (Fig. 2). At the level of the hypothalamus, thyrotropin-releasing hormone (TRH) is released which stimulates the pituitary to secrete in a pulsatile and diurnal fashion TSH. TSH in turn drives the thyroid gland to release the T4 into the circulation. Conversion of T4 in peripheral tissues produces the active hormone T3 and reverse T3 (rT3) which is thought to be metabolically inactive. T4 and T3 in turn exert a negative feedback control on the level of the hypothalamus and pituitary. The thyroid gland produces T4 in significantly larger quantities than the biologically active T3. Although released from the thyroid in a ratio of

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T4:T3 = 17:1, the circulating levels of each hormone are also determined by extra-thyroidal conversion of T4 to T3, which in healthy humans accounts for more than 80 % of T3 production (Pilo et al. 1990). In the circulation, thyroid hormone is bound to carrier proteins with only the amount of free or unbound hormone determining the activity level of thyroid hormone-regulated process. Only 0.03 % of total serum T4 and 0.3 % of total serum T3 are present in the free form, with the remaining part bound to thyroxinebinding globulin (TBG), thyroxine-binding prealbumin or transthyretin (TBPA), and albumin (Oppenheimer 1968). Normally, the amount of free hormone is kept constant by matching excretion to thyroid release. If changes do occur in total circulating hormone levels of healthy humans, these are mainly caused by altered amounts or affinity of carrier proteins. Free circulating T4 and T3 enter to their target cells in peripheral tissues via monocarboxylate transporters. In these cells, activation and inactivation of thyroid hormone are carried out by a group of three iodothyronine deiodinases, each of which is a selenoprotein encoded by a separate gene (Fig. 1). The deiodinases type 1, 2, and 3 (D1, D2, and D3) have distinct tissue distributions, substrate affinities, and physiological roles (Gereben et al. 2008a, b). All deiodinases are integral membrane proteins, and although their cellular localization varies, all their catalytic domains reside within the cell cytosol (Friesema et al. 2006). D1 and D2 activate T4 by removing an iodine atom from its outer ring (50 -deiodination), forming T3. In contrast, D3 inactivates both T3 and T4 by removing an iodine atom from the inner ring (50 -deiodanation) generating T2 and rT3, respectively, a reaction that can be also catalyzed by D1. D1 and D2 differ by their kinetic properties, substrate specificity, and susceptibility to inhibitory drugs as well as by their responses to changes in the thyroid hormone status. The higher levels of D1 activity in humans are found in the thyroid, liver, and kidney, while D2 is more widely expressed, being found in the pituitary, brain, thyroid, skin, skeletal, and heart muscle (Williams and Bassett 2011). The D1 and D3 isoenzymes are located in the plasma membrane,

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cytoplasm

T4

nucleus

T3 T4 T4

T3 T4 D3,D1

D1,D2

T3 D1,D2

T3

TR RXR mRNA

rT3 T2

D3,D1 protein

Fig. 1 Scheme representing the different aspects of peripheral thyroid hormone metabolism. Thyroid hormone is taken up from the blood via thyroid hormone transporters and subsequently metabolized in the cell. Iodothyronine deiodinases convert thyroid hormone.

T3 transfers to the nucleus and can then bind to its receptor (TR). TR forms a heterodimer with retinoid X receptor (RXR) and binds specific sequences in target genes (Reprinted with permission from Mebis et al. 2011)

while D2 is retained in the endoplasmic reticulum. The T3 produced from D2 thus potentially has ready access to the nucleus due to its close proximity, while T3 produced by D1 is more readily exported into the plasma (Zoeld et al. 2006). The D3 contributes to thyroid hormone homeostasis protecting tissue from excess of thyroid hormones. T4 and T3 regulate their own release by feedback inhibition on TSH secretion from the pituitary thyrotrope cells and at the level of the hypothalamus. T3 acts through binding with nuclear thyroid hormone receptors (TR). In the pituitary and in the hypothalamus, T4 acts via local conversion to T3 although T4 has also been shown to be able to bind TR and exert some biological effect (Bogazzi et al. 1997). In the hypothalamus, high levels of iodothyronines downregulate biosynthesis of TRH in the hypophysiotropic neurons of the paraventricular nucleus (Perello et al. 2006). These neurons project to the median eminence where TRH is released in the capillaries of the hypophysial portal system. So TRH positively regulates the biosynthesis and release of TSH from the pituitary, and together with the negative effect of thyroid hormones on TRH and TSH release from the hypothalamus and pituitary, a relatively stable concentration of TSH in the circulation

is achieved. Therefore, the measurement of circulating TSH is regarded as a sensitive marker for thyroid gland dysfunction.

Thyroid Axis in Critical Illness The pathophysiological mechanisms responsible for NTIS are complex and poorly understood. A wide range of mechanisms give rise to the hormonal changes seen in the NTIS. These changes include modifications to the hypothalamic-pituitary axis, altered binding of thyroid hormone to circulating binding proteins, modified entry of thyroid hormone into tissue, changes in thyroid hormone metabolism due to modified expression of the intracellular iodothyronine deiodinases, and changes in thyroid hormone receptor expression or function. Critical illness is hallmarked by some very distinct neuroendocrine alterations that are quite different in the prolonged phase of critical illness as compared with the first few hours or days after the onset of a severe illness (Fig. 2). The acute and chronic changes in pituitary-thyroid function are a multidisciplinary dynamic process that develops over time. The acute-stage endocrine and metabolic profiles differ from the prolonged critical illness, which may relate to the metabolic

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Fig. 2 Schematic outline of thyroid axis in health, acute critical illness, and prolonged critical illness (Reprinted with permission from Mebis and van den Berghe 2009)

and immunological alterations accompanying the medical conditions. The first reaction, which takes place within hours of the onset of acute illness, is the activation of the anterior pituitary gland, the associated suppression of anabolic pathways in the periphery (since 80–90 % of the circulating T3 are derived from T4), and the changes in receptor binding of thyroid hormones. The changes in the thyroid axis are so uniformly present in all types of acute illnesses that they have been interpreted as a beneficial and adaptive response, essential for survival, that does not warrant intervention. It is interesting that during recovery, T3 and rT3 normalize again, while in persistence of the disease, T3 levels remain suppressed. When patients are treated in the ICU for weeks or even months, a different set of hormonal changes may occur. The neuroendocrine abnormalities seem to predominate in prolonged disease with reduced TSH levels being the most frequent abnormality and suggesting a diminished hypothalamic-pituitary activity (Plikat et al. 2007). TSH levels show a transient rise during the first hours of acute illness but thereafter return to normal. When severe illness persists, TSH may become abnormally low. It seems that there is a timely overlap between acute- and chronic-phase metabolic alterations. The decrease in serum T3 and fT4 levels which develops over time gives us a

good explanation why typical adaptations of the thyroid axis may not be present in critically ill patients on admission to the ICU (Williams and Bassett 2011; Chopra et al. 1975). Interestingly, the chronic phase of the euthyroid sick syndrome is characterized by reversibly diminished secretion of TSH which can be reactivated by thyrotropinreleasing hormone (TRH) administration (Oppenheimer 1968; Gereben et al. 2008a, b).

Thyroid Hormones in Critical Illness Triiodothyronine The majority of critically ill patients have low serum T3 concentrations accompanied by an increase in rT3 levels, as do some ambulatory patients during severe illness (Tables 1 and 2). T3 low serum levels reflect altered thyroid homeostasis and mechanisms of adaptation in critical illness. Liver and skeletal muscle biopsies obtained within minutes after death from intensive care unit patients demonstrate reduced 50 -monodeiodinase activity and increased 50 -monodeiodinase activity (which converts T4 to rT3) (Peeters et al. 2003, 2005a). Moreover, patients with fatal illness have low tissue T4 and T3 concentrations (Peeters et al. 2005c; Arem et al. 1993).

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Inhibition of the enzyme 50 -deiodinase that catalyzes the conversion of T4 to T3 has been considered a possible mechanism resulting in NTIS (Fig. 3) (Burman and Wartofsky 2001; Mortoglou 2004). Several mechanisms such as poor nutrition, free oxygen radicals, cytokines, and drugs can contribute to the inhibition of 50 -monodeiodination and therefore to the low serum T3 concentrations in critically ill patients with nonthyroidal illness (Chopra et al. 1975; Chopra 1985b; Van der Poll et al. 1990; Stouthard et al. 1994; Corssmit et al. 1995).

Serum Reverse Triiodothyronine The conversion of reverse T3 to diiodothyronine (T2) is reduced in nonthyroidal illness because of inhibition of the 50 -monodeiodinase activity Table 1 TSH values during critical illness and clinical outcome

Undetectable

Serum TSH values (mU/L) 0.05 and 88 cm, 35 ins) Glucose (> 6.1 mmol/L) Triglycerides (> 1.7 mmol/L) Blood pressure (> 130/85 mmHg) HDL (men < 1.04 mmol/L, women < 1.29)

of mortality in the ICU is controversial. Results from prior studies are inconsistent, with findings ranging from increased mortality (Bercault et al. 2004; Yaegashi et al. 2005) to no or even to improved survival (Oliveros and Villamor 2008), a phenomenon known as “obesity paradox” (Habbu et al. 2006). Theoretically, morbidly obese patients might have worse outcomes due to limited cardiac reserve, the adverse consequences of morbid obesity on pulmonary physiology leading to difficulties with mechanical ventilation, and increased prevalence of comorbid conditions (Lewandowski and Lewandowski 2011). Three recent metaanalyses that tried to elucidate the impact of obesity on various outcome measures, including mortality, showed that higher BMI was associated with no or lower ICU mortality, but with longer ICU stay (Akinnusi et al. 2008; Oliveros and Villamor 2008; Hogue et al. 2009). Several explanations have been proposed for this “obesity paradox.” High levels of anti-inflammatory adipokines might positively modulate deleterious inflammatory processes,

high cholesterol and lipid levels might confer benefits by binding endotoxins or by providing necessary precursors for adrenal steroid synthesis, and increased nutrition reserves may help the patient respond to inflammation and metabolic stress (Rice 2007). Furthermore, disparities in provided care may constitute potential confounding factors biasing the observed association between BMI and outcomes in critical illness (O’Brien et al. 2012).

Applications to Critical or Intensive Care Obese patients present unique challenges to critical care clinicians in many areas.

Respiratory Function General anesthesia and paralysis impair pulmonary function even in normal individuals with healthy lungs, resulting in decreased oxygenation, reduction in FRC, and development of pulmonary

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ZEEP

EXP

PEEP 8 cm H2O

0 INSP

Flow (L/min)

100

EFL = 10% VT

NFL

–100 Volume I.............. 0.5L .............l Fig. 4 Flow-volume (V0 V) loops of negative expiratory pressure (NEP) test breath and preceding reference curve of a morbidly obese subject on zero positive end-expiratory pressure (ZEEP) (left) and after application of 8 cm H2O of positive end-expiratory pressure (PEEP) (right). On ZEEP, expiratory flow limitation (EFL) amounted to 10 % VT and

was heralded by an inflection point (i.e., the expiratory V0 V curve was S-shaped). With PEEP, the inflection point disappeared and the entire V0 V curve became concave toward the volume axis, indicating the absence of EFL (From Koutsoukou 2004, with permission)

atelectasis (Hedenstierna et al. 1985). In morbidly obese subjects, general anesthesia causes much more atelectasis than in normal subjects (Eichenberger et al. 2002). The increased abdominal mass and pressure can cause a cephalad displacement of the diaphragm and reduction in the passive movements of its dependent part, resulting in a further decrease of end-expiratory volume and, thus, in marked abnormalities of respiratory system mechanics. Indeed, reduced respiratory system compliance and increased respiratory resistance have been reported in postoperative morbidly obese subjects (Pelosi et al. 1996; Koutsoukou et al. 2004). Due to the fact that anesthesia-paralysis causes a further decrease of FRC in obese subjects, a high prevalence of EFL and PEEPi should be predictable. In fact, it has been shown that morbidly obese, postoperative mechanically ventilated subjects commonly exhibit EFL with concomitant PEEPi (Fig. 4) (Koutsoukou et al. 2004). As FRC becomes less than CV, airway closure will be present during tidal breathing. Together with alveolar collapse, this may lead to abnormal V/Q distribution and oxygenation impairment (Hedenstierna et al. 1976; Koutsoukou et al. 2004).

Peripheral airway closure, EFL, and atelectasis in the dependent lung zones constitute the basis for the lung heterogeneity and the development of shear stresses during tidal breathing, which may lead to lung injury (D’Angelo et al. 2002, 2005). In order to avoid lung injury, positive end-expiratory pressure (PEEP) should be applied in order to increase the end-expiratory lung volume above CV, as well as the expiratory flow limitation volume. Furthermore, application of adequate levels of PEEP is expected to abolish EFL, reduce PEEPi, and improve respiratory mechanics (Koutsoukou et al. 2004).

Acute Respiratory Distress Syndrome (ARDS) An increased prevalence of ARDS development should be expected in obese patients, given the high levels of circulating inflammatory mediators derived from adipose tissue, which may prime the lung to become more vulnerable to subsequent injurious insults such as sepsis or trauma. There have been few studies examining the relationship between the incidence/outcome of ARDS and

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obesity with conflicting results (Bercault et al. 2004; Yaegashi et al. 2005). Gong et al. in a specifically designed study found an association between obesity and increased development of ARDS that persisted even after accounting for known risk factors for the development of ARDS (Gong et al. 2010). Furthermore, they found that obese patients develop ARDS later in the course of their ICU hospitalization. According to the authors, higher tidal volumes, peak inspiratory pressures and PEEP, settings that are usually applied in this cohort of patients (O’Brien et al. 2004) and, as it is well known, are associated with ventilator-induced lung injury (Tremblay and Slutsky 1998) might explain the increased incidence of ARDS in obese subjects. No relationship has been found between BMI and ARDS mortality, but obesity was found to be associated with increased ICU and hospital stay (Gong et al. 2010). Mechanical ventilation for the obese patient with ARDS is challenging. Despite the absence of ventilator protocols specifically designed for these patients, it might be beneficial to implement lung-protective mechanical ventilation as described in the ARDS Network study (ARDSnet 2000), i.e., low tidal volumes (VT) of 6 mL/kg body weight, end-inspiratory plateau pressure (Pplat) less than 30 cm H2O, and appropriate levels of PEEP (Table 2). Delivered tidal volume should be calculated based on predicted body weight, not the measured body weight, since, when a patient gains weight, the lung does not actually change in size. Some questions arise, however, about the recommended plateau pressure limits. Transpulmonary pressure (TP), the effective distending pressure across the lung, is a function of both the applied airway pressure (PAW) and changes occurring in the pleural pressure (PPL) (PT=PAWPPL) (Marini and Amato 1998). Obese patients often have marked increase in pleural pressure, a condition that substantially may affect the TP. Consequently, in obese subjects, Pplat values higher than the ARDSnet recommended ones could be allowed without the risk of lung overdistention, since transpulmonary pressures at end-inspiration are expected to be

113 Table 2 Lung-protective ventilation in ARDS patients VT Pplat RR pH FiO2-PEEP

6 mL/kg PBW 30 cm H2O 6–35/min 7.30–7.45 PaO2, 55–80 mmHg or SaO2, 88–94 %

ARDS acute respiratory distress syndrome, VT tidal volume, PBW predicted body weight, Pplat plateau airway pressure, RR respiratory rate, FiO2 fraction of inspired oxygen, PEEP positive end-expiratory pressure, PaO2 arterial oxygen pressure, SaO2 arterial oxygen saturation

lower and, thus, within safe limits (Talmor et al. 2008). Furthermore, generous amounts of PEEP may be necessary to counterbalance the lung-collapsing effects of the large thoracic masses and the increased intra-abdominal pressure and prevent derecruitment. Current suggestions for the management of ARDS patients propose, among others, recruitment of the atelectatic areas through an intentional transient increase in airway pressure, known as recruitment maneuvers (RMs) (Lapinsky and Mehta 2005). Although several RM techniques have been described, the best RM technique for obese subjects is currently unknown. It should be pointed out, however, that the main component of the RM’s effect is the magnitude of the recruiting pressure, that is, the generated transpulmonary pressure and not the applied airway pressure. Failure to account for increased pleural pressure can result in underestimation of the effective recruiting pressure. In fact, it has been shown that BMI has an impact on RM’s effectiveness most probably by altering the transpulmonary pressure (Katsiari et al. 2012).

Hemodynamic Monitoring There are monitoring difficulties in obesity. Noninvasive measurement of blood pressure by cuff sphygmomanometer poses frequent problems because it has unpredictable accuracy when the selected cuff size is not correct, but inaccuracies may persist even with an appropriate-sized cuff. Thus, invasive hemodynamic monitoring

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techniques are often used in obese patients, and hemodynamic parameters are adjusted according to body surface area. Furthermore, invasive hemodynamic monitoring may be useful in assessing cardiac performance and in titrating fluid therapy, especially in patients who require large-volume fluid resuscitation. The potential variations in calculated indexed values depending on weight could lead to different conclusions regarding a patient’s status and treatment. Invasive monitoring requires the position of venous and arterial lines. Securing vascular access in these patients is difficult, because the usual anatomic landmarks are obscured, the distance from the skin to vessels is much farther than normal, and the angle of approach may be too steep to allow cannulation even after reaching the vessels. Application of ultrasound techniques may increase the probability of successful catheter placement and reduce complications.

Metabolic Derangements The enhanced metabolic rate, accelerated net protein breakdown, and alterations in lipid and carbohydrate metabolism of critical illness may exacerbate these preexisting metabolic derangements. The resultant hyperglycemia is associated with increased number of infections, delayed wound healing, decreased utilization of nutrients, and fluid imbalance. Consequently, monitoring and controlling blood glucose levels are important management considerations in patients with obesity. Although intensive insulin therapy used to maintain the blood glucose level between 80 and 110 mg/dL has been found to improve outcome in surgical critically ill adults (Van den Berghe et al. 2001), later studies showed increased mortality and morbidity associated with intensive glycemic control. Moreover, it was found that sustained hyperglycemia is less harmful than the non-stable blood sugar levels (Finfer et al. 2009). Thus, the general consensus has been that a protocolized approach to blood glucose management should be followed, targeting an upper blood glucose 180 mg/dL.

A. Koutsoukou et al.

Venous Thromboembolism Although obesity is an independent risk factor for the development of venous thromboembolism (VTE) (Goldhaber et al. 1997), the precise incidence of VTE in critically ill, morbidly obese patients is unknown. Immobility, venous stasis, venous catheters, and endothelial injury may increase the risk of VTE, especially in postoperative obese patients. In fact, pulmonary embolism is the most common cause of postoperative mortality after bariatric surgery, accounting for as many as 50 % of all deaths (Pieracci et al. 2006). Because of the clinically silent nature of VTE, primary prevention is the key to reduce morbidity and mortality. Unfortunately, limited data exist concerning effective prophylactic regimens in this cohort of patients. Obese subjects are frequently excluded from clinical trials because of altered pharmacokinetics and the difficulty to accurately diagnose VTE in such patients (El-Solh 2004). The clinical efficacy of low molecular weight heparins in preventing VTE has been tested only in limited trials of patients undergoing bariatric surgery. Enoxaparin, administered at 40 mg every 12 h, was superior to a lower dosage of 30 mg every 12 h in preventing postoperative deep venous thrombosis (Scholten et al. 2002). No difference in bleeding events was reported between the two doses. Given the lack of evidence for specific dosing regimens for subcutaneously administered unfractionated heparin, it would be appropriate to use low molecular weight heparin in these patients for VTE prophylaxis.

Pharmacologic Considerations The changes accompanying obesity markedly affect distribution, binding, and elimination of medications commonly used in the ICU. The altered physiology in obese patients is characterized by a larger volume of distribution for lipophilic drugs, increased clearance of hydrophilic drugs, and a decrease in lean body mass and tissue water content compared with normal individuals. Other important changes include total blood volume and cardiac output, alterations in plasma

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binding proteins, and changes in liver and kidney function. In the ICU, measurement of weight can also be affected by temporary changes in body water from the third spacing, which may or may not influence the distribution of medications. The lack of sufficient data in obese patients supports the use of ideal body weight when calculating loading and maintenance regimens for digoxin, procainamide, and propranolol (Abernethy et al. 1981; Christoff et al. 1983). Propranolol does not follow the general rule that lipophilic drugs have an increased volume of distribution in obese patients (Cheymol et al. 1997). Limited pharmacokinetic data suggest that actual body weight can be used for loading regimens for lidocaine and verapamil, but a more conservative approach, using adjusted body weight, seems reasonable. Non-weight-based dosing and adjustments can be made for maintenance doses (Abernethy and Greenblatt 1984). Amiodarone is a lipophilic drug also, with a large volume of distribution, and adequate loading and tissue saturation may take several weeks. There is a paucity of data regarding specific dosing of antibiotics for obese patients, so the dosing should be determined on an individual basis and the consequences of inadequate treatment should be kept in mind. Weight-based medication schedule is commonly used in order to avoid systemic side effects. If it is possible, doses should be titrated on the basis of plasma levels. The ideal body weight (IBW) is appropriate for dose calculation of cephalosporins, penicillins, and beta-lactams. Total body weight (TBW) is ideal for adjusting the dose titration of vancomycin, in the setting of normal renal function, volume of distribution, and drug clearance of the drug (Bauer et al. 1998). Dosing weight is for the selection for aminoglycosides and an upper dose limit has been advocated for once-daily dosing in morbidly obese patients. Meanwhile, dosing intervals should be based on the estimated renal function, and careful drug monitoring is essential if treatment is planned for more than 3 days (Traynor et al. 1995). Dosages at the upper end of recommended levels are suggested for fluoroquinolones for very obese patients with

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severe infections. Linezolid is another option for use in obese patients with multidrug-resistant soft tissue/skin infections. In general, therapeutic drug monitoring is advisable for all obese patients, probably regardless of renal function. The two most commonly used sedatives in ICU are propofol and benzodiazepines, both lipophilic drugs with increased volume of distribution in obese subjects. Dosing of propofol should be based on TBW, while dose calculations for continuous infusion of benzodiazepines should follow IBW because their clearance is not increased in obese patients (Leykin et al. 2011).

Applications to Other Conditions Overweight and obese patients are at an increased risk for various acute and chronic morbid conditions, such as cardiovascular disease, type II diabetes, hypertension, arthritis, chronic lung diseases, and certain types of cancer, which may result in increased mortality. Recent studies have suggested that morbidly obese adults may have substantially reduced life expectancy, by as much as 15–20 years (Whitlock et al. 2009). More detailed report of these problems, however, is outside the scope of this section that is focused on the obese patient in the ICU.

Postoperative Management Surgical therapy has become an effective, sustained means for the treatment of morbid obesity. Morbidity from surgery, however, can be in excess of 10 % (Choban and Flancbaum 1997). Early complications include wound dehiscence, bleeding, and pulmonary embolism. The risk of aspiration is increased due to the elevated intraabdominal pressure and high volume and low pH of gastric contents. Positioning the patient in reverse Trendelenburg at 45 may help in preventing gastroesophageal reflux. Furthermore, in this position, an improvement of respiratory mechanics is expected due to decreased intra-abdominal pressure and thus an easier weaning. The use of noninvasive ventilation

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with the bi-level positive airway pressure mode, postoperatively, may alleviate pulmonary dysfunction, improve gas exchange, and eliminate respiratory complications. Nowadays, most of bariatric procedures are performed by laparoscopic approach. This technique, however, requires abdominal insufflation with CO2 and an increase in the intraabdominal pressure of up to 15–20 mmHg, conditions that may further deteriorate the less favorable respiratory mechanics and should be taken into account in the early postoperative period.

Guidelines and Protocols Guidelines and protocols specifically designed for critically ill obese patients are lacking. Despite the absence of such guidelines, however, management of these patients in the ICU should follow protocolized approaches based on problemspecific guidelines available for the critically ill patients in general.

Summary Points Adequate levels of PEEP should be applied in mechanically ventilated obese patients in order to increase the end-expiratory lung volume, abolish expiratory flow limitation and open atelectatic areas, and thus avoid ventilator-induced lung injury. In obese patients with ARDS, the strategy of lung-protective ventilation with low tidal volume is paramount. Tidal volume should be based on predicted body weight. Invasive measurement of cardiac filling pressures and resultant flows with a pulmonary artery catheter may be helpful in titrating therapy. Direct intra-arterial blood pressure monitoring should be strongly considered. Enoxaparin 40 mg administered twice daily is preferred for VTE prophylaxis. Dosing adjustments for specific drugs should be considered.

A. Koutsoukou et al.

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Adipose Tissue and Endocrine Function in Critical Care Mirna Marques and Lies Langouche

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 The Role of Adiponectin During Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 The Role of Leptin in Critical Illness . . . . . . . . . . . . . 122 The Role of RBP4 in Critical Illness . . . . . . . . . . . . . . 123 Cytokine Production in Adipose Tissue During Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 The Obesity Paradox in Critically Ill Patients and Its Relation to the Endocrine Function of Adipose Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Applications to Critical Care . . . . . . . . . . . . . . . . . . . . . . 126 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

M. Marques • L. Langouche (*) Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Laboratory of Intensive Care Medicine, Leuven, Belgium e-mail: [email protected]; lies. [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_28

Abstract

In addition to energy storage and insulation, the white adipose tissue is a complex endocrine organ responsible for the secretion of a high number of adipocyte-originated signaling molecules. These so-called adipokines are involved in the control of metabolism, linking the nutrient status to the tissues involved in energy intake and expenditure and affecting insulin sensitivity. Additionally, resident and recruited macrophages constitute an important part of the adipose tissue, responsible for the secretion of inflammatory and anti-inflammatory cytokines. Up until now, more than 40 different adipokines have been described. From these, leptin and adiponectin are the most studied during critical illness. Although knowledge is still limited, current available literature suggests that the endocrine functions of adipose tissue might play an adaptive role during critical illness. In the acute phase of illness, the anti-inflammatory and insulin-sensitizing adiponectin is reduced, while pro-inflammatory cytokine expression in adipose tissue is upregulated. In the prolonged phase of critical illness, both adiponectin and anti-inflammatory cytokine production are increasing. Reports on the pro-inflammatory leptin during critical illness are controversial in both humans and animal investigations, possibly due to confounders such as gender, body mass index, and nutritional strategy. 119

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Observational studies report lower mortality in obese than in lean critically ill patients, an association referred to as the “obesity paradox.” Potentially, the altered adipokine secretion profile observed in obesity plays a protective role during critical illness. List of Abbreviations

AdipoR ARDS

Adiponectin receptor Acute respiratory distress syndrome CXCL10 C-X-C motif chemokine 10 EMR1 EGF-like module-containing mucin-like hormone receptor HMW High molecular weight IL Interleukin kDa Kilodalton LMW Low molecular weight LPS Lipopolysaccharide MCP-1 Monocyte chemoattractant protein1 MMW Medium molecular weight PAI-1 Plasminogen activator inhibitor-1 PPARγ Peroxisome proliferator-activated receptor γ RBP4 Retinol-binding protein 4 ROS Reactive oxygen species TNF-α Tumor necrosis factor-alpha

M. Marques and L. Langouche

and secretion of endocrine signals; the main function of brown and “beige” adipose tissue is the production of heat. In this chapter, the endocrine function of the white adipose tissue will be discussed. White adipose tissue is a heterogeneous tissue composed of adipocytes and multiple other cell types including pre-adipocytes, endothelial cells, fibroblasts, macrophages, and other immune cells, together secreting over 40 different signaling molecules. Some of these “adipokines” are mainly produced by the adipocytes (such as adiponectin and leptin), whereas others are preferentially secreted by endothelial cells (matrix proteins) or immune cells (cytokines). These secreted signaling factors are involved in energy homeostasis, appetite, inflammation, insulin sensitivity, and immunity. In patients with obesity, the presence of chronic inflammation appears to change the production and secretion of several adipokines, thereby affecting their role in insulin sensitivity and inflammation. The aim of this review is to summarize the current knowledge on the endocrine role of adipose tissue during critical illness, as several of these adipokines have been studied in the course of critical illness.

Introduction

The Role of Adiponectin During Critical Illness

Adipose tissue plays an important part in the regulation of energy homeostasis and nutrient intake. Next to its well-defined role in storage and release of energy, adipose tissue is also the largest endocrine organ of the human body, representing 20 % of total body weight in lean individuals to more than 50 % in morbidly obese individuals. Adipose tissue can be classified in white adipose tissue, brown adipose tissue, and “beige” or “brittle” adipose tissue. The recently identified “beige” adipose tissue is defined as brown-like cells interspersed in the white adipose tissue. Brown and “beige” adipose tissues are functionally similar, despite of being derived from different precursors (Wu et al. 2012). The main function of white adipose tissue is energy storage, insulation,

Adiponectin is a large (30 kDa) peptide, almost exclusively secreted into the bloodstream by adipocytes. Circulating levels are very high compared to other circulating peptides, representing 0.01 % of total plasma proteins. Despite its source of origin, circulating adiponectin has an inverse correlation with body mass index. Males display lower levels compared to females, which is believed to be attributable to testosterone. Adiponectin forms multimers and circulates in the form of low-molecular-weight trimers and hexamers or high-molecular-weight octodecamers (Fig. 1). The high-molecular-weight adiponectin is the main circulating form and considered the most biological active (Wang et al. 2008). Adiponectin acts on multiple receptors: adiponectin receptor

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Fig. 1 The polymerization of adiponectin. Adiponectin can be found in the circulation in various molecular forms. The low-molecular-weight (LMW) form is a trimer, which consists of three monomers assembled through

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hydrophobic interactions. Disulfide bridges are responsible for the assembly in the medium-molecular-weight (MMW) hexamer and high-molecular-weight (HMW) octodecamer

Fig. 2 Pleiotropic functions of adiponectin and its target organs. Adiponectin exerts insulinsensitizing effects in the liver and skeletal muscle, anti-inflammatory and antiatherogenic functions in endothelial cells, and antiproliferating functions on macrophages

1 (AdipoR1) (expressed predominantly in skeletal muscle), AdipoR2 (expressed predominantly in the liver), and T-cadherin receptor (expressed in endothelial and smooth muscle cells). Adiponectin is involved in lipid and glucose metabolism (Fig. 2): it works as an insulinsensitizing hormone, stimulating insulin signaling, decreasing hepatic glucose production, and increasing glucose uptake and fatty acid oxidation in skeletal muscle (Okamoto et al. 2006). In addition, adiponectin exerts antiatherogenic and anti-inflammatory actions. Adiponectin inhibits adhesion molecule expression on vascular endothelial cells; it increases endothelial nitric oxide (NO) production, downregulates T-lymphocyte recruitment, reduces macrophage growth, and interferes with the function of macrophages by reducing their phagocytic activity and lipopolysaccharide (LPS)-induced production of cytokines

and chemokines (Okamoto et al. 2006). Several of the anti-inflammatory actions of adiponectin may be regulated through its actions on tumor necrosis factor (TNF)-α signaling (Ouedraogo et al. 2007). In contrast with the low circulating adiponectin levels observed in obesity and associated comorbidities, elevated circulating levels of adiponectin are present in patients with inflammatory and immune-mediated diseases (Fig. 5; Fantuzzi 2008). Several studies have demonstrated reduced adiponectin levels in critically ill patients upon admission to intensive care with normal to high levels in the chronic phase of critical illness (Jernas et al. 2009; Langouche et al. 2007, 2009; Walkey et al. 2010; Venkatesh et al. 2009). Septic patients displayed higher levels that further increased over time (Vassiliadi et al. 2012). Low levels of adiponectin in the acute phase of illness could be induced by

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cytokines such as TNF-α, interleukin (IL) -6, and plasminogen activator inhibitor-1 (PAI-1) which have a known inhibitory effect on adiponectin secretion, but also hyperglycemia and high cortisol levels might modulate low adiponectin levels (de Oliveira et al. 2011). Walkey et al. demonstrated higher day 1 adiponectin levels in non-surviving patients with acute respiratory failure, compared to surviving patients (Walkey et al. 2010). Additionally, Venkatesh et al. described a positive correlation between sickness severity and plasma adiponectin at day 3 of illness (Venkatesh et al. 2009). From both studies, no admission data is available, so whether or not an initial drop in adiponectin occurred during the early phase of critical illness is not known. Possibly, the higher adiponectin levels that were observed in more severely ill patients might just be a reflection of the severity of their illness, as plasma adiponectin showed a positive correlation with plasma cortisol levels and with a higher insulin demand (Gavrila et al. 2003; Hillenbrand et al. 2011; Venkatesh et al. 2009). In this line of reasoning, one could speculate that higher adiponectin levels in the early phase of illness represent a dysfunctional response to the stress of the illness, whereas a reduction in adiponectin could be seen as adaptive. In a more prolonged setting, increasing adiponectin levels might potentially act protective by blunting the overwhelming pro-inflammatory response to illness. Interestingly, adiponectin knockout mice suffer from substantially increased mortality after cecal ligation and punctureinduced sepsis or thioglyocollate-induced peritonitis, largely attributable to impaired immune and endothelial function, while pre-treatment with adiponectin prior to the insult blunted these effects (Teoh et al. 2008). From these reports, one might theorize that adiponectin treatment during prolonged critical illness would improve outcome, by improving the inflammatory response, increasing insulin sensitivity, or reducing vasopressor needs (Robinson et al. 2011). In spite of the insufficient knowledge on the exact role of adiponectin during critical illness, it is clear that adiponectin holds promise as a prognostic marker and potentially as a

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therapeutic target. But a better knowledge of the pathophysiology of adiponectin in relation to severe illness is needed prior to human studies with the administration of exogenous adiponectin.

The Role of Leptin in Critical Illness Leptin is a 16 kDa hormone that is predominantly secreted by adipocytes. The level of circulating leptin during health is proportional to the total amount of fat mass; levels are higher in obese individuals and are lowered when body fat mass is reduced by dieting or bariatric surgery (Ahima and Lazar 2008; Cowley et al. 2001). Leptin interacts with its specific leptin receptor to initiate a wide array of functions and is primarily cleared by the kidney (Meyer et al. 1997). Leptin binds to receptors on the arcuate, dorsomedial, and ventromedial hypothalamic nuclei to regulate energy balance by reducing food intake and increasing basal energy expenditure (Ahima and Lazar 2008). In skeletal muscle, leptin increases fatty acid oxidation through phosphorylation/activation of AMPK (Minokoshi et al. 2004). Obese individuals exhibit very high leptin levels and are considered to be leptin resistant, thereby limiting the appetite-reducing and energy expenditure effects of the hormone (Konner and Bruning 2012). In addition to its regulation of the energy balance, leptin has clear pro-inflammatory properties. Leptin resembles the cytokine IL-6 in structure and function: it can modulate innate immune responses such as T-helper cell differentiation, macrophage phagocytosis, and cytokine synthesis (Mancuso et al. 2002). Furthermore, leptin can stimulate proliferation and migration of endothelial cells, upregulation of endothelial NO production, and reactive oxygen species (ROS) accumulation (Sweeney 2010). Importantly, adipose tissue contains a high number of residing macrophages, and leptin can stimulate cytokine production (IL-1Ra and IL-6) of monocytes (La Cava and Matarese 2004). In stressful conditions, leptin levels become disproportionate to fat mass and increase acutely. This sudden leptin increase during stress may be explained by the concomitant rise in cortisol.

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Indeed, glucocorticoids stimulate leptin gene expression and leptin secretion (Papaspyrou-Rao et al. 1997). Also elevated levels of endotoxin and certain cytokines result in a significant elevation of leptin (Bornstein et al. 1998; Grunfeld and Feingold 1991; Grunfeld et al. 1996). The role of leptin during critical illness is not yet fully elucidated as conflicting results have been reported (Fig. 5). Several studies reported elevated leptin levels in acute septic patients, whereas these levels declined again in the prolonged phase of sepsis (Arnalich et al. 1999; Bornstein et al. 1998; Orbak et al. 2003; Tzanela et al. 2006; Behnes et al. 2012). Levels of leptin were also significantly elevated in animal models of acute sepsis (Faggioni et al. 1998; Grunfeld et al. 1996; Heuer et al. 2004; Moshyedi et al. 1998). On the contrary, several other studies in critically ill patients described low to normal levels of leptin in the acute phase of illness and normal to elevated levels in the prolonged phase of illness (Jeevanandam et al. 1998; Langouche et al. 2009; Papathanassoglou et al. 2001; Quasim et al. 2004; Van den Berghe et al. 1998; Yousef et al. 2010). Animal results add up to the contradicting human findings. Mice that were either leptin deficient or leptin receptor deficient displayed increased mortality following intratracheal K. pneumoniae administration (Mancuso et al. 2002; Tschop et al. 2010). This increased susceptibility was associated with impaired bacterial clearance and defective alveolar macrophage phagocytosis in vitro and could be counteracted by administering high doses of leptin (Mancuso et al. 2002). In contrast, in a study by Shapiro et al., leptin receptor-deficient mice were protected from sepsis-induced mortality, and exogenous administration of leptin increased mortality (Shapiro et al. 2010). Jain et al. demonstrated that leptin receptor-deficient mice were resistant to the development of lung fibrosis, and they found higher leptin levels in the bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome (ARDS) (Jain et al. 2011). A likely contributor to the observed differences in leptin levels is the nutritional status of the patient population, both preadmission and during

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the stay in intensive care. Indeed, fasting or a period of malnutrition prior to surgery was shown to be associated with lowered leptin levels, whereas the administration of parenteral feeding increased leptin levels (Boden et al. 1996; Jeevanandam et al. 1998; LeGall-Salmon et al. 1999; McCowen et al. 2002). In a controlled, randomized human study on the impact of early parenteral nutrition during critical illness, it was demonstrated that the administration of parenteral feeding increased circulating leptin levels, whereas they were reduced by fasting (Langouche et al. 2013). Another factor that might explain the observed discrepancy is the time of sampling. Yousef et al. demonstrated in a study on the time course of leptin throughout sepsis and systemic inflammation that not the admission leptin levels but rather the day 2 levels were elevated and returned to normal levels after 1 week (Yousef et al. 2010). Another study in trauma patients demonstrated an initial decline in leptin in the first 6 h after major surgery, followed by a culminating increase 6–24 h after surgery, after which leptin levels again declined (Maruna et al. 2009). Because of the contradicting findings, at this time any conclusion on the potential role of leptin during critical illness remains speculative.

The Role of RBP4 in Critical Illness Retinol-binding protein 4 (RBP4) is an adipose tissue-derived specific transporter for retinol (vitamin A) circulating in the blood. More recently it has been described as an adipokine involved in the early pathological feature of insulin resistance (Yang et al. 2005). Circulating levels of RBP4 are elevated in subjects with obesity and type 2 diabetes and lowered with improved insulin sensitivity (Graham et al. 2006; Yang et al. 2005). Increasing RBP4 levels impair insulin IRS-1/Akt signaling (Yang et al. 2005). RBP4 is preferentially expressed in visceral adipose tissue and increased circulating levels of RBP4 are associated with increased visceral adipose tissue (Kolaczynski et al. 1996). However, in clinical studies, the link among serum RBP4 levels, RBP4 gene expression, insulin resistance, and obesity is currently

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somewhat debated as several studies found no correlation between circulating RBP4 levels, obesity, and the distribution of adipose tissue (Kotnik et al. 2011). As hyperglycemia and insulin resistance are typical features of critical illness, one could expect reduced RBP4 levels in such patients. Indeed, several studies have observed low admission levels of RBP4 in critically ill patients of diverse origin (Langouche et al. 2009; Koch et al. 2010; Moody 1982). Patients with sepsis had lower levels of RBP4 than non-septic patients (Langouche et al. 2009). Whether there is a functional consequence of reduced RBP4 levels during critical illness remains to be elucidated.

Cytokine Production in Adipose Tissue During Critical Illness In contrast with the extensive literature on circulating cytokine levels in the course of critical illness, information about cytokines secreted by the adipose tissue during critical illness remains scarce. In humans, cardiac surgery has shown to induce a strong elevation in gene expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), and TNF-α in adipose tissue (Kremen et al. 2006). LPS injection in mice caused elevation of adipose tissue-specific gene expression of TNF-α, MCP-1, and IL-6 (Leuwer et al. 2009; Starr et al. 2009). Experimental endotoxemia in healthy humans induced gene expression of pro-inflammatory cytokines IL-6, MCP-1, and TNF-α in gluteal adipose tissue (Leuwer et al. 2009; Mehta et al. 2010). Also the expression of the chemotactic C-X-C motif chemokine 10 (CXCL10) and the macrophage marker EGF-like module-containing mucin-like hormone receptor (EMR1) was upregulated (Mehta et al. 2010). These observations suggest that, during the acute phase of critical illness, adipose tissue seems to respond with the expression of pro-inflammatory cytokines. In contrast, in prolonged critically ill patients, the adipose tissue expression of the pro-inflammatory TNF-α was low, whereas the expression of the anti-inflammatory cytokine IL-10 was increased (Langouche et al. 2011).

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As explained above, adipose tissue contains several cell types besides the adipocytes, which might be responsible for the production of cytokines. In healthy lean individuals, macrophages count for around 5 % of the cells in adipose tissue, whereas in obese individuals this level can increase up to 60 % (Weisberg et al. 2006). Remarkably, also in critically ill patients, a distinct accumulation of macrophages was observed in subcutaneous and visceral adipose tissue biopsies from prolonged critically ill patients (Langouche et al. 2010, 2011). Experimental human inflammation leads to the increased gene expression of chemotactic factors MCP-1 and CXCL10, suggesting that these macrophages did not migrate randomly to adipose tissue but were attracted to it by chemotactic factors (Mehta et al. 2010). It is well known that macrophages adapt to the microenvironment by switching from one phenotype and function to the other. Among the main phenotypes, the classically activated macrophage M1 and the alternatively activated macrophage M2 can be identified (Fig. 3) (Gordon and Taylor 2005; Mantovani et al. 2002). M1 macrophages are mainly activated by interferon-γ and have an enhanced pro-inflammatory cytokine and nitric oxide production. M2 macrophages are activated predominantly by IL-4 and IL-13; they secrete high levels of the anti-inflammatory IL-10 and arginase1 (Gordon and Martinez 2010; Odegaard and Chawla 2008). In the prolonged phase of critical illness, the macrophages that accumulated in adipose tissue were identified as mainly M2 or “alternatively activated” macrophages. Curiously, while increased nutrient intake and obesity is associated with M1 macrophage accumulation, prolonged critical illness is associated with M2 macrophage accumulation. Why critical illness is associated with increased infiltration and a phenotypical switch of macrophages is not clear yet. There is a variety of M2 macrophage features such as increased phagocytic activity, tissue healing and remodeling, tumor progression, and promotion of insulin sensitivity, suggestive for a potential adaptive and protective role during critical illness (Sica and Mantovani 2012). A potential trigger for the switch to M2 macrophages might be the observed elevated levels peroxisome proliferator-activated receptor γ (PPARγ)

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Fig. 3 Schematic overview of macrophage polarization. Macrophages are plastic and change their function and physiology in response to environmental triggers. The two opposite sides of a continuous activation spectrum are M1 and M2 macrophages. M1 macrophages, or classically activated macrophages, are activated by LPS and

IFN-γ. They are pro-inflammatory immune cells and secrete high levels of TNF-α and nitric oxide. M2 macrophages or alternative activated macrophages are activated by Il-4 and Il-13 and display anti-inflammatory woundhealing features. They produce high levels of IL-10 and arginine

in adipose tissue during critical illness (Langouche et al. 2011). PPARγ is a nuclear receptor with fatty acids and prostaglandins as known endogenous ligands, and it plays an indispensable role in both the differentiation into M2 macrophages and in the formation of new adipocytes (Ahfeldt et al. 2012). Remarkably, critically ill patients also present increased number of small adipocytes (Langouche et al. 2010). Newly formed, small adipocytes are recognized as being more insulin sensitive (Roberts et al. 2009), so both small adipocytes and M2 macrophages observed during prolonged critical illness could act synergistically.

atherosclerosis, arterial hypertension, diabetes, cardiac ischemic disease, fatty liver disease, and cancer. Coinciding with its increasing prevalence in the general population, the number of obese patients in the intensive care unit has steadily increased over the years (Marik and Varon 2001). These morbidly obese patients do suffer from longer duration of mechanical ventilation and longer intensive care stay (Martino et al. 2011). But in contrast with the general population, in the intensive care unit, an inverse relationship is observed between body mass index and mortality (Fig. 4; Abhyankar et al. 2012; Hogue et al. 2009; Oliveros and Villamor 2008; Akinnusi et al. 2008). A possible explanation for this obesity paradox could be found in the endocrine role of the adipose tissue (Fig. 5). Indeed, one could postulate that excess adipose tissue might act as a source of beneficial adipokines. Obese, non-critically ill individuals generally display high leptin levels and low adiponectin levels. Leptin has been shown to modulate innate immune responses, which might point to a protective role in the acute critically ill setting. In addition, low

The Obesity Paradox in Critically Ill Patients and Its Relation to the Endocrine Function of Adipose Tissue In the general population, overweight and obesity are associated with an increased risk of death (Janke et al. 2006). Metabolic changes associated with obesity lead to deleterious conditions and diseases, among which are dyslipidemia,

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admission adiponectin levels were linked to better survival, possibly by allowing a pro-inflammatory response during the initial phase of illness (Papathanassoglou et al. 2001). So in contrast with the chronic detrimental consequences of high leptin and low adiponectin levels, obese patients might benefit from their endocrine profile during the acute stress phase of critical illness.

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Applications to Critical Care The endocrine role of adipose tissue during critical illness is a new field of investigation that requires further “in vitro” and “in vivo” research.

Summary Points

Fig. 4 The obesity paradox in critical illness. This schematic presentation of the association of mortality and body mass index of critically ill patients indicates the lower mortality levels that are observed in patients who are overweight and obese compared to the lean patient population (Reproduced from Marques and Langouche (2013). Copyright Wolters Kluwer Health)

Fig. 5 Adipose tissue alters during health and disease

• Endocrine functions of adipose tissue might play a role in the adaptation to critical illness. • Acutely, the anti-inflammatory adiponectin is reduced, and pro-inflammatory cytokine expression in adipose tissue is upregulated. • In the prolonged phase of critical illness, both adiponectin and anti-inflammatory cytokine production is elevated. • Accumulated macrophages switch to an antiinflammatory, insulin-sensitizing M2 type. • Studies on the pro-inflammatory leptin during critical illness are inconsistent possibly due to confounders such as gender, body mass index, and concomitant feeding. • Several of the changes in adipose tissue observed during critical illness could in theory be adaptive and protective.

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10

Steven J. Martin and Celeste A. Sejnowski

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Pneumonia and Ventilator-Associated Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology and Microbiology . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Guidelines and Protocols . . . . . . . . . . . . . . . . . Application to Critical Care . . . . . . . . . . . . . . . . . . . . . . . . .

133 133 133 133 134 134

Bloodstream Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Guidelines and Protocols . . . . . . . . . . . . . . . . . Applications to Critical Care . . . . . . . . . . . . . . . . . . . . . . . .

135 135 135 135 136 136 136

Urinary Tract Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Guidelines and Protocols . . . . . . . . . . . . . . . . . Application to Critical Care . . . . . . . . . . . . . . . . . . . . . . . . .

136 136 137 137 137 137 138

Clostridium difficile Gastrointestinal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Guidelines and Protocols . . . . . . . . . . . . . . . . . Applications to Critical Care . . . . . . . . . . . . . . . . . . . . . . . .

138 138 138 139 139 139 139

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

S.J. Martin (*) Department of Pharmacy Practice, Ohio Northern University Raabe College of Pharmacy, Ada, Ohio, USA e-mail: [email protected] C.A. Sejnowski Department of Pharmacy, Promedica Flower Hospital, Sylvania, Ohio, USA e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_140

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132

Abstract

Critically ill patients often display a systemic inflammatory response due to the presence of a catabolic stress state. Physical barriers are commonly altered in critical illness, presenting an opportunity for microorganisms to enter the body. Invasive devices or procedures compromise the body’s natural barrier functions in critically ill patients, leading to risk of infection. Altered host defense mechanisms can predispose critically ill patients to infections due to the presence of endotracheal tubes, arterial or venous catheters, urinary catheters, and broadspectrum antibiotic exposure. Treatment of infections can be difficult in critically ill patients due to increased resistance to common antimicrobial agents. Preventative strategies are crucial to reducing the prevalence of infection in health-care institutions. This chapter provides an overview of the epidemiology, microbiology, pathophysiology, and treatment of four major infectious problems in critical illness: pneumonia, urinary tract infection, bloodstream infection, and antibiotic-associated gastrointestinal infections. List of Abbreviations

BSI CAUTI

Bloodstream infections Catheter-associated urinary tract infection CDI Clostridium difficile infections CRBSIs Catheter-related bloodstream infections FMT Fecal microbiota transplant HLA-DR Human leukocyte antigen-DR ICU Intensive care unit MDR Multidrug resistant NAP1/BI/027 Toxinotype III REA type BI, PCR ribotype 027, pulsedfield type NAP-1 PO By mouth QID Four times daily TID Three times daily UTIs Urinary tract infections VAP Ventilator-associated pneumonia WBC White blood cell

S.J. Martin and C.A. Sejnowski

Introduction Critical illness often leads to infection. Critically ill patients often display a systemic inflammatory response due to the presence of a catabolic stress state. Exogenous fuels are essential to critically ill patients in order to preserve lean body mass, maintain immune function, and prevent metabolic complications during the body’s stress response (McClave et al. 2009). There are a number of inherent risks associated with critical illness that underlie the causes of infection. Data from a point prevalence trial in Europe suggested that the rate of infection exceeds 50 % in the intensive care unit (ICU), and greater than 70 % of ICU patients receive antibiotic therapy for suspected or documented infection (Angus et al. 2001). Additional data indicate that neurosurgical and mixed surgical/medical ICUs have higher prevalence of infection than medical, pediatric, or surgical ICUs. Pneumonia remains the most common type of infection (53.6 %), followed by bloodstream infection (23.4 %), urinary tract (16.7 %), and catheter-related infections (6.3 %) (Agodi et al. 2013). Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Acinetobacter baumannii are the most commonly isolated pathogens. Typically, the more severe the illness, the greater the likelihood of infection. Longer lengths of stay in the ICU are also associated with greater prevalence of infection. Infection more than doubles ICU and hospital mortality rates and is associated with longer ICU and hospital lengths of stay (Vincent et al. 2009). Physical barriers are commonly altered in critical illness, presenting an opportunity for microorganisms to enter the body. Invasive devices or procedures, such as endotracheal tubes, arterial or venous catheters, urinary catheters, and surgery, compromise the body’s natural barrier functions (Kress and Hall 2012). Additional barrier disruption, such as through mechanical ventilation, gut mucosal dysfunction,

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Extent and Nature of Infectious Diseases in Critical Care

or pressure-induced ulcerations, also leads to risk of infection. Immune system dysregulation as a result of critical illness may also predispose patients to infection. Innate immunity may be stimulated, but its effects are commonly blunted as a result of critical illness. Although circulating neutrophil activation is enhanced, impaired chemotaxis has been noted in patients with sepsis (Marshall et al. 2008). Adaptive immune response may also be affected in sepsis. Monocyte expression of HLA-DR is decreased, and the number of circulating and splanchnic dendritic cells is reduced (Marshall et al. 2008). Lymphocytic apoptosis is increased; T-cell responsiveness is blunted. The opportunistic nature of many infections in the critically ill host underscores the altered normal response to microbial invasion. Although critical illness can lead to myriad infectious complications, the altered host defense systems predispose to several common infections in ICU patients, including ventilatorassociated pneumonia (VAP), urinary tract infections (UTIs), bloodstream infections (BSI), intra-abdominal infections, fungal infections, central nervous system infections, skin and wound infection, sinusitis, and gastrointestinal infection (often with Clostridium difficile). Infection may also produce critical illness, through dysregulation in inflammatory and antiinflammatory immune system response. Examples include sepsis, community-acquired pneumonia, community-acquired UTI, meningitis, and gastrointestinal and peritoneal infection. The variety of microorganisms that cause infection in the critically ill host makes management of these patients challenging. Resistance to common antimicrobial agents is a leading cause of failure to successfully manage critical illnessrelated infection. The focus of this chapter is to review the epidemiology, pathophysiology, microbiology, and treatment of four of the most common infections in critically ill patients: lung, blood, urinary tract, and antibiotic-associated C. difficile gastrointestinal infections.

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Pneumonia and Ventilator-Associated Pneumonia Introduction Pneumonia is among the most common infections in the critically ill. Ventilator-associated pneumonia (VAP) affects 9–27 % of intubated patients and has an incidence of up to 20 times that of pneumonia in non-ventilated patients (American Thoracic Society, Infectious Disease Society of America 2005). The epidemiology of the microorganisms causing VAP is influenced by many factors, such as length of ICU and hospital stay, duration of mechanical ventilation, exposure of the patient and the environment to antimicrobial agents, and several patient-specific comorbidities. Antimicrobial exposure in the environment and in individual patients is responsible for the increasing prevalence of drug-resistant bacterial and fungal infections.

Epidemiology and Microbiology In nearly all epidemiologic studies performed over the past 10 years, the most common microbial causes of VAP are P. aeruginosa, other enteric Gram-negative bacilli, and S. aureus. Enterobacter species and Acinetobacter species are common enteric bacilli associated with antimicrobial resistance and poor outcomes. Polymicrobial pneumonia may occur in 20–40 % of respiratory infections, and bacterial, viral, and fungal pathogens have all been described. Viral and fungal disease is much less common than bacterial infection in critical illness, except in at-risk populations such as the immunologically compromised posttransplant patient. Table 1 provides a list of common pathogens in VAP.

Pathophysiology Pneumonia in critically ill patients often results from aspiration of oropharyngeal secretions or gastric contents colonized with microorganisms.

134 Table 1 Common pathogens in VAP in the critically ill (Aarts et al. 2008) No risk factorsa Streptococcus pneumoniae Haemophilus influenzae Antibacterial-sensitive enteric Gram-negative bacilli E. coli K. pneumoniae Enterobacter species Proteus species Serratia marcescens Late onset (>5 days) or one of the risk factorsa below: P. aeruginosa E. coli K. pneumonia Acinetobacter species S. aureus; including methicillin-resistant S. aureus a

Risk factors Antimicrobial therapy in preceding 90 days Current hospitalization of 5 days High prevalence of antimicrobial resistance in the community or in the specific hospital unit Hospitalization for 2 days in the preceding 3 months Residence in a nursing home or extended care facility Home infusion therapy Chronic dialysis within 30 days Home wound care Family member with multidrug-resistant pathogen Immunosuppressive disease or therapy

As described above, an impaired host defense mechanism is largely responsible for this aspiration, including the presence of an endotracheal tube that bypasses mucociliary clearance and cough, and establishes an unobstructed passage between the trachea and the upper airway. The endotracheal tube may also be a source of microbial colonization.

S.J. Martin and C.A. Sejnowski

hypopharyngeal hygiene. Other strategies that focus beyond prevention of VAP but have an association with lower incidence of VAP are proper nutrition (including route of administration), adequate analgesia and sedation, thromboembolic prophylaxis, gastric stress erosion prophylaxis, and glucose control (Vincent et al. 2009). Treatment of VAP includes early identification of infection, selection of antimicrobial agents that provide adequate coverage for the possible causative organisms, and rapid de-escalation to narrow and focused therapy for a limited duration to eradicate the pathogen involved. The challenge with initiating empiric antimicrobial therapy is that selection must occur before culture material has been processed, and culture and sensitivity data often take several days to be reported. Because of this delay, guidelines have been established to direct prescribers in identifying the most likely causative pathogens and broadly outlining effective therapy given current antimicrobial resistance data. Table 2 provides an overview for empiric antimicrobial therapy selection for VAP. The duration of therapy for VAP varies widely; recent trends have focused on shorter length of therapy, such as 8 days, rather than more traditional 10–14-day courses. A study performed in 51 French ICUs determined that treatment of VAP for 8 days was associated with no greater risk of recurrent infection, nor risk of death, than a 15-day regimen, with the exception of those infected with non-lactose-fermenting Gram-negative bacilli, including P. aeruginosa or Acinetobacter species. Recurrent infection was associated with higher rates of multidrug resistance in causative organisms, which increased as the duration of therapy increased (Chastre et al. 2003).

Treatment Guidelines and Protocols Application to Critical Care Prevention of lung infection is possible, and several institutions have eliminated VAP as an infection in their ICUs. Several strategies have been found to have an association with lower incidence of VAP, including daily evaluation for a spontaneous breathing trial, appropriate sedation level using a sedation scoring system, head-of-bed elevation to 30–45 , and daily oral and

Pneumonia, especially when associated with mechanical ventilation, is a common cause of morbidity and mortality in ICU patients. Several risks are present in the mechanically ventilated patient, but VAP can be dramatically reduced with protocols that address a variety of interventions that have demonstrated positive effects.

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Table 2 Ventilator-associated pneumonia treatment strategies (American Thoracic Society, Infectious Disease Society of America 2005) Empiric antimicrobial agent choice If late onset (5 days) or risk for multidrug-resistant (MDR) organisms Choose from Antipseudomonal cephalosporin (cefepime or ceftazidime) OR Antipseudomonal carbapenem (imipenem or meropenem) OR Beta-lactam/beta-lactamase inhibitor (piperacillin/ tazobactam) PLUS Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) OR Aminoglycoside (amikacin or gentamicin or tobramycin) Plus Linezolid or vancomycin If not late onset or no risk for MDR Ceftriaxone OR Levofloxacin or moxifloxacin or ciprofloxacin OR Ampicillin/sulbactam OR Ertapenem

Treatment of pneumonia is complicated by the need for broad-spectrum empiric coverage and increasing rates of antimicrobial resistance.

Bloodstream Infections Introduction A 2009 worldwide point prevalence study of infection in the ICU found that of the 13,796 adult patients studied, 7,087 (51 %) were classified as infected on the day of the study, and 1,071 (15.1 %) of infections were BSI. Bloodstream infections are commonly the result of indwelling intravenous catheters; central venous catheters predispose to even greater risks of infection (Centers for Disease Control and Prevention 2000).

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The crude rate mortality rate from BSI ranges from 35 % to 53 % (Mermel et al. 2009; Garnacho-Montero et al. 2008; Karchmer 2009). Prolonged ICU and hospital length of stay are common for patients with BSI. Intensive care unit stay has been reported to increase from 7.5 to 25 days, and total hospitalization time from 4.5 to 32 days (Garnacho-Montero et al. 2008). Proper antimicrobial therapy is a key in reducing mortality from BSI (Evans and Chitkara 2012).

Epidemiology Approximately 80,000 cases of catheter-related bloodstream infections (CRBSIs) occur every year in the United States in ICUs and are associated with infected intravascular devices (Mermel et al. 2009). The risk of bloodstream infection differs based on the type of catheter, insertion site, duration of placement, and technique of placement.

Pathophysiology Catheters can become contaminated by skin organisms at the insertion site that colonize the catheter tip or by contamination of the catheter or hub by contact with hands, fluids, or devices (O’Grady et al. 2011). The presence of a catheter itself is the most important risk factor related to CRBSIs. The highest rates of CRBSIs are from pulmonary artery catheters and central venous catheters (Evans and Chitkara 2012). Other risk factors for CRBSIs include malnutrition, burns, loss of skin integrity, advancing age, and immunosuppression (Evans and Chitkara 2012). The diagnosis of CRBSI can be made when the same organism grows from one catheter tip culture and one percutaneous blood culture or when the same organism grows from two blood samples (such as a catheter hub and peripheral vein). When cultured, the colony count from the catheter lumen blood culture must be three times or higher than the peripheral vein, or the growth detected from the catheter hub must be detected at least 2 h before blood is detected from peripheral vein culture (Mermel et al. 2009).

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Microbiology Common organisms causing BSI (Table 3) include coagulase-negative staphylococci, S. aureus, Enterococcus species, Candida species, and E. coli (Evans and Chitkara 2012).

Treatment Guidelines and Protocols

S.J. Martin and C.A. Sejnowski Table 3 Common pathogens in catheter-related bloodstream infections in the critically ill (Mermel et al. 2009; Garnacho-Montero et al. 2008; Karchmer 2009) Coagulase-negative staphylococci Staphylococcus aureusa Candida speciesb Enteric Gram-negative bacillib (E. colia and P. aeruginosa) Enterococcus speciesb a

Responsible for infection early in the hospital stay Responsible for infection significantly later during hospital stay

b

Ongoing education regarding the indications for intravascular catheter use and procedures for the insertion and maintenance of intravascular catheters is important for the prevention of CRBSIs. Hand hygiene procedures and aseptic technique should be performed before or after palpating or inserting a catheter (O’Grady et al. 2011). An upper-extremity site is preferred for catheter insertion in adult patients. If a central venous catheter is chosen for insertion, risks and benefits should be weighed due to infection risks (O’Grady et al. 2011). Table 3 provides an overview for empiric antimicrobial therapy selection for CRBSI. Empiric therapy for methicillin-resistant S. aureus and Gram-negative bacilli CRBSI should be based on local susceptibility patterns, whereas empiric therapy for multidrug-resistant (MDR) Gram-negative bacilli should be used in neutropenic patients, severely ill patients with sepsis, or colonized patients with MDR organisms (Mermel et al. 2009). Empiric therapy for catheter-related candidemia should be used for patients receiving total parenteral nutrition and long therapies of broad-spectrum antibiotics or with femoral catheterization, as well as those suffering from malignancy, bone marrow or solid-organ transplant patients, or who have demonstrated colonization with Candida species from multiple sites. Fluconazole may be used as empiric treatment for candidemia if the patient has not previously been exposed to an azole within the previous 3 months and if the risk of Candida krusei or Candida glabrata infection is low (Mermel et al. 2009). If the intravenous catheter has been removed, antibiotic therapy should be administered for 10–14 days after the first day of negative blood

cultures. If the bacteremia or fungemia is persistent (occurs more than 72 h after catheter removal), therapy should continue for 4–6 weeks, and patients should be evaluated for suppurative thrombophlebitis and endocarditis (Mermel et al. 2009).

Applications to Critical Care Critical care practitioners should be aware of the complications that can arise due to the use of intravenous catheters. Proper measures should be made to avoid infection by monitoring the indications, insertion, and maintenance of intravenous catheters. Nutritional supplementation may play a role in BSI in the critically ill. Enteral nutrition use has been associated with decreased infectious morbidity related to central line infections and is the preferred route over parenteral for nutrition support therapy (McClave et al. 2009).

Urinary Tract Infection Introduction Urinary tract infection (UTI) in critically ill patients is commonly associated with indwelling urinary catheter use. In distinction to the non-ICU setting, most ICU patients do not exhibit signs or symptoms attributable to UTI. Nosocomial catheter-associated UTI (CAUTI) is associated with exposure to antimicrobial agents and often

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Extent and Nature of Infectious Diseases in Critical Care

is caused by antimicrobial-resistant pathogens (Chant et al. 2011). Both ICU and hospital length of stay are increased with nosocomial UTI in the ICU, although there are insufficient data to link increased mortality to UTI (Laupland et al. 2005; Chant et al. 2011).

Epidemiology In the 2009 point prevalence trial, renal/urinary tract infection represented 14.3 % (1011) of all nosocomial ICU infections (Vincent et al. 2009). The rate of CAUTI in the ICU has decreased over the last two decades, probably from widespread interventions occurring nationwide (Burton et al. 2011).

Microbiology Catheter-associated UTI in critically ill patients is often monomicrobial and caused by multidrugresistant organisms. Enterobacteriaceae, especially E. coli, Serratia species, Citrobacter species, Enterobacter species, and Klebsiella species, are common pathogens. In the ICU setting, Candida species, Enterococcus species, and P. aeruginosa are also commonly observed (Chenoweth et al. 2014). Candida species now account for 28 % of CAUTIs reported from ICUs and represent a growing concern with fungal infection in this at-risk population (Chitnis et al. 2012). Antimicrobial resistance is common in urinary pathogens, with the highest resistance being reported to ciprofloxacin, gentamicin, tobramycin, ceftazidime, piperacillin, and piperacillin/ tazobactam (Laupland et al. 2005).

Pathophysiology Risks for CAUTI include increasing duration of catheterization, severity of illness, age greater than 50 years, diabetes mellitus, and serum creatinine greater than >2 mg/dl. Additional risks may include female gender and improper catheter insertion technique (Chenoweth et al. 2014).

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Table 4 Common pathogens in catheter-associated urinary tract infection in the critically ill (Chenoweth et al. 2014) E. colia, b Candida species Enterococcus species P. aeruginosa Klebsiella (pneumoniae/oxytoca)a, b a

Many Enterobacteriaceae produced extended-spectrum beta-lactamases b Carbapenem resistance is rapidly increasing

Treatment Guidelines and Protocols The heterogeneity of critical illness, along with the common finding of multiple sites of infection, has led to a paucity of well-designed clinical trials of UTI in the ICU setting. In 2010, the Infectious Diseases Society of America published guidelines regarding catheter-associated UTI, which may be extrapolated to the critically ill ICU patient (Hooton et al. 2010). Unlike surgical procedures where prophylactic antimicrobial use diminished subsequent infection, there are no data to support this practice in critically ill patients to prevent UTI. Prior to treatment, a urine specimen should be obtained for culture and sensitivity testing. Catheters that have been in place for greater than 2 weeks should be replaced prior to specimen collection. Table 4 provides an overview for empiric antimicrobial therapy selection for CAUTI. Unless urosepsis is suspected, or the patient’s condition is unstable, antimicrobial therapy can often be delayed until definitive evidence of infection and pathogen is received from the microbiology laboratory. If empiric drug selection is required, it should be based on local epidemiology and antimicrobial resistance patterns. Antimicrobial agents that are concentrated in the urinary tract (undergo primarily renal elimination) are preferred. For the past decade, there has been increasing fluoroquinolone resistance among E. coli, and more recently other Enterobacteriaceae have demonstrated similar resistance patterns. Candida species, Enterococcus species, and many P. aeruginosa are also resistant to

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fluoroquinolones, which reduces the use of this class of antibiotics for empiric monotherapy for suspected CAUTI.

S.J. Martin and C.A. Sejnowski Table 5 Clostridium difficile infection risk factors (Surawicz et al. 2013; Bobo et al. 2011) 1. Exposure to antibiotics (especially broad-spectrum antibiotics)a 2. Exposure to C. difficile (usually through health-care facility admission)a 3. Older age (>65 years old) 4. Gastrointestinal tract surgery 5. Nasogastric tube feeding 6. Reduction of gastric acid (such as the use of proton pump inhibitors) 7. Comorbid conditions (such as inflammatory bowel disease, chronic liver disease, organ transplant patients, chronic corticosteroid use) 8. Prolonged hospital stay

Application to Critical Care Urinary tract infection is a common infection in the critically ill, and there are multiple predisposing factors for it in the ICU patient. Avoidance of indwelling urinary catheters, strict institutional protocols for catheter placement, early removal of indwelling catheters, aseptic techniques for care of catheters, and protocols for early management of suspected CAUTI are all strategies to reduce the likelihood of these infections.

Clostridium difficile Gastrointestinal Infections Introduction The focus of this section will be on antibioticassociated C. difficile infection (CDI), the most commonly diagnosed diarrheal illness in the hospital. Clostridium difficile is a Gram-positive, spore-forming bacterium that produces toxins A and B and is usually spread by the fecal to oral route. The spores can be transmitted in hospital settings from environmental surfaces or via carriage by health-care providers or other patients (Gerding and Johnson 2012).

Epidemiology Clostridium difficile infection is very common among hospitalized patients in North America and Europe. The incidence of CDI has increased since 2000; between 2000 and 2005, the incidence of CDI in adults increased from 5.5 to 11.2 cases per 10,000 (Surawicz et al. 2013). Mortality from CDI was as high as 16.7 % during severe outbreaks due to a hypervirulent toxinotype III ribotype 027 strain of C. difficile (Pepin et al. 2005).

a

Denotes the two major risk factors of CDI

Antibiotic use is the most common predisposing factor for CDI. Almost all classes of antimicrobials have been associated with CDI, but the agents most commonly associated with CDI are clindamycin, fluoroquinolones, and cephalosporins (Gerding and Johnson 2012). Table 5 lists other common predisposing factors of patients for CDI. Clostridium difficile is carried in the colon of 5–15 % of healthy adults, but the carriage prevalence may be as high as 57 % in elderly adults (Surawicz et al. 2013). The carriage incidence is associated with residence in long-term care facilities. Since 2000, the toxinotype III, REA type BI, PCR ribotype 027, pulsed-field type NAP-1 (NAP1/BI/027) strain has been present in the environment. The NAP1/BI/027 strain does not respond well to standard antimicrobial therapy, produces more toxins A and B in vitro than other strains, and is highly resistant to fluoroquinolones (Martin and Jung 2011). The predominant clinical presentation of CDI is a watery diarrhea (more than 3 stools in 24 h), but other signs and symptoms include fevers, abdominal pain, and cramping. Severe disease is associated with hypoalbuminemia and a leukocytosis (white blood cell count greater than or equal to 15 cm3/mm3) and abdominal tenderness. Although diarrhea is common in symptomatic CDI, severe abdominal pain with no diarrhea can indicate the patient has ileus with toxic megacolon. Severe and complicated CDI may

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Extent and Nature of Infectious Diseases in Critical Care

require ICU admission and can produce hypotension, fever, ileus or abdominal distention, mental status changes, white blood cell count greater than 35,000 cells/mm3, serum lactate levels greater than 2.2 mmol/L, and end-organ failure (Surawicz et al. 2013). Clostridium difficile infection can be characterized based on the onset of symptoms and where the symptoms first originate. The definition of health-care facility-onset, health-care facilityassociated disease is when the onset of symptoms occurs 3 days after admission to a health-care facility. Clostridium difficile infection can also develop in the community after health-care facility discharge. Recurrent CDI may occur up to 8 weeks after the onset of a previous episode, but the symptoms from the previous episode must have been resolved (Surawicz et al. 2013).

Pathophysiology Once the normal flora is disrupted, C. difficile colonization can occur and toxins A (an enterotoxin) and B (a cytotoxin) are released in the colon, leading to disruption of the actin cell cytoskeleton, which leads to loss of cell shape, tight cell junctions, fluid leakage into the intestinal lumen, and cell death (Bobo et al. 2011; Gerding and Johnson 2012). The contact of the toxins to the submucosa causes a proinflammatory response. Proinflammatory mediators are upregulated from the lamina propria. The lamina propria can become severely inflamed, which may lead to fulminant colitis and eventual death (Bobo et al. 2011).

Microbiology Many microbiological tests are available to detect the presence of C. difficile. Current treatment guidelines recommend the use of nucleic acid amplification tests, such as the reverse transcriptase polymerase chain reaction test, instead of the toxins A and B enzyme immunoassay test (Surawicz et al. 2013). Nucleic acid amplification tests are highly sensitive, and only one sample is necessary for accurate results.

139

Treatment Guidelines and Protocols Along with discontinuing the offending agent, fluid and electrolyte therapy is important in patients with CDI (Martin and Jung 2011). Metronidazole is the drug of choice for mild to moderate CDI. In patients with severe disease, oral vancomycin is recommended. Table 6 provides a summary of treatment recommendations for CDI. Of note, oral vancomycin must be administered to treat CDI since intravenous vancomycin does not penetrate into the gut lumen in high enough concentrations to eradicate the organism. A new treatment option is fidaxomicin, which was approved by the United States Food and Drug Administration for mild to moderate CDI. The use of fidaxomicin in severe CDI is unclear. Of note, fidaxomicin is eight times more potent in vitro than is vancomycin against clinical isolates of C. difficile, including NAP1/BI/027 (Cornely et al. 2012). Intravenous immune globulin may be helpful in patients with hypogammaglobulinemia, and probiotics have limited evidence to decrease recurrence of CDI. Fecal transplant is also a therapy option in recurrent CDI (Surawicz et al. 2013).

Applications to Critical Care Critical care patients have a high incidence of diarrhea (up to 40 % of patients overall) (Riddle and Dubberke 2009). Once diarrhea develops, patients can be at risk for dehydration, malnutrition, electrolyte imbalances, and skin breakdown. Critical care practitioners should be aware of risk factors that may lead to diarrhea, specifically CDI, and attempt to prevent infection by using appropriate hand hygiene (Riddle and Dubberke 2009).

Summary Infection is a common complication in the ICU, and clinicians must understand the most frequently observed infection types, apply preventative strategies to reduce their prevalence, and apply guidelines or best practices in infection

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S.J. Martin and C.A. Sejnowski

Table 6 Treatment of Clostridium difficile infection (Surawicz et al. 2013) Degree of severity Mild

Moderate

Severe

Not complicated CDI Metronidazole 500 mg PO TID  10 days Special populations: 1. Metronidazole should be avoided in pregnancy and breastfeeding 2. Vancomycin enema should be considered in patients with Hartmann’s pouch, ileostomy, or colon diversion Metronidazole 500 mg PO TID  10 days Vancomycin 125 mg PO QID  10 days

Complicated CDI

If no abdominal distention: vancomycin 125 mg PO QID + metronidazole 500 mg TID IV If abdominal distention, possible ileus, or toxic megacolon: vancomycin 500 mg PO QID + vancomycin 500 mg/500 mL enema rectally QID + metronidazole 500 mg IV TID

First recurrence Same regimen as initial episode (NOTE: duration of metronidazole therapy limited due to risk of cumulative neurotoxicity)

Second recurrence Pulsed PO vancomycin (e.g., 125 mg PO QID, 125 mg daily pulsed every 3 days for 10 doses)

Third recurrence Fecal microbiota transplant (FMT) via NG duodenal tubes, colonoscopy, enema

Same regimen as initial episode

Pulsed PO vancomycin

FMT

Vancomycin 125 mg PO QID  10 days

Pulsed PO vancomycin

FMT

Key: PO by mouth, TID three times daily, QID four times daily, FMT fecal microbiota transplant

management. Ventilator-associated pneumonia, CRBSI, CAUTI, and C. difficile colitis are very common infectious complications caused by critical illness and, which of themselves, can cause critical illness.

Summary Points • Critical illness can lead to infectious complications due to the body’s altered host defense systems.

• Pneumonia in critically ill patients often results from aspiration of oropharyngeal secretions or gastric contents colonized with microorganisms. • Pneumonia is a common cause of morbidity and mortality in ICU patients and can be prevented by performing spontaneous breathing trials daily, using appropriate sedation assessment, head-of-bed elevation, and daily oral hygiene. • Catheter-related bloodstream infections can occur due to the contamination of catheters by skin organisms at the insertion site or by

10

• •

•

•

Extent and Nature of Infectious Diseases in Critical Care

contamination of the catheter or hub by contract with hands, fluids, or devices. Proper measures should be made to avoid CRBSIs by monitoring the indications, insertion, and maintenance of catheters. Urinary tract infection in critically ill patients is commonly related to indwelling urinary catheter use and should be removed if in place for more than 2 weeks. Clostridium difficile infection is common among hospitalized patients in North America and Europe and can be transmitted in hospital settings from environmental surfaces or via carriage by health-care personnel. Health-care practitioners should be aware of preventative strategies and best practices for health-care-associated infections.

References Aarts MA, Hancock JN, Heyland D, et al. Empiric antibiotic therapy for suspected ventilatorassociated pneumonia: a systematic review and metaanalysis of randomized trials. Crit Care Med. 2008;36:108–17. Agodi A, Auxilia F, Barchitta M, et al. Trends, risk factors and outcomes of healthcare- associated infections within the Italian network SPIN-UTI. J Hosp Infect. 2013;84:52–8. American Thoracic Society, Infectious Disease Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcareassociated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388–416. Angus DC, Linde-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(7):1303–10. Bobo LD, Dubberke ER, Kollef M. Clostridium difficile in the ICU: the struggle continues. Chest. 2011;140(6):1643–53. Burton D, Edwards J, Srinivasan A, et al. Trends in catheter-associated urinary tract infection in adult intensive care units-United States, 1990–2007. Infect Control Hosp Epidemiol. 2011;32:748–56. Centers for Disease Control and Prevention (CDC). Monitoring hospital-acquired infections to promote patient safety – United States, 1990–1999. MMWR Morb Mortal Wkly Rep. 2000;49(8):149–53. Chant C, Smith OM, Marshall JC, Friedrich JO. Relationship of catheter-associated urinary tract infection to mortality and length of stay in critically ill

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patients: a systematic review and meta-analysis of observational studies. Crit Care Med. 2011;39:1167–73. Chastre J, Wolff M, Fagon J, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588–98. Chenoweth CE, Gould CV, Saint S. Diagnosis, management, and prevention of catheter-associated urinary tract infections. Infect Dis Clin North Am. 2014;28(1):105–19. Chitnis A, Edwards J, Ricks P, et al. Device-associated infection rates, device utilization, and antimicrobial resistance in long-term acute care hospitals reporting to the National Healthcare Safety Network, 2010. Infect Control Hosp Epidemiol. 2012;33(10):993–1000. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;11:281–9. Evans L, Chitkara N. Chapter 136. Prevention in the intensive care unit setting. In: McKean SC, Ross JJ, Dressler DD, Brotman DJ, Ginsberg JS, editors. Principles and practice of hospital medicine. New York: McGrawHill; 2012. http://0-accessmedicine.mhmedical.com. carlson.utoledo.edu/book.aspx?bookid=496#. Accessed 1 Mar 2014. Garnacho-Montero J, Aldabo-Pallas T, Palomar-MartinezM, et al. Risk factors and prognosis of catheter-related bloodstream infection in the critically ill: a multicenter study. Intensive Care Med. 2008;34(12):2185–93. Gerding DN, Johnson S. Chapter 129. Clostridium difficile infection, including Pseudomembranous colitis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J, editors. Harrison’s principles of internal medicine. 18th ed. New York: McGrawHill; 2012. Hooton TM, Bradley BF, Cardenas DD. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625–63. Karchmer AW. Bloodstream infections: the problem and the challenge. Int J Antimircob Agents. 2009;34 Suppl 4:S2–4. Kress JP, Hall JB. Chapter 267. Approach to the patient with critical illness. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J, editors. Harrison’s principles of internal medicine. 18th ed. New York: McGraw-Hill; 2012. http:// 0-accessmedicine.mhmedical.com.carlson.utoledo.edu/ content.aspx?bookid=331§ionid=40727052& jumpsectionID=40752995. Accessed 19 Feb 2014. Laupland KB, Bagshaw SM, Gregson DB, et al. Intensive care unit-acquired urinary tract infections in a regional critical care system. Crit Care. 2005;9(2):R60–5.

142 Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008;29(4):605–16. Martin S, Jung R. Chapter 122. Gastrointestinal infections and enterotoxigenic poisonings. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, editors. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York: McGraw-Hill; 2011. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition. J Parenter Enteral Nutr. 2009;33:277–316. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1–45.

S.J. Martin and C.A. Sejnowski O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52:162–93. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037–42. Riddle DJ, Dubberke ER. Clostridium difficile infection in the intensive care unit. Infect Dis Clin North Am. 2009;23:727–43. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478–98. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–9.

Critically Ill Patients and Circulating Amino-Terminal Pro-C-Type Natriuretic Peptide

11

Alexander Koch and Frank Tacke

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 Regulation of NT-proCNP in Critically Ill Medical Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Association of Serum NT-proCNP in Critically Ill Medical Patients with Survival . . . . . 146 Applications of Serum NT-proCNP to Critical or Intensive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

A. Koch • F. Tacke (*) Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany e-mail: [email protected]; [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_24

Abstract

The natriuretic peptide family members, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), exert multiple potent diuretic, natriuretic, and vasorelaxant functions, thereby directly influencing body-fluid homeostasis and blood pressure control. C-type natriuretic peptide (CNP) is mainly synthesized in the vasculature. We have evaluated the diagnostic and prognostic value of N-terminal proCNP (NT-proCNP) in 273 critically ill patients (197 patients with sepsis or septic shock, 76 without evidence of sepsis) in comparison to 43 healthy controls. Critically ill patients displayed significantly elevated NT-proCNP serum concentrations upon admission to the ICU compared to healthy controls, especially in conditions of sepsis. NT-proCNP correlated with inflammatory parameters (i.e., C-reactive protein, procalcitonin, and TNF-α), biomarkers of organ dysfunction, and clinical composite scores (APACHE II, SOFA, SAPS2). Despite its potential involvement in the pathogenesis of critical illness and sepsis, NT-proCNP may also be valuable as a prognostic biomarker in the ICU setting, because NT-proCNP levels at admission and day 3 were found to be predictive for ICU and overall survival. Further studies are warranted to elucidate the underlying pathomechanisms of NT-proCNP in critical illness and to validate its potential as a biomarker at the ICU. 143

144

List of Abbreviations

ANP Atrial natriuretic peptide AP Alkaline phosphatase APACHE Acute Physiology and Chronic Health Evaluation AUC Area under the curve BNP Brain natriuretic peptide CNP C-type natriuretic peptide CRP C-reactive protein GFR Glomerular filtration rate ICU Intensive care unit IL-6 Interleukin 6 NO Nitric oxide NTAmino-terminal pro-C-type natriproCNP uretic peptide PCT Procalcitonin ROC Receiver operating characteristic SOFA Sequential organ failure assessment TNF-α Tumor necrosis factor α

Introduction The family of natriuretic peptides is comprised of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), and urodilatin. These neuropeptides have been shown to exert multiple potent diuretic, natriuretic, and vasorelaxant functions, thereby directly influencing body-fluid homeostasis and blood pressure control (Nakao et al. 1992; Rubattu et al. 2008). The main stimulus for synthesis and secretion of ANP and BNP peptides is cardiac wall stress (Rubattu et al. 2008; Suttner and Boldt 2004). Due to the fact that cardiac ventricular myocytes constitute the major source of BNP-related peptides, NT-proBNP, the more stable circulating BNP protein, in serum is considered a reliable marker for cardiac diseases and congestive heart failure (Panagopoulou et al. 2013). In severe sepsis, BNP has been proposed as a useful biomarker to predict survival (Brueckmann et al. 2005; Varpula et al. 2007), most likely by indicating septic myocardial depression (Brueckmann et al. 2005; Varpula et al. 2007). More recently, physiological

A. Koch and F. Tacke

levels of A-, B-, and C-type natriuretic peptides were found to shed the endothelial glycocalyx and enhance vascular permeability, thus suggesting a participation of natriuretic peptides in pathophysiological processes like heart failure, inflammation, or sepsis (Fig. 1) (Jacob et al. 2013). CNP is synthesized as a precursor proCNP protein, and conversion of proCNP to the biologically active hormone CNP is processed by the intracellular endoprotease furin (Wu et al. 2003). Amino-terminal pro-C-type natriuretic peptide (NT-proCNP) is the N-terminal fragment of the C-type natriuretic peptide precursor. As a cleavage product of proCNP, NT-proCNP circulates in equimolar amounts with CNP in human plasma and is considered to be a more reliable marker of the extent of CNP biosynthesis (Vlachopoulos et al. 2010). Due to its extracardiac origin and its high expression in the brain, CNP was initially believed to be a neuropeptide, involved in central regulatory mechanisms (Komatsu et al. 1991; Sudoh et al. 1988). At present it is known that CNP is widely expressed in various tissues, with particularly high concentrations in the vascular endothelium (Suga et al. 1992) and chondrocytes (Hagiwara et al. 1994), inducing vasorelaxation and vascular remodeling, as well as regulating bone growth (Schulz 2005). Compared with ANP and BNP, CNP exerts limited diuretic and natriuretic functions but counteracts angiotensin II- or endothelin-1-induced vasoconstriction and complements the actions of other endothelial vasorelaxant mediators such as nitric oxide (NO) and prostacyclin (Scotland et al. 2005). Interleukin-1, endotoxins, and particularly tumor necrosis factor (TNF)-α, which are increased in states of sepsis, can stimulate CNP release from isolated endothelial cells and in this way regulate local vascular tone (Suga et al. 1993). CNP release in response to proinflammatory cytokines suggests an interaction of macrophageal cytokine synthesis and vascular endothelium (Barr et al. 1996). This link indicates a potential pathophysiological role of CNP in sepsis and septic shock, which are characterized by arteriolar vasodilatation, hypotension, and inadequate tissue perfusion (Glauser et al. 1991). In a small cohort of patients with sepsis and septic shock, high CNP

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Critically Ill Patients and Circulating Amino-Terminal Pro-C-Type Natriuretic Peptide

145

Fig. 1 Structural similarities between the three major natriuretic peptides. In our book chapter, we focus on the role of C-type natriuretic peptide in critically ill patients. While CNP is mainly derived from the vasculature, ANP and BNP are primarily released from the atrium and ventricle of the heart, respectively. All three natriuretic

peptides exert multiple potent diuretic, natriuretic, and vasorelaxant functions, thereby directly influencing bodyfluid homeostasis, blood pressure control, and also inflammation. (The figure was adapted from Witthaut R, Critical Care 2004; 8:342–9)

serum concentrations have been demonstrated (Hama et al. 1994). Moreover, in a recent study, NT-proCNP has been proposed as a novel biomarker for predicting the development of sepsis in multiple-trauma patients (Bahrami et al. 2010). The diagnostic and prognostic value of NT-proCNP measurements in critically ill medical patients has been obscure. We therefore conducted a large study with critically ill patients in a medical ICU, performing longitudinal measurements of NT-proCNP serum concentrations during the first week of ICU treatment, to address whether NT-proCNP is activated in critical illness, whether NT-proCNP has diagnostic value for sepsis and/or multiorgan failure, and whether NT-proCNP can serve as a prognostic predictor for ICU and long-term survival (Koch et al. 2011). This book chapter will mainly summarize and discuss important findings from this study (Koch et al. 2011).

Table 1 Baseline patient characteristics and NT-proCNP serum concentrations

Regulation of NT-proCNP in Critically Ill Medical Patients We investigated 273 patients (172 male, 101 female with a median age of 64 years; range 18–90 years) who were admitted consecutively to the general internal medicine ICU at the RWTH-University Hospital Aachen, Germany (Table 1). Written informed consent was obtained from the patient, his or her spouse, or the appointed legal guardian.

Parameter Number Sex (male/ female) Age median (range) [years] APACHE II score median (range) Mechanical ventilation n (%) Death during ICU n (%) Death during follow-up n (%) NT-proCNP day 1 median (range) [pmol/L] NT-proCNP day 3 median (range) [pmol/L] NT-proCNP day 7 median (range) [pmol/L]

All patients 273 172/101

Sepsis 197 128/69

Nonsepsis 76 44/32

64 (18–90)

65 (20–90)

60 (18–85)

17 (2–40)

18 (3–40)

15 (2–31)

194 (73.2 %)

144 (75 %)

50 (68.5 %)

76 (27.8 %) 132 (50.2 %)

61 (31.0 %) 101 (53.2 %)

15 (19.7 %) 31 (42.5 %)

4.07 (0–42)

5.6 (0–42) **

1.48 (0–42)**

4.79 (0–42)

5.81 (0–42)*

0.90 (0–42)*

3.91 (0–42)

4.59 (0–42)

2.37 (0–41.34)

APACHE acute physiology and chronic health evaluation, ICU intensive care unit. Significant differences between sepsis and non-sepsis patients are marked by *p < 0.05 or **p < 0.001

146

Patients that were expected to have a short-term (8 pmol/L, gray) have an increased short-term mortality at the ICU as compared to patients with low NT-proCNP serum concentrations. P-values are given in the figure. (d) Kaplan-Meier survival curve of ICU patients is displayed, showing increased overall mortality in the long-term follow-up in patients with high NT-proCNP levels (on admission >8 pmol/L, gray) as compared to patients with low NT-proCNP serum concentrations. P-values are given in the figure.

we also tested whether NT-proCNP levels during the early course of ICU treatment could predict the long-term survival. Patients that will die during long-term follow-up had significantly higher

NT-proCNP levels than survivors at ICU admission and day 3. By Cox regression analyses, high NT-proCNP levels at admission ( p = 0.002) and day 3 ( p = 0.013) predicted long-term mortality in

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A. Koch and F. Tacke

Table 2 Correlations with NT-proCNP serum concentrations at admission All patients Parameters r Markers of inflammation Leukocytes 0.178 CRP 0.296 Procalcitonin 0.456 IL-6 0.188 TNF-α 0.500 Markers of organ function Creatinine 0.715 Urea 0.648 Cystatin C 0.700 Cystatin C GFR 0.707 AP 0.441 PCHE 0.279 Albumin 0.329 Clinical scores APACHE II 0.206 SOFA 0.261 SAPS2 0.230

Sepsis r

p

Non-sepsis r

p

p

0.006 30 ng/ml (75 nmol/L). Consequently, the ES recommends higher doses for both daily use and

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an upper limit of vitamin D which is thought to be safe, as summarized in Table 3. Also, in a 2009 Paris meeting, a panel of vitamin D researchers endorsed a serum 25(OH)D concentration of 30–40 ng/mL (75–100 nmol/L) (Souberbielle et al. 2010). The guidelines further state that in order to maximize vitamin D’s effect on calcium, bone, and muscle metabolism, the vitamin D level should be at least 30 ng/mL (75 nmol/L). Numerous studies have suggested that a vitamin D level of at least 30 ng/mL may also decrease the risk of type 2 diabetes and cardiovascular disease, as well as certain cancers, autoimmune diseases, and infectious diseases. Moreover, adequate vitamin D level is needed to maintain a normal parathyroid hormone levels. A study in Canada found that older people required higher serum 25(OH)D levels to maintain low PTH levels (Vieth et al. 2003). In elderly Italian women, serum 25(OH)D levels above 110 nmol/L were needed to keep PTH levels 70 years 400 IUb Pregnancy/lactation 14–18 years 400 IUb 19–50 years 400 IUb

Endocrine Society recommendations (apply specifically to at-risk patients) Daily requirement ULd

1,000 IU 1,500 IU

400–1,000 IU 400–1,000 IU

2,000 IU 2,000 IU

600 IU 600 IU

2,500 IU 3,000 IU

600–1,000 IU 600–1,000 IU

4,000 IU 4,000 IU

600 IU 600 IU 800 IU

4,000 IU 4,000 IU 4,000 IU

600–1,000 IU 1,500–2,000 IU 1,500–2,000 IU

4,000 IU 10,000 IU 10,000 IU

600 IU 600 IU

4,000 IU 4,000 IU

600–1,000 IU 1,500–2,000 IU

4,000 IU 10,000 IU

AI adequate intake, EAR estimated average requirement, RDA recommended dietary allowance, UL upper limit a AI is estimated as the evidence is insufficient for the development of EAR/RDA. b EAR indicates the median intake needs of the general population. c RDA indicates the intake that covers the needs of 97.5 % of the general population. d UL indicates the level above which there is risk of adverse events.

challenges. Initially, the assays for 25(OH)D used the competitive protein binding format with the vitamin D-binding protein (DBP) as the binder. DBP recognized 25(OH)D2 equally as 25(OH)D3. But this assay measured 25(OH)D in a serum sample that contained other vitamin D metabolites, and bias existed when high concentration of 25(OH)D2 is present (Horst and Hollis 1999). Radioimmunoassay (RIA) (DiaSorin@) also recognized 25(OH)D2 equally as 25(OH)D3 and vitamin D metabolites. These two assays, DBP and RIA assays, overestimated 25(OH)D levels by approximately 10–20 % (Hollis 2004). Simple preparative chromatography was developed to separate 25(OH)D from more polar metabolites that interfered with the assay. High-performance liquid chromatography (HPLC) was applied to the 25(OH)D assay (Jones 1978). This assay consists of lipid extraction of the serum followed by preparative chromatography. 25(OH)D fraction was applied to HPLC, and the UV absorption of 25 (OH)D was used to measure its concentration. This assay was considered the gold standard but was a very cumbersome assay. Liquid chromatography-tandem mass spectroscopy

(LC-MS) quantitatively measured both 25(OH) D2 and 25(OH)D3 (Holick 2005; Guo et al. 2006). However, mass spectroscopy is very expensive. These existing 25(OH)D assays lack comparability to the candidate reference method, causing difficulties in diagnosis and monitoring of vitamin D deficiency. The accuracy of three automated assays (Roche Diagnostics Elecsys ® Total 25OHD assay, Abbott Architect ® Total vitamin D assay, ADVIA Centaur ® Vitamin D Total assay) and DiaSorin ® radioimmunoassay (RIA) compared to a routine laboratory liquid chromatography-tandem mass spectrometry (LC-MS/MS) was studied. Those assay performances were inadequate secondary to differences in method of extraction of vitamin D from vitamin D-binding protein; cross-reactivities to 25(OH) D2, 25(OH)D3, and other vitamin D metabolites; matrix interferences; and a lack of standardization (Ong et al. 2012). Immunoassay is the predominant mode of measurement for 25(OH)D, but problems with equimolar recovery of the D2 and D3 metabolites continue to exist (Fraser and Milan 2013). Also all automated 25(OH)D assays may

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Intensive Care and Vitamin D Status

not be equally accurate especially in patients with renal failure on hemodialysis. This could be due to the role of matrix effects like elevated urea or other retained metabolites in hemodialysis sera, causing incomplete binding disruption between 25(OH)D and DBP and poor assay accuracy (Depreter et al. 2013). The new competitive protein binding assay measures 25(OH)D3 more accurately than 25(OH)D2 and may overestimate 25(OH)D3 and underestimate 25(OH)D2 in comparison to LC-MS/MS (Su et al. 2013). The choice of method for each laboratory remains a balance mainly between turnaround time, convenience, cost, and specificity and accuracy of the information obtained.

Factors Influencing the Interpretation of the Values 25(OH)D is the major circulating form of vitamin D; thus, the total serum 25(OH)D level is currently considered the best indicator of vitamin D supply to the body from cutaneous synthesis and nutritional intake. Interpretation of 25(OH)D can be challenging owing to wide variability in patients’ weight, ethnicity, assays, and laboratory procedures (Harris 2006; Binkley et al. 2004) As described above, despite the advances in methodologies to measure 25(OH)D levels, there is still wide inter-assay and interlaboratory variability. Extraction from binding proteins and procedural losses also play a role in variations of values. Acute fluid shifts in critical illness could influence vitamin D levels, because more than 99 % of 25(OH)D is attached to vitamin D-binding protein and albumin (Krishnan et al. 2010). However, other studies showed that despite a reduction of 25(OH)D of 40 % following an expansion of 3 l of fluids, there was only 10 % reduction in DBP and 15 % decrease in albumin. Critically ill patients often manifest low DBP and albumin (Jeng et al. 2009). In critical illness, increased vascular permeability due to inflammation, decreased synthesis of binding proteins, and acute changes in volumes may increase the renal wasting of 25(OH)D. One more factor is that in critical illness, patients manifest a temporary

997

hypocalcemia that leads to a rise in parathormone (PTH) level. This latter increases the conversion of 25(OH)D into 1,25(OH)D and thus could worsen the low levels of 25(OH)D (Lucidarme et al. 2010; Flynn et al. 2011). Additionally, significant variation in 25(OH)D levels can occur on an hourly basis in acute illness, and thus singletime assessments in critical illness may not be reflective of the true vitamin D status and may not be helpful in interpreting their vitamin D level (Venkatesh et al. 2012). Until a unified method has been established, caution in interpreting results of vitamin D levels should be undertaken especially when comparing research studies. Measuring 25(OH)D level on multiple occasions during the hospital stay is important. Several values are likely more reliable than a single measurement.

Role of Vitamin D-Binding Protein and Acute Phase Reactants Such as Albumin Like all steroids, vitamin D and its metabolites circulate in human plasma bound to protein. The vitamin D-binding protein (DBP), also known as Gc-globulin, is the major plasma carrier for vitamin D and its metabolites. It belongs to the albumin gene family, together with human serum albumin and alpha-fetoprotein. Vitamin D-binding protein (DBP) is a multifunctional plasma protein with many important functions. It binds to vitamin D and its plasma metabolites and transports them to target tissues. The vitamin D-binding protein is identical with group-specific component protein, Gc-globulin. These include transport of vitamin D metabolites, control of bone development, binding of fatty acids, and sequestration of actin and a range of less defined roles in modulating immune and inflammatory responses (Gomme and Bertolini 2004). Because DBP is the primary transporter of vitamin D, it has a role in maintaining the total levels of vitamin D for the organism and in regulating the amounts of free (unbound) vitamin D available for specific tissues and cell types to utilize (Chun 2012). Vitamin D-binding protein (DBP) can also be a

998

determinant of 25(OH)D levels in infants and toddlers (Carpenter et al. 2013). Two missense variants of the DBP gene – rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys – change the amino acid sequence and alter the protein function. Thus constitutive differences in vitamin D status may exist, based on assay of 25(OH)D. DBP and vitamin D may jointly or independently contribute to a variety of adverse health outcomes unrelated to classical notions of their function in bone and mineral metabolism. There are associations between DBP variants and various chronic and infectious diseases. DBP variants are a significant and common genetic factor in some common disorders (Malik et al. 2013). Some data indicate that DBP plays a pivotal role in regulating the bioavailability of 25(OH)D to monocytes. Vitamin D-dependent antimicrobial responses are therefore likely to be strongly influenced by DBP polymorphisms. In patients with primary hyperparathyroidism, both serum 25(OH)D and DBP levels were lower than controls, suggesting that the low DBP level is a mechanism contributing to low 25(OH)D levels in such patients (Chun et al. 2010; Wang et al. 2013). In one study concerning critically ill veterans, patients with vitamin D deficiency had a significantly lower average albumin level compared with those who were not deficient. The lower albumin levels seen in the vitamin D-deficient group were likely related to the severity of acute illness (Mckinney et al. 2011).

Vitamin D Deficiency in Critical Illness Vitamin D deficiency is associated with adverse health outcomes including increased risk of cardiovascular disease, morbidity, and mortality in the general population. In critically ill patients, the pleiotropic effects of vitamin D including its role in immune function are of great interest. Low vitamin D levels are common among patients admitted to ICU because of lack of exposure to sunlight and dietary supplementation (Lee et al. 2009a). Critically ill patients frequently

D. Youssef et al.

suffer from diseases with recurrent admissions and have a decrease in sunlight exposure due to restricted mobility which contributes to a persistence of their vitamin D deficiency status. Vitamin D deficiency is associated with poor outcomes and increased mortality in severely ill patients. In intensive care, pronounced muscle weakness may alert the clinical provider to vitamin D deficiency; however, in mechanically ventilated patients, clinical suspicion of vitamin D deficiency is virtually impossible. To date, it is not clear whether vitamin D deficiency is a surrogate marker for increased morbidity or whether treatment with sufficiently large doses of vitamin D may improve patient outcome in an intensive care setting. Vitamin D insufficiency was seen as a possible risk factor for sepsis (Grant 2009). Vitamin D not only maintains calcium and phosphorus homeostasis but also works in immune modulation, endothelial and mucosal functions, and glucose metabolism (Adams and Hewison 2010). Myocardial infarction, diabetes, autoimmune disease, chronic obstructive pulmonary disease, neoplasia, tuberculosis, and increased mortality have been associated with deficient states. Severe hypocalcemia, hyperglycemia, organ dysfunction, and increased mortality in critically ill patients with vitamin D deficiency have been seen (Arnson et al. 2012). The pathways by which vitamin D deficiency may contribute to the deterioration of the immune response and metabolic dysfunctions in the critically ill population are presented in Fig. 2. Figure 3 represents the potential mechanisms by which vitamin D may act to influence outcomes in acute illness. ▶ Chapter 67, “Specific Considerations Relevant to Critical Illness” will go through the mechanisms and the manifestations of vitamin D deficiency in more detail.

Prevalence of Vitamin D Deficiency in Critically Ill Patients Several studies have examined vitamin D deficiency in critical care. Despite using different cutoff points for vitamin D deficiency, the

74

Intensive Care and Vitamin D Status

999

Vitamin D

Physical health

Mental health

•Improved balance and muscle strength •Reduced Pro-inflammatory cytokines •Enhanced B cell and natural killer cell activity •Improvement in cardiac ejection fraction •Reduction of coronary calcium score •Better blood pressure control. •Toll receptor modulation •Reduced endotoxins •Improved glucose insulin homeostasis •Reduced prevalence of hypocalcemia •Enhanced antimicrobial peptide production

•Improved cognition, wellbeing, mood and pain relief

Improved health outcomes in acute illness

Fig. 3 Putative mechanisms by which vitamin D may help outcomes in acute and chronic illness (Courtesy of Youssef et al. (2011))

prevalence of vitamin D deficiency/insufficiency ranged between 38 % and 100 % (Lee et al. 2009a; Jeng et al. 2009; Lucidarme et al. 2010). The prevalence was 50 % higher in intensive care than the patients on general medical wards (Jeng et al. 2009). Vitamin D insufficiency in intensive care unit (ICU) patients may be as high as 50 %, with undetectable vitamin D levels seen in 17 % (Lee et al. 2009b). These results reflect the high prevalence of vitamin D insufficiency or deficiency in critical illness. Table 4 summarizes vitamin D status and prevalence of deficiency in critically ill patients. In children as well, a larger percentage of deficiency was seen in critically ill children than controls, 60 % vs. 30 % (McNally et al. 2012). Similar results were seen in another study that also found a higher prevalence of deficiency in critically ill children (Madden et al. 2012).

Does Illness Cause Vitamin D Deficiency or Vice Versa? Whether vitamin D deficiency is a predictor or contributor to critical illness remains highly controversial. It may be argued that vitamin D levels only act as a surrogate biomarker representing the general health condition of the patient. To assess that issue, Arnson et al. examined some parameters commonly used for evaluation of general well-being such as blood count, electrolytes, and albumin levels. Vitamin D status did not show a correlation with any of these parameters, except for a weak correlation between vitamin D levels and white blood cell count (Arnson et al. 2012). In chronic diseases, Visser et al. reported lower 25(OH)D was associated with higher mortality

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D. Youssef et al.

Table 4 Summary of vitamin D status and prevalence of vitamin D deficiency in adult critically ill patients Author Nierman et al. Jeng et al.

Year 1998 2009

N

Lee et al. Lucidarme et al. Mata-Granados et al. McKinney et al. Venkatram et al. Flynn et al. Ginde et al. Braun et al. (61) Zajic et al.a

2009 2010 2010

42 134 33

2011 2011 2011 2011 2012 2013

136 437 66 81 1,325 655

49 49

Admission diagnosis Respiratory failure Sepsis Non-sepsis Mixed Mixed Sepsis

Prevalence (definition used) 92 % (3 pH units during 24 h. All animals had a gastroparesis with the capsules located in the stomach as indicated by the pressure and pH data and confirmed by autopsy (Rauch et al. 2011). Intra-abdominal hypertension has become a widely accepted complication that is associated with increased morbidity and mortality (Malbrain et al. 2004, 2005). The intravesical pressure measurement as the reference standard for assessing intra-abdominal pressures is mainly indirect and discontinuous. The potential application for the motility capsule could be the continuous monitoring of intra-abdominal pressures and the effect on motility in critically ill patients. Therefore, the motility capsule was evaluated for continuous intraabdominal pressure measurement in another animal model with a high probability for increased intraabdominal pressure due to a capillary leakage and intestinal edema. The intra-abdominal pressures ranged from 3 to 15 mmHg [7.8  2.4 mmHg (mean  SD)] measured via the bladder. The capsule pressure recordings ranged from 1 to 3 mmHg [1.7  0.5 mmHg (mean  SD)]. A Bland-Altman analysis revealed an unacceptable bias between the two methods. The test bias was 6.2 (1.4) mmHg and the limits of agreement were from 3.3 to 8.9 mmHg. Pressures in the stomach as measured by motility capsule underestimated the intravesical pressures. Discrepancies between gastric and intravesical pressures could be caused by gastric dilatation or a different position of the two devices to the zero reference point. Therefore, it is rather the location than the device that leads to the insufficient agreement (Rauch et al. 2012a).

Guidelines and Protocols There are no universally applied guidelines so far regarding the monitoring of gastrointestinal function in the critical care setting. Finally, with different evolving capsule technologies, researchers as well as clinicians are able to examine the gastrointestinal tract in critically ill patients that may lead to better diagnostic and therapeutic decisions.

1319

Summary Points • Wireless capsule technology is a relatively new technique that allows investigation of gastrointestinal morphology and motility. • Clinically used parameters are a poor or unreliable correlate of propulsive peristalsis in the intestine. • Other methods are time-consuming, operator dependent, and impractical. • Wireless capsule technology offers for the first time the opportunity to investigate gastrointestinal motility and morphology at the bedside in real time. • Despite the advances in the care of critically ill patients, further work is needed for the diagnosis and treatment of gastrointestinal dysfunction. • Apart from the technological aspect, gastrointestinal research has to figure out which of the gut dysfunction is responsible for the increased morbidity and mortality in critical care patients.

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1320 Chapman MJ, Fraser RJ, et al. Gastric emptying and the organization of antro-duodenal pressures in the critically ill. Neurogastroenterol Motil. 2008;20(1):27–35. Christman JW, McCain RW. A sensible approach to the nutritional support of mechanically ventilated critically ill patients. Intensive Care Med. 1993;19(3):129–36. Delvaux M, Fassler I, et al. Clinical usefulness of the endoscopic video capsule as the initial intestinal investigation in patients with obscure digestive bleeding: validation of a diagnostic strategy based on the patient outcome after 12 months. Endoscopy. 2004;36(12):1067–73. Dive A, Moulart M, et al. Gastroduodenal motility in mechanically ventilated critically ill patients: a manometric study. Crit Care Med. 1994;22(3):441–7. Ekelund M, Qader SS, et al. Effects of total parenteral nutrition on rat enteric nervous system, intestinal morphology, and motility. J Surg Res. 2005;124(2):187–93. Farrar JT, Zworykin VK, et al. Pressure-sensitive telemetering capsule for study of gastrointestinal motility. Science. 1957;126(3280):975–6. Fireman Z, Kopelman Y, et al. Age and indication for referral to capsule endoscopy significantly affect small bowel transit times: the given database. Dig Dis Sci. 2007;52(10):2884–7. Guedon C, Schmitz J, et al. Decreased brush border hydrolase activities without gross morphologic changes in human intestinal mucosa after prolonged total parenteral nutrition of adults. Gastroenterology. 1986;90(2): 373–8. Heyland DK, Tougas G, et al. Impaired gastric emptying in mechanically ventilated, critically ill patients. Intensive Care Med. 1996;22(12):1339–44. Heyland DK, Dhaliwal R, et al. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr. 2003a;27(5):355–73. Heyland DK, Schroter-Noppe D, et al. Nutrition support in the critical care setting: current practice in Canadian ICUs–opportunities for improvement? JPEN J Parenter Enteral Nutr. 2003b;27(1):74–83. Iddan G, Meron G, et al. Wireless capsule endoscopy. Nature. 2000;405(6785):417. Iiboshi Y, Nezu R, et al. Total parenteral nutrition decreases luminal mucous gel and increases permeability of small intestine. JPEN J Parenter Enteral Nutr. 1994;18(4): 346–50. Kao CH, ChangLai SP, et al. Gastric emptying in headinjured patients. Am J Gastroenterol. 1998;93(7): 1108–12. Kehlet HHK. Review of postoperative ileus. Am J Surg. 2011;182:3S–10. Kloetzer L, Chey WD, et al. Motility of the antroduodenum in healthy and gastroparetics characterized by wireless motility capsule. Neurogastroenterol Motil. 2010; 22(5):527–33, e117. Kompan L, Kremzar B, et al. Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intensive Care Med. 1999;25(2):157–61.

S. Rauch and M. Fischer Kuo B, McCallum RW, et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther. 2008;27(2):186–96. Mackay RS, Jacobson B. Endoradiosonde. Nature. 1957; 179:1239–40. Malbrain ML, Chiumello D, et al. Prevalence of intraabdominal hypertension in critically ill patients: a multicentre epidemiological study. Intensive Care Med. 2004;30(5):822–9. Malbrain ML, Chiumello D, et al. Incidence and prognosis of intraabdominal hypertension in a mixed population of critically ill patients: a multiple-center epidemiological study. Crit Care Med. 2005;33(2):315–22. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med. 2001;29(12):2264–70. McMahon MM, Farnell MB, et al. Nutritional support of critically ill patients. Mayo Clin Proc. 1993;68(9): 911–20. Meurling S, Roos KA. Gut structure changes in rats on continuous and intermittent complete parenteral nutrition. Acta Chir Scand. 1981;147(6):451–7. Mochizuki H, Trocki O, et al. Mechanism of prevention of postburn hypermetabolism and catabolism by early enteral feeding. Ann Surg. 1984;200(3):297–310. Nakasaki H, Mitomi T, et al. Gut bacterial translocation during total parenteral nutrition in experimental rats and its countermeasure. Am J Surg. 1998;175(1):38–43. Nöller HG. Die Endoradiosonde. Dtsch Med Wochenschr. 1960;85:1707–13. Ohta K, Omura K, et al. The effects of an additive small amount of a low residual diet against total parenteral nutrition-induced gut mucosal barrier. Am J Surg. 2003;185(1):79–85. Ott L, Young B, et al. Altered gastric emptying in the headinjured patient: relationship to feeding intolerance. J Neurosurg. 1991;74(5):738–42. Power I, Easton JC, et al. Gastric emptying after head injury. Anaesthesia. 1989;44(7):563–6. Rao SS, Kuo B, et al. Investigation of colonic and wholegut transit with wireless motility capsule and radiopaque markers in constipation. Clin Gastroenterol Hepatol. 2009;7(5):537–44. Rastogi A, Schoen RE, et al. Diagnostic yield and clinical outcomes of capsule endoscopy. Gastrointest Endosc. 2004;60(6):959–64. Rauch S, Krueger K, et al. Determining small intestinal transit time and pathomorphology in critically ill patients using video capsule technology. Intensive Care Med. 2009;35(6):1054–9. Rauch S, Krueger K, et al. Clinical experience in the placement of a novel motility capsule by using a capsule delivery device in critical care patients. Endoscopy. 2010;42 Suppl 2:E77–8. Rauch S, Muellenbach RM, et al. Gastric pH and motility in a porcine model of acute lung injury using a wireless motility capsule. Med Sci Monit. 2011;17(7): BR161–4.

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Rauch S, Johannes A, et al. Evaluating intra-abdominal pressures in a porcine model of acute lung injury by using a wireless motility capsule. Med Sci Monit. 2012a;18(5):BR163–6. Rauch S, Krueger K et al. Use of wireless motility capsule to determine gastric emptying and small intestinal transit times in critically ill trauma patients. J Crit Care. 2012b;27(5):534 e537-512. Rey JF, Ladas S, et al. European Society of Gastrointestinal Endoscopy (ESGE). Video capsule endoscopy: update to guidelines (May 2006). Endoscopy. 2006;38(10): 1047–53. Rigaud D, Chastre J, et al. Intragastric pH profile during acute respiratory failure in patients with chronic obstructive pulmonary disease. Effect of ranitidine and enteral feeding. Chest. 1986;90(1): 58–63. Ritz MA, Fraser R, et al. Delayed gastric emptying in ventilated critically ill patients: measurement by 13 C-octanoic acid breath test. Crit Care Med. 2001;29(9):1744–9. Sax HC. Early nutritional support in critical illness is important. Crit Care Clin. 1996;12(3):661–6. Sedman PC, MacFie J, et al. Preoperative total parenteral nutrition is not associated with mucosal atrophy or bacterial translocation in humans. Br J Surg. 1995;82(12):1663–7. Shiotani A, Opekun AR, et al. Visualization of the small intestine using capsule endoscopy in healthy subjects. Dig Dis Sci. 2007;52(4):1019–25.

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Simren M, Stotzer PO. Use and abuse of hydrogen breath tests. Gut. 2006;55(3):297–303. Sturniolo GC, Di Leo V, et al. Small bowel exploration by wireless capsule endoscopy: results from 314 procedures. Am J Med. 2006;119(4):341–7. Swain P, Fritscher-Ravens A. Role of video endoscopy in managing small bowel disease. Gut. 2004;53(12): 1866–75. Tarling MM, Toner CC, et al. A model of gastric emptying using paracetamol absorption in intensive care patients [see comment]. Intensive Care Med. 1997;23(3):256–60. Triantafyllou K, Kalantzis C, et al. Video-capsule endoscopy gastric and small bowel transit time and completeness of the examination in patients with diabetes mellitus. Dig Liver Dis. 2007;39(6):575–80. van der Hulst RR, von Meyenfeldt MF, et al. Gut permeability, intestinal morphology, and nutritional depletion. Nutrition. 1998;14(1):1–6. Velayos Jimenez B. Study of gastrointestinal transit times with capsule endoscopy. Gastroenterol Hepatol. 2005;28:315–20. Von Schrenck T, DerHerr G, Matsui U. Hydrogen breath tests: can these non-invasive function tests be used in ICU patients? Anasth Intensivmed Notfallmed Schmerzther. 1998;33:624. Weekes E, Elia M. Observations on the patterns of 24-hour energy expenditure changes in body composition and gastric emptying in head-injured patients receiving nasogastric tube feeding. JPEN J Parenter Enteral Nutr. 1996;20(1):31–7.

Prokinetic Agents with Enteral Nutrition

99

Ron R. Neyens, Melissa L. Hill, Michelle R. Huber, and Julio A. Chalela

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324 Pathophysiology and Risk Factors . . . . . . . . . . . . . . . 1324 Enteral Intolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1324 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metoclopramide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Erythromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Naloxone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cisapride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Domperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neostigmine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prokinetic Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1325 1326 1326 1327 1327 1327 1327 1328

Prokinetic Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1329 Future Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1329 Applications to Critical or Intensive Care . . . . . . 1329 Application to Other Conditions . . . . . . . . . . . . . . . . . 1331

Early and adequate enteral nutrition is associated with reduced morbidity and mortality in the critically ill patient, but due to high rates of enteral intolerance and concerns for aspiration and pneumonia, many patients do not receive it in a timely fashion. Although not definitively proven to reduce the rates of aspiration and pneumonia, prokinetic therapy has a modest benefit in improving enteral tolerance and delivery of enteral nutrition. Therapeutic selection is dependent upon the clinical scenario, patient’s comorbidities, drug-drug interactions, and end-organ function. Patients deemed to be at high risk of intolerance, prokinetic adverse events, or failed prokinetic therapy may benefit from placement of a post-pyloric tube.

Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1331 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1331 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1332 R.R. Neyens (*) Department of Pharmacy, Medical University of South Carolina, Charleston, SC, USA e-mail: [email protected] M.L. Hill • J.A. Chalela Department of Neurosciences, College of Medicine, Medical University of South Carolina, Charleston, SC, USA e-mail: [email protected]; [email protected]; [email protected] M.R. Huber Department of Pharmacy, University of Alabama at Birmingham, Birmingham, AL, USA e-mail: [email protected]; [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_80

List of Abbreviations

5-HT4 ACPO ASPEN

Serotonergic agonist Acute colonic pseudoobstruction American Society for Parenteral and Enteral Nutrition CCK Cholecystokinin CrCl Creatinine clearance CYP450 Cytochrome P450 D2 Dopaminergic antagonist EPS Extrapyramidal symptoms ESPEN European Society of Parenteral and Enteral Nutrition GRV Gastric residual volume ICU Intensive care unit IV Intravenous 1323

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TBI VAP

R.R. Neyens et al.

Traumatic brain injury Ventilator-associated pneumonia

Introduction Enteral nutrition is the preferred method for feeding as it supports the functional integrity of the gastrointestinal tract, does not require central venous access, reduces the risk of infectious complications, and is the most economical (McClave et al. 2009). It should be initiated early with goal delivery rates achieved within 48–72 h, which is associated with reduced morbidity. Despite this recognition, many patients do not achieve goal enteral nutrition, partially attributable to patient intolerance defined as abdominal pain or distention, vomiting, and most commonly high gastric residual volumes (GRV). A strong correlation of these markers, specifically GRV, to actual gastrointestinal function is lacking; however, it often leads to delays or cessation of enteral nutrition. The prevalence of undernutrition in critically ill patients, largely secondary to enteral intolerance, is as high as 50 % (McClave et al. 2009; AraujoJunqeuira and De-Souza 2012). It is imperative to identify patients at risk and to develop an appropriate treatment plan, which may include utilization of pharmacologic prokinetic agents to enhance enteral tolerance.

Pathophysiology and Risk Factors Gastrointestinal motility is a complex process divided into fasting and postprandial patterns (Deane et al. 2009; Ukleja 2010). Fasting motility is less relevant in the critically ill as many enteral protocols utilize continuous administration of feedings. The gastrointestinal tract consists of the stomach, small intestine, and large intestine. It is innervated by a complex bundle of nerves referred to as Auerbach’s (myenteric) plexus, which is dependent upon several neurotransmitters, including serotonergic, cholinergic, and dopaminergic, to initiate functional motility. Delayed gastric emptying in the critically ill patient is often the result of poorly integrated

Table 1 Incidence of gastric dysfunction Diagnosis Burns Multisystem trauma Intracranial injury Septic shock Respiratory failure Cardiac injury

Incidence (%) 77 72 67 61 33 27

Table 1 provides the reported incidence of gastric dysfunction across various critically ill patient populations and reflects wide variance (McClave et al. 2009; Nguyen et al. 2007)

coordination throughout the entire stomach and upper small intestine. The proximal stomach experiences decreased frequency and amplitude of fundic waves, whereas the distal stomach experiences decreased frequency and amplitude of antral contractions and impaired transpyloric pressure waves. This coupled with enhanced duodenal negative feedback and retrograde duodenal motor contractions all contribute to gastric residuals and enteral intolerance (Deane et al. 2009). Critically ill patients have many unmodifiable risk factors, such as advanced age, severe illness, neurological compromise, and immobility, which all impact normal gastrointestinal function (McClave et al. 2009; Deane et al. 2009). Table 1 describes the estimated incidence of gastrointestinal dysfunction based on critical care admission diagnosis. It is important to provide excellent supportive care and to control any modifiable risk factors, such as glucose control, intensity and depth of sedation, as well as exposure to medications known to alter gastrointestinal motility. Table 2 lists the medications commonly utilized in the intensive care unit (ICU) that impact motility.

Enteral Intolerance Delayed gastric emptying occurs in up to 80 % of critically ill patients, with enteral intolerance accounting for approximately one-third of enteral stoppage time (McClave et al. 2009; Ukleja 2010; Btaiche et al. 2010). However, only about

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Table 2 Medications slowing gastric motility Medication classes Benzodiazepines/barbiturates Opioids Catecholamines Alpha2 agonists Anticholinergics Tricyclic antidepressants Antihistamines Phenothiazines Dopamine agonists Calcium-channel antagonists Iron supplements Calcium and aluminum antacids Table 2 provides a list of common medications known to impair gastric motility. The list is not comprehensive, but reflects the most common medication classes (Btaiche et al. 2010)

one-half of this is considered to be true intolerance. The term GRV stimulates considerable controversy as its application carries a high degree of subjectivity, lacks a standardized definition, and there is poor correlation between GRV and gastric emptying, regurgitation, aspiration, and pneumonia. A summary of randomized studies, with GRV ranging from 150 to 500 mL, reports no difference in pneumonia and aspiration rates when comparing various residual volumes (McClave et al. 2009). See Table 3 for a summary of GRV and pneumonia rates. However, the amount of caloric and nitrogenous intake is significantly less with cessation of enteral nutrition at predetermined lower cutoff values. A recent randomized study questioned the value of measuring GRV and utilizing it as a surrogate for enteral intolerance and cessation of nutrition (Reignier et al. 2013). In a predominately critically ill medical population, the rates of ventilator-associated pneumonia were similar between the two study groups: unmonitored GRV vs. monitored GRV. However, the incidence of vomiting was nearly twice as high (39 % vs. 27 %) in the unmonitored group; however, this did not translate to pneumonia, aspiration pneumonitis, or a greater duration of mechanical ventilation. The rate of vomiting is higher than the previous literature suggested and likely an attribute of an aggressive enteral

1325 Table 3 Gastric residual volume and pneumonia Gastric residual volume (mL) 150 vs. 200 150 vs. 250 200 vs. 500 250 vs. no monitoring

Mean pneumonia rates (%) 63 vs. 44 0 vs. 2 27 vs. 28 16 vs. 17

Table 3 provides a summary of studies reporting gastric residual volume cut points and mean rates of pneumonia. It reflects wide variance attributable to study design and population heterogeneity (McClave et al. 2009)

protocol designed to initiate feedings at a goal rate rather than initiating at a very low rate and slowly titrating toward goal. Despite this, the results support the previous literature that challenges the stomach as a reservoir of ventilator-associated pneumonia-causing bacteria, with a more likely culprit being oropharyngeal bacterial aspirates (Reignier et al. 2013; Bonten 2011). Caloric deficits were greater in the GRV monitored arm; however, an observed difference in the ICU length of stay and mortality was lacking. Available evidence certainly casts doubt on the utility of GRV, at least in isolation, to predict enteral intolerance with the subsequent development of aspiration pneumonia. Certainly, a host of questions remain to be answered. It may be that GRV volume has a role when measured trends are taken into context with other clinical variables, such as medical history, admitting diagnosis, severity of illness, intensity of hemodynamic support, vomiting, and abdominal exam.

Treatment Despite the limitations of GRV, it remains in many nutrition algorithms and directs decision-making for both non-pharmacological and pharmacological interventions to enhance enteral tolerance. It is important to adhere to good supportive measures such as semi-recumbent position with the head of the bed elevated to a minimum of 30–45 (McClave et al. 2009). In addition, potassium and magnesium levels should be maintained

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within normal ranges to provide optimal gastrointestinal myenteric conductivity and muscular contractility (McClave et al. 2009; MacLaren 2000). In most ICU patients, continuous rather than intermittent or bolus delivery of enteral nutrition should be considered, particularly if they are at high risk for aspiration (McClave et al. 2009). A well-accepted non-pharmacological method is the placement of a transpyloric enteral tube, which is commonly performed if intolerance remains despite pharmacologic prokinetic therapy. Transpyloric feeding tubes have been shown to improve caloric intake, yet evidence for decreasing aspiration pneumonia or other pertinent clinical end points is quite limited and largely confined to meta-analysis of small underpowered studies (McClave et al. 2009; Heyland et al. 2002). Despite small studies with a lot of heterogeneity, the core treatment strategy for enteral intolerance predominately involves pharmacologic measures to enhance gastric motility. A survey among European hospitals has detailed that up to one-third of ICUs prescribe a prokinetic agent to more than one-half of patients (Preiser et al. 1999). The most common prokinetics utilized in the critically ill patient are erythromycin and metoclopramide, with other agents, such as cisapride, domperidone, and naloxone, used more sparingly (McClave et al. 2009; MacLaren 2000; Fraser and Bryan 2010; Ridley et al. 2011). See Table 4 for a summary of prokinetic agents.

Metoclopramide Metoclopramide is a dopaminergic (D2) antagonist and serotonergic (5-HT4) agonist that stimulates motility via input on the efferent myenteric plexus cholinergic neurons. It enhances antral and duodenal motility, with limited effect on the distal small bowel (Deane et al. 2009; MacLaren 2000). Utilizing acetaminophen as a surrogate marker enhances gastric emptying compared to placebo (McClave et al. 2009; MacLaren 2000; Fraser and Bryan 2010). However, in a very high risk population, such as those with traumatic brain injury, metoclopramide monotherapy did not enhance gastric emptying (Marino et al. 2003; Dickerson et al. 2009). Looking beyond surrogate markers, in a mixed ICU population randomized to metoclopramide 10 mg intravenous (IV) every 8 h or placebo, the rates of pneumonia were rather low, yet similar (17 % vs. 14 %) (Yavagal et al. 2000). Nutritional outcomes, such as GRV and caloric intake, were not reported. Metoclopramide appears to have a small, yet measurable prokinetic effect (Marino et al. 2003).

Erythromycin Erythromycin is a macrolide antibiotic that stimulates the motilin receptor to produce highamplitude antral contractions, which propagate into the duodenum (Deane et al. 2009; MacLaren 2000). Similar to metoclopramide, erythromycin

Table 4 Summary of prokinetic agents for enteral intolerance Drug Metoclopramide

Dose 10 mg IV every 6–8 h

Monitoring EPS, QTc

Erythromycin

Mechanism Dopamine (D2) antagonist Serotonin (5-HT4) agonist Motilin agonist

250 mg IV every 6–8 h

Naloxone

Mu-opioid antagonist

Domperidone Neostigmine

Dopamine (D2) antagonist Acetylcholine esterase (AchE) inhibitor

8 mg enterally every 6h 10 mg IV every 6 h 0.4 mg/h IV continuous

QTc, CYP450 3A4 interactions Systemic analgesia reversal EPS, QTc Heart rate, secretions

Table 4 provides a summary of the prokinetic agents and their respective mechanism, dosing, and monitoring strategy (McClave et al. 2009; Deane et al. 2009)

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enhances motility in acetaminophen absorption models (McClave et al. 2009; MacLaren 2000; Fraser and Bryan 2010). In a trauma population randomized to erythromycin 250 mg IV every 6 h or placebo, the rates of pneumonia were similar (40 % vs. 50 %); however, a greater proportion of patients in the erythromycin arm tolerated enteral nutrition at 48 h (58 % vs. 48 %) (Dickerson et al. 2009). In addition, studies show superiority of erythromycin over metoclopramide (MacLaren 2000; Nguyen et al. 2007). In one study, erythromycin improved the proportion of patients with successful feeding at 24 h (87 % vs. 62 %) in comparison to metoclopramide (Nguyen et al. 2007). It is difficult to conclude superiority of one agent over another, given the degree of heterogeneity among studies and current outcome measures (enteral tolerance defined by a GRV). However, critically ill patients do appear to respond better to combination (metoclopramide + erythromycin) prokinetic therapy. Combination therapy may overcome compensatory block of alternative myenteric neuronal pathways. It has been shown that as many as 92 % of patients who failed monotherapy with either metoclopramide or erythromycin was successful in achieving successful feeding with rescue combination therapy (Nguyen et al. 2007). This was again demonstrated in a high-risk head trauma population, where intolerance to monotherapy metoclopramide was as high as 55 %, with only 22 % remaining intolerant after combination therapy (Dickerson et al. 2009).

Naloxone Naloxone is a mu-opioid antagonist that does not directly stimulate gastric emptying but blocks the effects of opioids on the myenteric plexus. In a mixed ICU population randomized to naloxone given enterally at a dose of 8 mg every 6 h or placebo, the rates of pneumonia were significantly reduced (34 % vs. 56 %), despite a clinically insignificant reduction in GRV (54 mL vs. 129 mL) (McClave et al. 2009). Naloxone has limited bioavailability (approximately 1–2 %)

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and is not expected to significantly reverse systemic analgesia (Smith et al. 2012). If reversal is observed, then smaller and more frequent (e.g., every 4–6 h) dosing may be preferred. Alternative agents (e.g., alvimopan and methylnaltrexone), designed to not cross the blood-brain barrier and reverse systemic analgesia, are available; however, they lack evidence in the ICU and carry their own concerns (Neyens and Jackson 2007).

Cisapride Cisapride is a serotonergic (5-HT4) agonist that stimulates motility via input on the efferent myenteric plexus cholinergic neurons (McClave et al. 2009; MacLaren 2000; Ridley et al. 2011). Similar to the previous prokinetic agents, cisapride enhances gastric emptying via acetaminophen absorption models (Ridley et al. 2011). However, it has been removed from the market in most countries due to significant concerns for QT prolongation and life-threatening tachyarrhythmias.

Domperidone Domperidone is a dopaminergic (D2) antagonist that stimulates motility via input on the efferent myenteric plexus cholinergic neurons (Deane et al. 2009). It enhances antral and duodenal motility, with limited effect on the distal small bowel. Domperidone has not been studied specifically in the ICU setting, but does have clinical data for use as a prokinetic in various ambulatory gastrointestinal motility disorders. However, it has been removed from the market in the United States due to significant concerns for QT prolongation and life-threatening tachyarrhythmias.

Neostigmine Neostigmine is an acetylcholine esterase inhibitor, which rapidly enhances gastric motility by increasing the concentration of acetylcholine at the neuromuscular junction of the cholinergic

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neurons within the myenteric plexus (Deane et al. 2009; Fraser and Bryan 2010). There is very limited literature for use of neostigmine outside of acute colonic pseudoobstruction. One study compared neostigmine, at a low IV infusion of 0.4 mg/h, to placebo and found a nonsignificant increase in gastric emptying (Lucey et al. 2003). At present, evidence does not support the use of neostigmine for improving gastric emptying and enteral tolerance. In addition, neostigmine carries its own cardiovascular concerns.

Prokinetic Concerns Adverse Reactions The focus will be on the most common prokinetic agents: metoclopramide and erythromycin. Although adverse effects of prokinetic agents are possible, the actual clinical incidence in critically ill patients remains undefined. In a study utilizing prokinetic agents over a 7-day period, no extrapyramidal symptoms, QT prolongation, or cardiac arrhythmias were observed (Nguyen et al. 2007). It is best to identify patients at risk, optimize electrolytes (e.g., potassium and magnesium), and, if feasible, avoid concomitant pharmacologic agents that may compound the risk. If the risk is deemed to be too great, then non-pharmacological strategies should be utilized first-line. Metoclopramide Metoclopramide via its central (D2) antagonism is associated with central nervous system adverse effects. In a noncritically ill population, acute EPS including akathisia, acute dystonia, and drug-induced parkinsonism occurred in up to 20 % of patients (Ganzini et al. 1993). These adverse effects are dose and duration dependent, with a low anticipated incidence in the ICU given its short-term utilization. However, if it were to occur, the treatment can be challenging and prolonged, with a risk of irreversible tardive dyskinesia. The cardiovascular effects of metoclopramide are controversial and likely rare; however, some have been fatal. The mechanism is not well understood, but it may directly alter normal myocardial conduction pathways, given its

R.R. Neyens et al.

structural similarity to procainamide (Rumore 2012). It is best to identify and use caution in those patients at greatest risk, e.g., familial prolonged QT syndromes, underlying cardiac abnormalities, electrolyte deficiencies, and/or concomitant drugs that significantly prolong the QT interval. In addition, metoclopramide will require dose adjustment in patients with renal disease and a creatinine clearance (CrCl) 500 mL may help identify very high risk populations (McClave et al. 2009). However, if a GRV monitoring strategy is utilized, the focus must remain on avoidance of inappropriate enteral cessation and treatment of true intolerance to ensure timely and adequate nutritional therapy. Refer to Fig. 1 for a suggested enteral nutrition protocol, incorporating the utilization of pharmacologic prokinetic agents.

Gastric Feeding Intolerance (clinical symptoms +/−GRV > 500 mL) [Assess and limit contributing factors, e.g. medications]

Metoclopramide 10 mg IV every 6 hours OR Erythromycin 250 mg IV every 6 hours

Metoclopramide Plus Erythromycin

Yes

Yes Intolerant

Intolerant

No

Continue gastric feeding (Reassess prokinetic daily)

Consider enteral naloxone (if on opioid analgesics) Consider post-pyloric feeding tube

No

Continue gastric feeding (Reassess prokinetic daily)

Fig. 1 Prokinetic algorithm for enteral intolerance. Provides a proposed treatment algorithm incorporating prokinetic therapy for patients displaying enteral intolerance (McClave et al. 2009)

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Application to Other Conditions Enteral nutrition is certainly more frequent in critically ill patients. However, in non-critically ill patients, it would likely be safe to assume that similar principles regarding enteral intolerance, monitoring, and treatment would apply. In fact, enhanced verbal and nonverbal communication may allow for intolerance to be better diagnosed in a non-critically ill patient population. Regardless, the same principles for the utilization of pharmacologic prokinetic agents would apply. Refer to Fig. 1 for a suggested enteral nutrition protocol.

1331 Table 5 Summary recommendations Guideline ASPEN ESPEN Canadian

of

prokinetic

Recommendation Metoclopramide, erythromycin, or naloxone Metoclopramide or erythromycin Metoclopramide

guideline Grade C C –

Table 5 provides a summary of the respective guideline recommendations, reflecting a low-level recommendation for prokinetic therapy (McClave et al. 2009; Kreymann et al. 2006; Heyland et al. 2003)

Canadian Clinical Practice guidelines (2003) for nutrition support in mechanically ventilated, critically ill adult patients (Heyland et al. 2003):

Guidelines and Protocols The American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines (2009) on enteral nutrition include a statement on enteral intolerance and pharmacologic prokinetic agents (McClave et al. 2009): • Inappropriate cessation of enteral nutrition should be avoided (Grade E). • Holding enteral nutrition for gastric residual volumes 70 mmHg without requirement for fluid boluses or increasing doses of vasoactive agents, for at least 1 h. List of Abbreviations

G.S. Doig (*) • F. Simpson • P.T. Heighes Northern Clinical School Intensive Care Research Unit, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, Australia e-mail: [email protected]; [email protected]; [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_99

ASPEN American Society for Parenteral and Enteral Nutrition h Hour ICU Intensive care unit mmHg Millimeters of mercury MODS Multiple organ dysfunction syndrome 1333

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In the early to mid-1980s, surgeons began investigating the impact of nutrition on recovery from major traumatic injury. Based on the results of these landmark clinical trials, clinical practice guidelines express a strong preference for enteral nutrition compared to other forms of nutrition support (nil per os until return of bowel sounds or parenteral nutrition) (Jacobs et al. 2004). Many surgeons with extensive experience caring for major trauma patients support these guideline recommendations and make extraordinary efforts to ensure their patients receive early enteral nutrition (Frizzi et al. 2005). The provision of enteral nutrition early during recovery from traumatic injury is accepted to result in reduced septic morbidity (Kudsk et al. 1992; Moore and Jones 1986; Moore et al. 1989, 1992), reduced ventilator-associated pneumonia (Kompan et al. 2004), and a reduction in the severity of multiple organ dysfunction syndrome (Kompan et al. 1999). A recent systematic review and metaanalysis of all available clinical trials demonstrates that enteral nutrition, provided within 24 h of injury or intensive care unit (ICU) admission, also significantly reduces mortality (Doig et al. 2011). Furthermore, the benefits reported in trauma patients are consistent with the benefits reported in other patient groups, and, perhaps most importantly, systematic research documents no significant harms arising from early enteral nutrition in any patient groups (Heighes et al. 2010).

in major trauma patients requiring care in the ICU. Under the classical paradigm of withholding oral or enteral nutrition until return of bowel sounds, ileus can progress to abdominal distension, nausea, and vomiting. Concerns regarding increased abdominal complications and vomiting leading to aspiration pneumonia are often reported as major barriers to initiating enteral nutrition early after surgery for major trauma (Byrnes et al. 2010). To investigate the relationship between early enteral nutrition and gut dysfunction in a broad base of critically ill and major trauma patients, we applied the most recent consensus definition of gut dysfunction (Warren et al. 2011), which includes ileus, high gastric residuals, vomiting, and diarrhea, across all clinical trials included in a recent systematic review and meta-analysis of early enteral nutrition (Doig et al. 2009). We found a trend toward less gut dysfunction among patients receiving enteral nutrition within 24 h of admission to the ICU (33 % of early enteral nutrition patients experience gut dysfunction vs. 43 % of standard care patients, p = 0.09, I2 = 0 %; Fig. 1) (Chiarelli et al. 1990; Kompan et al. 2004; Pupelis et al. 2001). Mounting clinical and laboratory evidence demonstrates that early enteral nutrition, provided before the return of bowel sounds, actually decreases the severity of the expected clinical consequences of ileus (Warren et al. 2011). This reduction in gut dysfunction attributable to early enteral nutrition is consistent with the finding of lower aspiration rates (Doig et al. 2008) and reduced ventilator-associated pneumonia when enteral nutrition is initiated within 24 h of ICU admission (Kompan et al. 2004). In patients requiring ICU care, the paradigm of waiting for return of bowel sounds is no longer recommended as reasonable care (Martindale et al. 2009).

Barriers to Early Enteral Nutrition: Nausea, Vomiting, and Aspiration Pneumonia

Pathophysiology: From Gut Dysfunction to Multiple Organ Dysfunction Syndrome

Detected clinically as lack of bowel sounds, postoperative ileus occurs frequently after abdominal or gastrointestinal surgery and is especially common

During the early 1970s, surgeons began to recognize the impact and importance of the sequential failure of organ systems on patient outcomes after

OR p SCCM US

Odds ratio P value Society of Critical Care Medicine United States of America

Introduction

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Mortality in Intensive Care and the Role of Enteral Nutrition in Trauma Patients

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Review: Early EN (4.0 due to a variety of reasons including age of patient, delayed gastric emptying and presence of enteral feed, and prophylactic use of acid inhibitors that will alter the gastric pH. Table 1 shows the percentage of gastric aspirate samples for which a correctly placed nasogastric tube would be identified at different pH cutoff values with and without the presence of antacid medication (Gilbertson et al. 2011). This is consistent with another study that reported an 85 % confirmation rate for correctly placed NGTs at pH 5.0 cutoff (Ellett et al. 2005). Use of H2 receptor antagonists and/or proton pump inhibitors as prophylactic antacid medications will directly effect the pH aspirate results. Antacid medication (such as pantoprazole, omeprazole, lansoprazole, and ranitidine) does decrease the percentage of

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Use of pH Cutoff Level for Enteral Nutrition

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Table 1 Percentage (95 % CI) of gastric aspirate samples for which a correctly placed nasogastric tube would be identified at different pH cutoff valuesa. Results indicate that as the pH cutoff level increases, the percentage of gastric aspirate samples for which a correctly placed nasogastric tube would be identified is also increased, but pH values >5 warrant further investigation as is not indicative of gastric placement. Antacid medication decreases the percentage of gastric aspirate samples obtained from correctly placed nasogastric tubes falling within the ideal pH cutoff values 5.0. Higher levels should not simply be assumed to be correct and warrant further investigation. Tube position can be differentiated by pH testing of aspirate obtained as shown in Table 2. The data in Table 2 clearly shows an overlap in the pH region of five to six placing uncertainty around tube position (Bankhead et al. 2009; Metheny et al. 1993, 1999; Metheny and Meert 2004; Gilbertson et al. 2011). Readings in this range warrant further investigation, with radiographic confirmation being the preferred method. Use of commercial pH strips that have multicolored pads, a pH reading range 2–9, and increase in 0.5 graduations are

Table 2 The pH range of aspirate samples from the gastrointestinal, tracheobronchial, and pleural regions. Tube position can be differentiated by pH testing of aspirate obtained from different locations; however, at a pH cutoff >5, it becomes more difficult to differentiate between the different locations (Source: Taylor 2013, with permission from Elsevier) Site Stomach Small intestine Tracheobronchial secretions and pleural fluid

N 519 490 275

pH % 0–4 60.2 1 0

5–6 18.3 5.1 0.7

7 21.5 93.9 99.3

recommended for this purpose (Fig. 2) and have been shown to highly correlate with pH meter results (Duggan et al. 2008). A limitation of pH strips is that the pH result recorded relies on the ability of the individual clinician to determine the color change on the strip. Litmus paper relies on color change from blue to red in acidic environments (which can be within pH range 4.5–8.3) and hence lacks the sensitivity and specificity required to accurately measure pH to differentiate NGT location (Taylor 2013). For this reason, litmus paper is not

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Fig. 2 Validated pH testing strips. An example of an acceptable commercial pH testing strip that has multicolored pads with 0.5 graduation markings and a pH reading range between 2 and 9

recommended for use in determining NGT position. It is not always possible to obtain a gastric aspirate sample. Literature suggests that obtaining aspirate from a tube can fail in 10–50 % of cases (Sorokin and Gottlieb 2006, Metheny et al. 1998b; Gilbertson et al. 2011), leading to use of other less reliable methods to validate tube position which are not ideal, but used commonly in clinical practice (Gilbertson et al. 2011; ENRDC 2011; Metheny et al. 2012). Ability to obtain an aspirate from a tube can be enhanced by air insufflation of the tube before reattempting to obtain aspirate, repositioning patient on their side, offering oral fluids if safe to do so, and/or using larger bore NGT tubes (Metheny et al. 1993; May 2007; NPSA 2011). (c) Gastric aspirate enzyme levels (trypsin, pepsin, bilirubin)

H. Gilbertson

These laboratory tests can be done in conjunction with pH testing to improve the accuracy for determining NGT placement. The stomach contains high levels of pepsin and minimum trypsin levels, whereas the small intestine contains high levels of trypsin and minimum pepsin levels. Reliability of pepsin enzyme levels to verify tube position has been reported at 91.2 % accuracy, similar to trypsin enzyme levels at 91.8 % (Metheny et al. 1999). The lungs should be enzymefree and hence contain minimal trypsin and pepsin levels; however, gastric aspiration into the lungs can complicate the interpretation of these results (Metheny et al. 1999). Furthermore this test is less reliable in young infants under 1 year of age because pepsin secretion levels are typically low and highly variable (Gharpure et al. 2000). Bilirubin testing is another laboratory marker that can be used for NGT placement verification, with high levels of bilirubin usually present in the intestinal tract (Metheny et al. 2000). Reliability of bilirubin levels alone is reported to be 91 % (Metheny et al. 2000), but when used in combination with pH testing, reliability to identify the nasogastric tube position was increased to 98.6 % (Metheny et al. 2000) as shown in Table 3. The advantage of using these additional laboratory tests is the increased specificity and accuracy for NGT placement determination; however, this test is not readily available at the bedside so may lead to a delay in feeding and increase associated cost. (d) Capnography and capnometry Capnography and use of colorimetric capnometry paper are methods used to measure end-tidal carbon dioxide (CO2) levels as an indicator of lung misplacement. Typically, 2–5 % CO2 levels are found in the lung. These testing methods have been shown to have high sensitivity (0.88–1.00) and specificity (0.95–1.00) (Chau et al. 2011) to identify lung misplacement and has also been validated for use in premature infants (Ellett et al. 2007). However,

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Use of pH Cutoff Level for Enteral Nutrition

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Table 3 Classification of lung, gastric, and intestinal placement using combined pH and bilirubin criteria for assessment. The accuracy and reliability to identify nasogastric tube position is increased when combining pH and bilirubin criteria when assessing tube placement (Source: Taylor 2013, with permission from Elsevier) Position Lung Stomach Intestine

Criteria pH >5.0 5.0

Bilirubin (mg/L) 4.0, making it difficult to interpret. Although both of these studies reported slightly elevated pH levels in the groups that were using antacid medications, the mean pH levels were not significantly different. This has also been demonstrated in adult studies where the majority of gastric aspirate pH readings were 5.0 with or without the presence of antacid medication (Griffith et al. 2003). Caution is warranted when evaluating gastric aspirate samples with a pH > 5.0 for any patient. NPSA guidelines recommend that a pH value between 5 and 6 should be confirmed by a second competent clinician before proceeding to use the NGT (NPSA 2011). The pediatric critical care patient is also at increased risk of aspiration, and therefore tracheobronchial fluid may potentially present as being acidic (Goodwin 1996). Although this is thought to be unlikely since it is argued that the aspirate should quickly distribute to the lung peripheries (Zaloga 1991), it remains an important point to consider when assessing the individual patient. Furthermore, pain or stress in the critical care patient may cause duodenal reflux and contribute to increased gastric pH readings making pH results difficult to interpret (Fuchs and DeMeester 1990).

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Continuous feeding regimes are often reported in critically ill patients to improve feeding tolerance. Such feeding regimes make it difficult to obtain gastric aspirate for testing pH levels if feed is still present in the stomach. Most enteral feeds have been shown to have pH 6.6 (Metheny and Titler 2001). Ceasing feeds for 1 h prior to testing gastric aspirate pH has been recommended (Metheny et al. 1993), but fasting for longer periods may be required if delayed gastric emptying is present. This interrupts the feeding plan and delays delivery of adequate nutrition targets to the critical care child. Fasting for procedures is one of the main barriers identified in critical care that prevents patients from achieving their nutrition targets (Rogers et al. 2003). Delay in achieving nutrition targets in the critically ill patient leads to poorer health outcomes (Artinian et al. 2006). Ideally, these factors should be considered when determining the feeding regime and adjusting feeding rates to meet nutrition targets allowing for fasting interruptions during procedures (e.g., feed target volume over 20 h rather than 24 h).

Application to Other Conditions These issues and risks apply to all patients receiving NGT feeding if tube position is not correctly verified at initial insertion or before every use. To ensure safer feeding practices, clinical practice guidelines that incorporate standardized policies and procedures need to be adopted by all health services using enteral feeding to support their patients. These guidelines need to be evidence based and clinically applicable to ensure safe administration of feeds and medications via the NGT without placing the patient at unnecessary risk or compromising their nutritional status. The other group of concern that needs to be considered are the home enterally fed patients using NGT to administer their feeds. These patients are also at major risk as they are often fed by family members or carers with little/no medical expertise. The importance of clear policies and procedures is again critical to ensure safe and practical feeding practices that can be extended into the home environment.

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Education is paramount to ensure caregivers are aware of the critical risks associated with a misplaced tube to improve compliance in verifying the position before every use. Provision of appropriate pH strip paper (as opposed to litmus paper) and an assessment of caregiver competency to read the color changes on the pH paper for correct interpretation should be mandatory before the patient is discharged for care into the home setting.

Guidelines and Protocols Evidence-based guidelines and recommendations exist (NPSA 2011; Bankhead et al. 2009; Richardson et al. 2006) that should form the basis of local NGT policy documents within individual health settings. These documents provide evidence-based information for checking and confirming correct placement of the NGT, a feeding chart algorithm (see Fig. 3), and mandatory procedures that should be included in the policy document including bedside documentation, staff training, competency frameworks, staff supervision, and regular audits/surveillance to ensure compliance to the policy (NPSA 2011). All health services that undertake enteral feeding need to have their own policy and protocols in place. Policies and procedures should contain a clear step-by-step process or flow chart that clearly describes the validated and acceptable methods that can be used within the individual health service to verify tube position. Education to increase the awareness of the associated risks of not identifying a misplaced tube is also imperative to improve adherence to these policies and highlight the importance for initial confirmation and ongoing verifications before each use. Adequate training and support for all personnel involved with NGT feeding is imperative to ensure not only valid and reliable methods are used to test NGT position, but that correct interpretation of the results obtained is also ensured. The e-learning teaching module (developed in response to the NPSA report) was enforced as mandatory training for all junior doctors in the UK to address the high rate of radiographic interpretation errors. Evaluation of this e-learning module indicated increased

H. Gilbertson

awareness of interpretation errors and reduced junior doctors’ interpretation errors from 4 % to 0.05 %. The e-learning module is endorsed by the NPSA and is readily available online at www. trainingngt.co.uk so it can be utilized by any health service. Documentation records need to be very clear and information well communicated to all members of the healthcare team. Information must include patient assessment details and the rationale for NGT feeding and detailed insertion notes (including verification method used to confirm position, result obtained, and who performed the check including name, time, grade, and signature). If any difficulties were encountered with insertion or verification, this needs to be clearly stated and communicated to alert those interpreting the results that this patient is potentially at a higher risk of NGT misplacement. The timing of the NGT insertion is also an important consideration. Insertion of NGT tubes should be performed within normal working hours where possible to ensure access to appropriate equipment and expertise for verification such as an expert radiographer who can provide immediate expert image interpretation in radiology. Any insertions ordered outside of normal working hours should need to be authorized by a senior clinician (Law et al. 2013).

Summary Points • Testing the pH value of the NGT aspirate remains the first-line most appropriate, convenient, and valid method to confirm NGT placement: pH 5.0 pH between 5.0 and 6.0 pH >6.0

Verification that the NGT is located within the gastric region Recheck pH reading with second competent clinician and/or radiographic confirmation Does not confirm gastric position. NGT cannot be used

• If there is any doubt regarding aspirate pH result or in the case of not being able to obtain an aspirate from the NGT, the clinician should

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Use of pH Cutoff Level for Enteral Nutrition

1379 NHS National Patient Safety Agency

Decision tree for nasogastric tube placement checks in CHILDREN and INFANTS (NOT NEONATES) • Estimate NEX measurement (Place exit port of tube at tip of nose. Extend tube to earlobe, and then to xiphistemum) • Insert fully radio-opaque nasogastric tube for feeding (follow manufacturer’s instructions for insertion) • Confirm and document secured NEX measurement • Aspirate with a syringe using gentle suction

Aspirate obtained? NO

YES

Try each of these techniques to help gain aspirate: • • • • •

If possible, turn child/infant onto left side Inject 1-5ml air into the tube using a syringe Wait for 15-30 minutes before aspirating again Advance or withdraw tube by 1-2cm. Give mouth care to patients who are nil by mouth (stimulates gastric secretion of acid) • Do not use water to flush Test aspirate on CE marked pH indicator paper for use on human gastric aspirate

YES

Aspirate obtained? NO

pH between 1 and 5.5

pH NOT between 1 and 5.5

Competent clinician (with evidence of training) to document confirmation of nasogastric tube position in stomach

PROCEED TO FEED or USE TUBE Record result in notes and subsequently on bedside documentation before each feed/medication/flush.

Proceed to x-ray: ensure reason for x-ray documented on request form

YES NO DO NOT FEED or USE TUBE Consider re-siting tube or call for senior advice

A pH of between 1 and 5.5 is reliable confirmation that the tube is not in the lung, however it does not confirm gastric placement as there is a small chance the tube tip may sit in the oesophagus where it carries a higher risk of aspiration. If this is any concern, the patient should proceed to x-ray in order to confirm tube position. Where pH readings fall between 5 and 6 it is recommended that a second competent person checks the reading or retests.

www.npsa.nhs.uk/alerts

Fig. 3 Decision tree for nasogastric tube placement checks in children and infants. Decision tree for nasogastric tube placement checks in children and infants developed by the National Patient Safety Agency (NPSA) in response to a series of adverse events that resulted in

death and serious harm from misplaced nasogastric tubes. These procedures aim to make a misplaced nasogastric tube a “never event” (Source: NPSA 2011, with permission from NPSA NHS www.npsa.nhs.uk/alerts)

1380

seek radiographic confirmation as the most appropriate second-line confirmation process. • No NGT confirmation method guarantees correct placement used in isolation. Other valid methods are available to confirm NGT position but are often not readily available at the bedside, leading to delays in feeding and increased costs, and some involve complex techniques that require training and competency assessment before use to ensure correct interpretation. A combination of methods will improve the accuracy of determining tube location and should be based on individual patient risk assessment. • Adequate training and support for staff are essential for whichever method is used in the health setting to ensure competency in interpretation. • Clear policies and protocols need to be established in each health setting based on NPSA guidelines that clearly outline the process, documentation, and communication required to ensure safer feeding practices and to achieve the aim of a misplaced NGT becoming a “never event.”

References Artinian V, Krayem H, DiGiovine B. Effects of early enteral feeding on the outcome of critically ill mechanically ventilated medical patients. Chest. 2006;129: 960–7. Astles T, Ravi R, Moore R. The radiographic appearance of nasogastric tubes. Intensive Care Med. 2011;37: S170. Bankhead R, Boullata J, Brantley S, Corkins M, Guenter P, Krenitsky J, Lyman B, Metheny NA, Mueller C, Robbins S, Wesel J, ASPEN Board of Directors. Enteral nutrition practice recommendations. JPEN. 2009;33(2):122–67. Chan EY, Ng IH, Tan SL, Jabin K, Lee LN, Ang CC. Nasogastric feeding practices – a survey using clinical scenarios. Int J Nurs Stud. 2012;48:310–9. Chau JPC, Lo SHS, Thompson DR, Fernandez R, Griffiths R. Use of end-tidal carbon dioxide detection to determine correct placement of nasogastric tube: a meta-analysis. Int J Nurs Stud. 2011;48:513–21. Cohen MD, Ellett M. Quality of communication: different patterns of reporting the location of the tip of a nasogastric tube. Acad Radiol. 2012;19(6):651–3.

H. Gilbertson Creel A, Winkler MK. Oral and nasal enteral tube placement errors and complications in a paediatric intensive care unit. Pediatr Crit Care Med. 2007;8(2):161–4. Duggan S, Smyth N, Egan S, Roddy M, Conlon K. An assessment of the validity of enteral aspirate pH measurements made with commercial pH strips. Clin Nutr. 2008;3:303–8. Ellett ML. What is known about methods of correctly placing gastric tubes in adults and children. Gastroenterol Nurs. 2004;27(6):253–9. Ellett ML, Beckstrand J. Examination of gavage tube placement in children. J Soc Pediatr Nurs. 1999;4: 51–60. Ellett M, Maahs J, Forsee S. Prevalence of feeding tube placement errors and associated risk factors in children. Matern Child Nurs. 1998;23:234–9. Ellett MLC, Croffie JMB, Cohen MD, Perkins SM. Gastric tube placement in young children. Clin Nurs Res. 2005;14(3):238–52. Ellett MLC, Woodruff KA, Stewart DL. The use of carbon dioxide monitoring to determine orogastric tube placement in premature infants. Gastroenterol Nurs. 2007;30(6):414–7. ENRDC: Emergency Nursing Resources Development Committee, Proehl JA, Heaton K, Naccarato MK, Crowley MA, Storer A, Moretz JD, Li S. Emergency nursing resource: gastric tube placement verification. J Emerg Nurs. 2011;37(4):357–62. Farrington M, Lang S, Cullen L, Stewart S. Nasogastric tube placement verification in pediatric and neonatal patients. Pediatr Nurs. 2009;35:17–24. Fuchs K, DeMeester T. Intragastric pH pattern analysis in patients with duodenogastric reflux. Dig Dis. 1990; 8(sup 1):54–9. Gharpure V, Meert K, Sarnaik A, Metheny N. Indicators of postpyloric feeding tube placement in children. Pediatr Crit Care. 2000;28:2962–6. Gilbertson HR, Rogers EJ, Ukoumunne OC. Determination of a practical pH cut-off level for reliable nasogastric tube placement. JPEN. 2011;35:540–4. Goodwin RS. Prevention of aspiration pneumonia: a research-based protocol. Dimens Crit Care Nurs. 1996;15(2):58–71. Griffith DP, McNally AT, Battey CH, Forte SS, Cacciatore AM, Szeszycki EE, Bergman GF, Furr CE, Murphy FB, Galloway JR, Ziegler TR. Intravenous erythromycin facilitates bedside placement of postpyloric feeding tubes in critically ill adults: a double-blind, randomized, placebo-controlled study. Crit Care Med. 2003;31(1):39–44. Huynh D, Chapman MJ, Nguyen NQ. Nutrition support in the critically ill. Curr Opin Gastroenterol. 2013;29(2): 208–15. Lamont T, Beaumont C, Fayez A, Healey F, Huehns T, Law R, Lecko C, Panesar S, Surkitt-Parr M, Stroud M, Warner B. Safety alerts: checking placement of nasogastric feeding tubes in adults (interpretation of xray images): summary of a safety report from the NPSA. Br Med J. 2011;342:7806.

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Law R. 2012 Reducing the risk of feeding through a misplaced nasogastric tube E-module. http://www. trainingngt.co.uk/site/home.aspx. last Accessed Feb 2014. Law RL, Pullyblank AM, Eveleigh M, Slack N. Avoiding never events: improving nasogastric intubation practice and standards. Clin Radiol. 2013;68:239–44. Longo MA, Society of Pediatric Nurses Clinical Practice Committee. Best evidence: nasogastric tube placement verification. J Pediatr Nurs. 2011;26:373–6. May S. Testing nasogastric tube positioning in the critically ill: exploring the evidence. Br J Nurs. 2007;16(7): 414–8. McWhirter L, Healy M, Price M. To feed or not to feed, that is the question. Intensive Care Med. 2011;37:S198. Metheny NA, Meert KL. Monitoring feeding tube placement. Nutr Clin Pract. 2004;19:487–95. Metheny NA, Titler MG. Assessing placement of feeding tubes. Am J Nur. 2001;101(5):36–45. Metheny N, Reed L, Wiersema L, McSweeney M, Wehrle M, Clark J. Effectiveness of pH measurements in predicting feeding tube placement: an update. Nurs Res. 1993;42:324–31. Metheny NA, Clouse RE, Clark JM, Reed L, Wehrle MA, Wiersema L. pH testing of feeding-tube aspirates to determine placement. Nutr Clin Pract. 1994;9(5): 185–90. Metheny NA, Aud MA, Ignatavicius DD. Detection of improperly positioned feeding tubes. J Health Risk Manag. 1998a;18(3):37–48. Metheny N, Wehrle M, Wiersema L, Clark J. Testing feeding tube placement: auscultation versus pH method. Am J Nur. 1998b;98:37–42. Metheny N, Stewart B, Smith L, Yan H, Diebold M, Clouse R. pH and concentrations of pepsin and trypsin in feeding tube aspirates as predictors of tube placement. Nurs Res. 1999;48(4):189–97. Metheny N, Smith L, Stewart B. Development of a reliable and valid bedside test for bilirubin and its utility for improving prediction of feeding tube location. Nurs Res. 2000;49(6):302–9. Metheny NA, Meert KL, Clouse RE. Complications related to feeding tube placement. Curr Opin Gastroenterol. 2007;23(2):178–82. Metheny NA, Stewart BJ, Mills AC. Blind insertion of feeding tubes in intensive care units: a national survey. Am J Crit Care. 2012;21(5):352–60.

1381 National Patient Safety Agency (NPSA). Patient safety alert 05. How to confirm the correct position of nasogastric feeding tubes in infants, children and adults. London: NPSA; 2005. NPSA 2011. Patient safety alert NPSA/2011/PSA002: reducing the harm caused by misplaced nasogastric feeding tubes in adults, children and infants. Supporting Information. 2011. NPSA National Patient Safety Agency: nasogastric tubes audit. 2010b. Available online at www.nrls.nhs.uk/ resources/?entryid45=66675. Last Accessed Feb 2014. NPSA National Patient Safety Agency: never events annual report 2009–2010. 2010a. Available online at www.nrls.nhs.uk/resources/collections/never-events/? entryid45=83319. Last accessed Feb 2014. Richardson DS, Branowicki PA, Zeidman-Rogers L, Mahoney J, MacPhee M. An evidence-based approach to nasogastric tube management: special considerations. J Pediatr Nurs. 2006;21(5):388–93. Rogers EJ, Gilbertson HR, Heine RG, Henning R. Barriers to adequate nutrition in critically ill children. Nutrition. 2003;19:865–8. Sorokin R, Gottlieb JE. Enhancing patient safety during feeding-tube insertion: a review of more than 2000 insertions. J Parenter Enteral Nutr. 2006;30(5):440–5. Sparks DA, Chase DM, Coughlin LM, Perry E. Pulmonary complications of 9931 narrow-bore nasoenteric tubes during blind placement: a critical review. J Parenter Enter Nutr. 2011;35:625–9. Taylor SJ. Confirming nasogastric feeding tube position versus the need to feed. Intensive Crit Care Nur. 2013;29:59–69. Taylor S, Manara A, Brown J. Nasointestinal placement versus prokinetic use when treating delayed gastric emptying in ICU patients. Br J Intensive Care. 2010;20:38–44. Turgay AS, Khorshid L. Effectiveness of the auscultatory and pH methods in predicting feeding tube placements. J Clin Nur. 2010;19(11–12):1153–9. Wilkes-Holmes C. Safe placement of nasogastric tubes in children. Paediatr Nurs. 2006;18(9):14–7. Yardley IE, Donaldson LJ. Patient safety matters: reducing the risks of nasogastric tubes. Clin Med. 2010;10: 228–300. Zaloga GP. Bedside method for placing small bowel feeding tubes in critically ill patients. A prospective study. Chest. 1991;100(6):1643–6.

Initiating Safe Oral Feeding in Critical Care

105

Steven B. Leder, Debra M. Suiter, and Lewis J. Kaplan

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1384 Differentiating a Screen from a Diagnostic Tool . . . 1384 Intensivist Decision-Making Process . . . . . . . . . . . . . 1385 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . Criteria for a Successful and Reliable Swallow Screen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Can Non-swallowing Variables Be Used to Determine Aspiration Risk? . . . . . . . . . . . . . . . . . . . . . . . . Can Enteral Tube Feedings Continue During Swallowing Testing? . . . . . . . . . . . . . . . . . . . . . . .

1386 1386 1388 1389

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1390

S.B. Leder (*) Department of Surgery, Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA e-mail: [email protected] D.M. Suiter University of Kentucky Voice and Swallow Clinic, Lexington, KY, USA L.J. Kaplan Surgical Critical Care, Philadelphia VAMC, Philadelphia, PA, USA

Criteria for a successful swallow screen include sensitivity >95 % for accurate identification of patients with aspiration risk, use by a variety of trained healthcare professionals, quick to perform, easy to interpret, cost-effective, and, importantly, effective with all patients regardless of diagnosis. The decision-making process for determining which intensive care unit (ICU) patients require a swallow screen and when to recommend oral alimentation is discussed. The Yale Swallow Protocol, comprised of a brief cognitive screen, oral mechanism evaluation, and drinking 3 oz of water completely and uninterrupted, has been shown to have a 96.5 % sensitivity, 97.9 % negative predictive value, and a 5 mcg/kg/ min (i.e., chronic heart failure patient awaiting transplantation) Renal No severe acidosis or alkalosis requiring mechanical ventilation Hepatic No or minimal hepatic encephalopathy Endocrine Acceptable glycemic control without uncontrolled acidosis No endocrine emergency (i.e., acute hypothyroidism, hypercalcemic crisis) Nutrition No osmotic diarrhea No ileus or unresolved obstruction General No open thoracic cage No near obstructing upper aerodigestive tract masses

mass and subsequent weakness. As a result, such patients are more likely to have swallowing dysfunction. Certain conditions increase the pretest probability that a particular patient will have swallowing dysfunction in the ICU (Table 1) and may be used in a checklist fashion to help select patients who would benefit from screening prior to oral alimentation. Several key prerequisites are optimally satisfied prior to selecting an ICU patient for oral alimentation (Table 2). When there is a question regarding suitability for oral alimentation despite having satisfied these criteria, screening, e.g., the Yale Swallow Protocol, is a safe and efficacious way to render an accurate assessment of aspiration risk.

S.B. Leder et al. Table 2 Conditions in ICU patients that benefit from swallowing dysfunction screening prior to oral alimentation Neurologic: Stroke Glasgow Coma Scale 24 h with large volume resuscitation Upper aerodigestive tract injury or surgery Change in vocal quality from baseline Cardiac: Severe heart failure Hepatic: Encephalopathy GI: Odynophagia Dysphagia Nutrition Severe protein-calorie malnutrition Nil per os >7 days General: Diffuse weakness Neuromuscular disabling conditions (e.g., myasthenia gravis, muscular dystrophy, etc.)

Guidelines and Protocols Criteria for a Successful and Reliable Swallow Screen The key to optimal patient care is use of a reliable and validated swallow screen. Criteria for a successful swallow screen are accuracy with a sensitivity of >95 % (Leder and Espinosa 2002), use by a variety of trained healthcare professionals, quick to perform, easy to interpret, cost-effective, and, importantly,

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Initiating Safe Oral Feeding in Critical Care

Table 3 Yale Swallow Protocola

1387 Table 4 Yale Swallow Protocola

Step 1: Exclusion criteria Protocol deferred: NO risk factors for aspiration Protocol deferred in any YES answer to the following criteria Yes No __ __ Unable to remain alert for testing __ __ No thin liquids due to preexisting dysphagia __ __ Head-of-bed restriction to 30 ) Ask patient to drink the entire 3 oz (90 cm3) of water from a cup or with a straw, in sequential swallows, and slow and steady but without stopping (note: cup or straw can be held by staff or patient) Assess patient for coughing or choking during or immediately after completion of drinking

a

Leder SB, Suiter DM. The Yale Swallow Protocol An Evidence Based Approach to Decision Making, Springer, Switzerland, 2014. Used with kind permission from Springer Science + Business Media

effective with all patients regardless of diagnosis (Cochrane and Holland 1971). Use of such a screen saves both time and money, as it relegates use of objective dysphagia testing, i.e., FEES or VFSS, only to patients who fail the clinical swallow screen. The Yale Swallow Protocol (Tables 3, 4, and 5) has been shown to fit all of these criteria (Leder and Suiter 2014). The Yale Swallow Protocol has expanded upon research that used a 3 oz water swallow in a small cohort (n = 44) of stroke patients (DePippo et al. 1992). The Yale Swallow Protocol was validated using a large (n = 3,000) and heterogeneous (14 distinct diagnostic categories) sample of hospitalized individuals (Suiter and Leder 2008) and is comprised of a 3-oz water swallow challenge, a brief cognitive screen (Leder et al. 2009), and an oral mechanism examination (Leder et al. 2013), with the latter two again using a large and heterogeneous sample of hospitalized individuals (n = 4,102). The protocol requires drinking 3 oz of water directly from a cup or via a straw without interruption. Criteria for failure are the inability to drink the entire volume, interrupted drinking, or coughing during drinking or immediately after completion of drinking. The cognitive screen requires answers to three questions: What is your

a

Leder SB, Suiter DM. The Yale Swallow Protocol An Evidence Based Approach to Decision Making, Springer, Switzerland, 2014. Used with kind permission from Springer Science + Business Media b Information from the brief cognitive screen and oral mechanism examination provide information only on odds of aspiration risk with the 3-ounce water swallow challenge and should not be used as exclusionary criteria for screening c It is permissible to repeat the 3-oz water swallow challenge if it is thought the patient may pass the second attempt

name? Where are you right now? And what year is it? (Leder et al. 2009). The oral mechanism examination includes visual assessment of adequate labial closure, lingual range of motion, and facial symmetry (smile/pucker) (Leder et al. 2013). Heffner (2010) suggested using the Yale Swallow Protocol because of its robust operating characteristics. To wit, aspiration risk was determined with 96.5 % sensitivity, 97.9 % negative predictive value (Suiter and Leder 2008), and a 300ml per day or • > 4 loose stools per day or • risk of contamination of wounds or catheters • readily apparent abdominal distension OR • increased abdominal girth OR • clinically detected aspiration OR

Is stool clinically significant?

Is the patient receiving antibiotics?

Is the diarrhoea resolved?

aminophyline erythromycin phosphorus sorbital

YES Change medications, feed to tolerance

YES

NO

** Medications that commonly cause diarrhoea: • • • •

Continue same enteral feeding

NO

Consider elemental formulation

metoclopramide magnesium xylitol quinidine

NO

YES Are medications the possible cause?**

• gastric residuals > 200ml for nasogastric feeds

• • • •

Addressing tube feeding associated diarrhoea

Is diarrhoea present?

YES

Check stool for C. difficile toxins, feed to tolerance

Continue same enteral feeds

NO Decrease rate until tolerance achieved

Advance to goal rate as tolerance improves

Evidence updated by the ANZICS CTG Feeding Investigators Group Oct 28th, 2003. Chief Investigator: Dr. Gordon S. Doig, University of Sydney. Contact: [email protected]

Fig. 2 Addressing tube-feeding associated diarrhea (With permission from Dr. Gordon Doig, Chief Investigator ANZICS CTG (Australia & New Zealand Intensive Care Society Clinical Trials Group) 2003)

into an algorithm (Kiss et al. 2012). The algorithm was based on the 2009 SCCM/ASPEN and the ESPEN guidelines to suit local European practices, with references to sections of the guideline incorporated in the guideline, e.g., A4 “Enteral feeding should be started within the first 24–48 h following admission” (Fig. 3). An eight-page document was provided with flow diagrams and information to guide practice, since there was no designated dietitian or nutrition support team (Kiss et al. 2012). The algorithm specifically targeted patients eligible for EN and addressed timing of feeding initiation, selection of EN formula, determination of target energy requirements, incremental increases in feeding volume, assessment of gastrointestinal tolerance, and

strategies to improve tolerance or change feeding route (Fig. 3). It further defined indications for PN, additives to PN, and monitoring of tolerance. A blood glucose protocol was already instituted in this ICU; therefore, this was not included as part of the algorithm. A nutrition support protocol was developed and implemented to enable senior nursing staff to set safe and nutritionally adequate target feed volumes based upon patient body weight (Dobson and Scott 2007). The evaluation was through a 3-month prospective audit by specialist ICU dietitians, with data collected from electronic patient records and observation of feeding practices. Data collected for the evaluation of the algorithm included prescribed feed type, infusion rate versus

1402

A. Reeves et al.

D3

Nutrition Support ICU Target patient population

A2

ICU patients, especially mechanical ventilated patients, expected to require an ICU stay of >2-3 days and not able to eat orally. The judgment of the responsible physician based on individual circumstances of the patient must always take precedence over these general recommendations.

Nutrition support

Like other supportive therapies in the ICU, nutrition support delivery of nutrients by means other than normal eating, such as enteral and parenteral nutrition.

Aims of nutrition support

To minimize the loss of lean body mass, support of the immune system and organ functions, avoiding complications caused by nutrition support therapy

Risks of inadequate nutrition

Decrease of 2-3% lean body mass per day without adequate nutrition. Protein-energy malnutrition increases the risk of complications (especially infections and delayed wound healing).

Indicators and risk factors for malnutrition

Body-Mass-Index (BMI) 70 years. Albumin is not a suitable parameter of nutrition status in the ICU setting.

A1

Refeeding-Syndrome

In case of malnutrition, with initiation of nutrition support there is a risk of refeeding syndrome (resulting in PO4↓, K↓, Mg↓, H2O-Retention)

Validity period

Date 11/09, subject to yearly review and adaptation (products, experiences, new scientific evidence). Prepared by C. Kiss (extern RD), M. Moser, R. Lötscher, reviewed by R. Meier, A. Mehlig.

References

SCCM/ASPEN Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patients (2009) http://pen.sagepub.com/cgi/reprint/33/3/255 ESPEN Guidelines on Enteral Nutrition Intensive Care (2006) ESPEN Guidelines on Parenteral Nutrition: Intensive Care (2009) http://www.espen.org/espenguidelines.html

Fig. 3 (continued)

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Aid to Enteral Feeding in Critical Care: Algorithm

1403

Enteral Nutrition/ Tube Feeding (TF) A3 yes

Oral nutrition within 24 h?

Diet and/or Oral Supplement Resource ®250 kcal, 19 g protein

A4

B1

no

G1

yes Initiate “trickle feeding” = 10 ml/h TF if: - hemodynamically compensated? - head of the bed >30°? - RV 250 ml

Parenteral Nutrition

- prokinetics? - Continue “trickle feeding”

D4

A5

C3 G1

Control RV 4 – 6 hourly < 250 ml

Increase TF by 10 ml/h until energy target

Fig. 3 (continued)

> 250 ml

RV repeatedly >250 ml

- prokinetics? - decrease TF by10 ml/h

TF= Tube Feeding RV = Residual volume

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A. Reeves et al.

Target energy Body weight from anesthesia protocol, previous ward weight, ask patient/relatives.

Normal-/Under-/Overweight

C1

Energy target 1st ICU week

Energy target ICU course*

Body weight

25 kcal/kg

30 kcal/kg

kg

kcal/day

kcal/day

40 – 50

1000 – 1250

1200 – 1500

50 – 60

1250 – 1500

1500 – 1800

60 – 70

1500 – 1750

1800 – 2100

70 – 80

1750 – 2000

2100 – 2400

80 – 90

2000 – 2250

2400 – 2700

90 – 100

2250 – 2500

2700 – 2300 *Cave PN: Avoid overfeeding

G2

Obesity BMI >30 kg/m2 (Upper arm circumference >35 cm)

C5

Energy target 1st ICU week

Energy target ICU course*

Body weight

15 kcal/kg

20 kcal/kg

kg

kcal/Tag

kcal/Tag

70 – 80

1050 – 1200

1400 – 1600

80 – 90

1200 – 1350

1600 – 1800

90 – 100

1350 – 1500

1800 – 2000

100 – 120

1500 – 1800

2000 – 2400

120 – 140

1800 – 2100

2400 – 2800 *Cave PN: Avoid overfeeding

G2

Consider additional non-nutritional energy delivery (esp. with PN): - Glucose e.g. 500 ml Glucose 5% = 85 kcal - Glutamine z.B. 100 ml Dipeptiven = 55 kcal - Propofol z.B. 100 ml Propofol 1%/2% = 10 g lipids = 110 kcal - CAPD per day ca. 120 g glucose = 500 kcal

Fig. 3 (continued)

TF= Tube Feeding PN = Parenteral Nutrition

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Aid to Enteral Feeding in Critical Care: Algorithm

1405

Choice of product and dose of tube feeding (TF) Decreased digestional function? e.g. short bowel, fistula

I) Hydrolysed HN yes

C4

MCT, protein 20%

no

Compromised kidney function? Creatinin-Clea. 48 hours • There are no exclusions to EN • Are unlikely to meet > 70% of their nutrition needs orally

YES

GRV < 500ml • Replace all of aspirate • Flush with 20 ml water • Continue with EN

Can this patient receive EN?

NO

1. Insert gastric tube 2. Confirm position by X-Rray 3. Confirm commencement of EN with ICU medical team Contact the dietitian between 0830 –2000_to obtain a TARGET rate for feeding. Contact details: Mon to Fri 0830-1700: p6178 After hours: Mon to Fri 1700-2000 and Sat and Sun 0800-2000: p4850

Perform an initial Gastric Residual Volume (GRV)

Commence EN at TARGET RATE

Exclusions to EN • Tolerating adequate oral intake • 500ml: • Refer to intolerance chart and follow management

Check GRV q6h hourly NB: If GRV remains < 500 ml for 48 hrs, aspirates can be done q8h

Intolerance Chart st

1 GRV > 500ml:

2nd GRV >500ml

More than 2 GRV>500ml

1. Replace all of the aspirate up to 500ml, discard the rest and flush with 20ml of water 2. Commence Metoclopramide IV 10 mg q6h together with Erythromycin (unless contraindicated: see guideline page 8) IV 200mg q12h for 24 –72hrs. 3. Continue with EN at TARGET rate 4. Continue to monitor GRV q6h

1. Replace all of the aspirate up to 500ml, discard the rest and flush with 20ml of water 2. Halve feed rate for 6 hours (review insulin if required). 3. Continue to monitor GRV q6h 4. Increase back to target after 6 hours if GRVs are < 500ml

1. Cease EN via gastric delivery (review insulin if required). 2. Request ICU review 3. Consider naso-jejunal tube placement 4. Consider supplementing with PN

Fig. 5 Algorithm for an ICU with a comprehensive dietetic service. ICU enteral nutrition flow chart relating to feeding processes with starting rate and standard enteral feed specified (Source: The Alfred ICU, Melbourne,

Australia (Ridley et al. 2012) With Permission from Emma Ridley, Senior ICU Dietitian). ICU Intensive Care Unit

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hospital, a closed ICU, a strong focus on multidisciplinary team approach, and a multidisciplinary daily ICU ward round including intensivists, nurses, dietitians, and pharmacists (Cahill et al. 2010). Another enabler is their focus on education demonstrated by annual symposia since 2010 (The Alfred 2012). Regular training of medical staff has also been recommended as a measure to improve nutrition prescription and delivery (Quenot et al. 2010).

The Future Simple formulae have the advantage of being readily adapted to computerized systems. Computerized systems enable visualization of realtime energy delivery, as well as aiding research and data collection and assessing the impacts of treatment (Berger and Pichard 2012). Visualization of real-time energy delivery allows adjustments for the precise measurement of feeding solutions and energy contributions from sedatives like propofol (lipids) and glucose-containing solutions. This can help to reduce hypercaloric feeding with its adverse consequences on glycemic control, liver function, and infections (Berger and Pichard 2012). Increasing use of computerization could lead to mechanical ventilators with equipment incorporated to determine resting energy expenditure, which in turn can be converted by a computer algorithm into the rate and type of feed (Berger and Pichard 2012). Despite increasing computerization, there will continue to be a need for clinicians to interpret emerging evidence, adjust algorithms based on evidence, and encourage adherence to protocols.

Summary Points • High-level evidence supports the use of nutrition support protocols related to feeding processes in improving delivery of enteral and parenteral nutrition in the critical care setting. • Evidence is accumulating to support the value of nutrition support algorithms that enable nursing staff to select target rates of feeding.

A. Reeves et al.

• Following the implementation of an algorithm, continual monitoring and audit are needed to promote guideline adherence. • A key role for the dietitian in ICU is to provide expertise for developing nutrition support protocols that improve patient outcomes. Protocols or algorithms need to be continually updated in line with changing evidence. • Barriers to guideline adherence include paucity of evidence or lack of agreement supporting guidelines, lack of expertise and training, workload constraints, concerns with patient comfort, and probable poor outcome. • Enablers to promote guideline acceptance include protocols presented in a simple userfriendly format, fostering of a team approach, daily multidisciplinary ward rounds, and staff attendance at educational workshops and training.

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severe sepsis and septic shock. Intensive Care Med. 2008;34(1):17–60. Dobson K, Scott A. Review of ICU nutrition support practices: implementing the nurse led enteral feeding algorithm. Nurs Crit Care. 2007;12(3):114–23. Doig G, Simpson F. Evidence-based guidelines for nutritional support of the critically ill. Results of a bi-national guideline development conference. 2005. Sydney. www.EvidenceBased.net Driscoll D, Bistrian B. Parenteral and enteral nutrition in the intensive care unit. In: Irwin R, Rippe J, editors. Intensive care medicine. 7th ed. Philadelphia: Wolters Kluwer/Lippincott, Williams & Wilkins Health; 2011. p. 1974–90. Elliott R, McKinley S, Aitken L, et al. The effect of an algorithm-based sedation guideline on the duration of mechanical ventilation in an Australian intensive care unit. Intensive Care Med. 2006;32(10):1506–14. Fahey B, Sheehy A, Coursin D. Glucose control in the intensive care unit. Crit Care Med. 2009;37(5): 169–76. Ferrie S, East V. Managing diarrhoea in intensive care. Aust Crit Care. 2007;20(1):7–13. Frankenfield D, Ashcraft C. Estimating energy needs in nutrition support patients. JPEN. 2011;35(5):563–70. Freshwater-Turner D, Boots R, Bowman R, et al. Difficult decisions in the intensive care unit: an illustrative case. Anaesth Intensive Care. 2007;35 (5):748–59. Glynn C, Greene W, Winkler M, et al. Predictive versus measured energy expenditure using limits-of-agreement analysis in hospitalized, obese patients. JPEN. 1999;23(3):147–54. Heidegger C, Romand J, Treggiari M, et al. Is it now time to promote mixed enteral and parenteral nutrition for the critically ill patient? Intensive Care Med. 2007; 33(6):963–9. Heyland D, Dhaliwal R, Drover J, et al. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN. 2003;27(5):355–73. Hise M, Halterman K, Gajewski B, Parkhurst M, et al. Feeding practices of severely ill intensive care unit patients: an evaluation of energy sources and clinical outcomes. J Am Diet Assoc. 2007;107(3): 458–65. Horner D, Bellamy M. Care bundles in intensive care. In: Langton J, editor. Continuing education in anaesthesia, critical care & pain. London: Oxford University Press; 2012;12(4):199–202. Ireton-Jones C. Estimating energy requirements. In: Shikora A, Martindale R, Schwaitzberg S, editors. Nutritional considerations in the intensive care unit – science, rationale and practice. 1st ed. Dubuque: Kendall/Hunt; 2002. p. 31–7. Kiss C, Bihar-Gray L, Denmark R, et al. The impact of implementation of a nutrition support algorithm on nutrition care outcomes in an intensive care unit. Nutr Clin Pract. 2012;27(6):793–801.

1411 Kreymann K, Berger M, Deutz N, et al. ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr. 2006; 25(2):210–23. Mackenzie S, Zygun D, Whitmore B, et al. Implementation of a nutrition support protocol increases the proportion of mechanically ventilated patients reaching enteral nutrition targets in the adult intensive care unit. JPEN. 2005;29(2):74–80. Martin C, Doig G, Heyland D, et al. Multicentre, clusterrandomized clinical trial of algorithms for critical-care enteral and parenteral therapy (ACCEPT). Can Med Assoc J. 2004;170(2):197–204. McClave S, Martindale R, Vanek V, et al. Guidelines for the provision and assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN. 2009;33(3):277–316. doi:10.1177/ 0148607109335234. Mechanick J, et al. Diabetes-specific nutrition algorithm: a transcultural program to optimize diabetes and prediabetes care. Curr Diab Rep. 2012;12:180–94. doi:10.1007/s11892-012-0253-z (open access at Springerlink.comtranscultural). Myers T. The value of care algorithms. Pharmacotherapy. 2006;26:S181–92. Nierhaus G. Introduction. In: Algorithmic composition: paradigms of automated music generation. Wien: Springer-Verlag; 2009. p. 1–6. Nompleggi D. Nutritional therapy in the critically ill patient. In: Irwin R, Rippe J, editors. Intensive care medicine. 7th ed. Lippincott: Williams and Wilkins; 2011. p. 1969–73. Pittas A, Siegel R, Lau J. Insulin therapy for critically ill hospitalised patients: a meta-analysis of randomized controlled trials. Arch Intern Med. 2004;164(18):30–8. Quenot J, Plantefeve G, Baudel J, et al. Bedside adherence to clinical practice guidelines for enteral nutrition in critically ill patients receiving mechanical ventilation; a prospective, multi-centre, observational study. Crit Care. 2010;14:R37. Rahman S. Formulation and analysis of a rule-based shortterm load forecasting algorithm. Proc IEEE. 1990;78: 805–16. Reeves A, White H, Sosnowski K, et al. Multidisciplinary evaluation of a critical care enteral feeding algorithm. Nutr Diet. 2012;69(4):242–9. Ridley E, Davies A, Murch L, et al. Excellence in nutrition therapy: lessons learned from the international nutrition survey and the best of the best awards. ICU Manag. 2012;1:17–20. Rycroft-Malone J. Formal consensus: the development of a national clinical guideline. Qual Health Care. 2001; 10(4):238–44. Shikora S, Naylor M. Nutritional support for the obese patient. In: Shikora A, Martindale R, Schwaitzberg S, editors. Nutritional considerations in the intensive care unit – science, rationale and practice. 1st ed. Dubuque: Kendall/Hunt; 2002. p. 325–34.

1412 Simpson F, Doig G. The relative effectiveness of practice change interventions in overcoming common barriers to change: a survey of 14 hospitals with experience implementing evidence-based guidelines. J Eval Clin Pract. 2007;13(5):709–15. Singer P, Berger M, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr. 2009;28:387–400. Soguel L, Revelly J, Schaller M, et al. Energy deficit and length of hospital stay can be reduced by a two-step quality improvement of nutrition therapy: the intensive care unit dietitian can make the difference. Crit Care Med. 2012;40:412–9. Stapleton R, Jones N, Heyland D. Feeding critically ill patients: what is the optimal amount of energy?. Critical Care Medicine. 2007;35(9 Suppl):S535–540. Stratton R, Green C, Elia M. Appendix 5. A detailed analysis of the effects of enteral tube feeding in the hospital setting. In: Disease-related malnutrition: an evidence-based approach to treatment. 1st edn. Wallingford: CABI; 2003. p. 602–677. Stroud M, Duncan H, Nightingale J. Guidelines for enteral feeding in adult hospital patients. Gut. 2003; 52(Suppl VII):vii1–2. Tefferi A, Vardiman J. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic

A. Reeves et al. algorithms. Leukemia. 2008;22:14–22. doi:10.1038/ sj.leu.2404955; published online 20 September 2007. The Alfred Intensive Care Unit. Nutrition. In: Special interest groups. 2012. http://www.alfredicu.org.au/spe cial-interest-groups/nutrition/. Accessed 2 June 2013. Turconi G, Hellas C. Epidemiology of obesity – current status. In: Bagchi D, Preuss H, editors. Obesity: epidemiology, pathophysiology and prevention. 2nd ed. Boca Raton: CRC Press/Taylor & Francis Group; 2013. p. 3–6. Vanek V. Assessment and management of fluid and electrolyte abnormalities. In: Shikora A, Martindale R, Schwaitzberg S, editors. Nutritional considerations in the intensive care unit – science, rationale and practice. 1st ed. Dubuque: Kendall/Hunt; 2002. p. 79–100. Villet S, Chiolero R, Bollmann M, et al. Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin Nutr. 2005; 24(4):502–9. White H, Sosnowski K, Tran K, et al. A randomised controlled comparison of early post-pyloric versus early gastric feeding to meet nutritional targets in ventilated intensive care patients. Crit Care. 2009;13:R87. doi:10.1186/cc8181. Wilson M, Weinreb J, Soo Hoo G. Intensive insulin therapy in critical care: a review of 12 protocols. Diabetes Care. 2007;30(4):1005–11.

Enteral Decision Tree in Critical Illness

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Jean-Charles Preiser and Mathieu De Ryckere

Abstract

Contents

The successful implementation of enteral feeding in critically ill patients is frequently impeded by several obstacles, which can often be anticipated. A standardized approach using systematic decision trees for the delivery of enteral feeding has been shown to increase the awareness of the caregivers toward nutritional issues and to improve the adequacy of nutrition delivery, when adapted to the local constraints. Hence, the use of decision trees for enteral nutrition should be widely promoted as an easy and cost-effective increase in the quality of care.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413 Applications to Critical or Intensive Care . . . . . . 1414 Educational Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1414 Applications to Other Conditions . . . . . . . . . . . . . . . . 1415 Management of Current Complications . . . . . . . . . . . . 1415 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1415 Design of Decision Trees . . . . . . . . . . . . . . . . . . . . . . . . . . . 1415 Experiences of the Implementation of Systematic Decision Trees . . . . . . . . . . . . . . . . . . . . . . . . . . 1416 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1418 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1419

List of Abbreviations

ICU Intensive care unit

Introduction

J.-C. Preiser (*) • M. De Ryckere Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium e-mail: [email protected]; [email protected]

The importance of nutrition therapy in critically ill patients is increasingly acknowledged. Indeed, critically ill patients with overt undernutrition have a much worse prognosis than well-nourished subjects. A common view is a reduction of the risk of complications when the caloric deficit, calculated as the difference between energy expenditure and caloric intake, is minimized. Therefore, achieving an “adequate” nutrition support, i.e., the provision of an adequate amount of calories, proteins, and micronutrients at the right time to the right patient by the right route, represents the

# Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_109

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ultimate goal. However, during the stay in the intensive care unit (ICU), both under- and overfeeding were found associated with an increased rate of complications. For instance, a study (Villet et al. 2005) reported from a cohort on long stayers a clear correlation between the magnitude of the cumulative caloric debt (the difference between caloric intake and energy expenditure) and the rate of complications. Conversely, a large-scale prospective study (Casaer et al. 2011) demonstrated an increased rate of complications in patients randomized to an early and large caloric intake provided by parenteral nutrition. These contrasting findings highlight the complexity of nutrition therapy in the critically ill, which is only partially understood. Hence, the determination of the caloric needs of critically ill patients is not straightforward. Besides these complex, eagerly debated, and partially unsolved issues, guidelines for clinical practice are available to address the daily concerns of nutrition care (MacClave et al. 2009; Heyland et al. 2003; Kreymann et al. 2006). These guidelines consistently recommend the use of the enteral route as the first choice for the delivery of nutrition. The trophic effect of enteral feeding, the prevention of gut mucosal atrophy, and the maintenance of the integrity of the submucosal immune system and of the gastrointestinal flora all support the concept of early enteral nutrition. In practice, the enteral route is always preferred over parenteral nutrition, and the early initiation of enteral feeding as soon as possible in patients unlikely to cover at least 50 % of their nutritional needs within 3 days after the onset of critical illness is recommended by different boards of experts (MacClave et al. 2009; Heyland et al. 2003; Kreymann et al. 2006). However, the implementation and management of enteral nutrition in the critically ill are often impeded by several hurdles including delays in gastric emptying resulting in emesis or high gastric residual volumes, diarrhea, constipation, and planned or unplanned interruptions for the administration of medications, for transfer to an exam or to the operating theater, and for extubation. Therefore, a systematic and multidisciplinary approach is definitely needed for a proper management of enteral nutrition and to allow the delivery of

J.-C. Preiser and M. De Ryckere

enteral feeding in agreement with current updated recommendations.

Applications to Critical or Intensive Care In this chapter we will focus on the implementation of systematic decision trees to facilitate the administration of enteral nutritional formulas and to prevent and/or to manage current complications. The educational aspects, the reports of the experiences of several teams of investigators worldwide, and the suggested attitudes for the management of frequent complications will be summarized.

Educational Aspects As the degree of knowledge, interest, and training in the field of nutrition can differ considerably among ICUs and between the different categories of healthcare providers within one unit, the way in which enteral nutrition is used can vary widely. In a survey sent to the nursing staffs of five ICUs in Belgium, we found that although theoretical knowledge of enteral nutrition was globally poor, its advantages over parenteral nutrition were usually known (Ista et al. 2002). Interestingly, the responses to questions related to practical issues associated with enteral feeding were more influenced by the site of work and local habits than by other factors. This finding highlights the importance of education and professional environment on the skill and clinical practice. In order to promote the knowledge and adherence to recommendations for clinical practice, there are several possible approaches. The use and dissemination of mnemonics is probably very useful. Specifically, several mnemonics can be used to remind the caregivers that feeding is a critical component of the care of critically ill patients. For instance, the F letter of the acronym “FAST HUG” refers to “Feeding” (Vincent 2005). Another mnemonics “CAN WE FEED” has been suggested to promote a systematic and safe approach (Miller et al. 2011). The use of these

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mnemonics by each caregiver is very efficient if repeatedly reminded. Likewise, in addition to the use of mnemonics, regular feedbacks on the nutritional performance of an ICU will help to keep the motivation of the staff members. Unexpected concerns or issues can be discussed and solved on the basis of the data collected in the unit. Indeed, several different teams reported that administration of more than 60–70 % of the prescribed amount of enteral feeding is prevented by common hurdles. The management of these hurdles and daily concerns widely differs between the different ICUs (Preiser et al. 1999; De Jonghe et al. 2001; Cahill et al. 2010), underlying large discrepancies in the nutritional performances. For instance, the justification for interruptions of enteral infusion of feeds is highly variable, and unjustified interruptions are commonly encountered (Gramlich et al. 2004; MacClave et al. 1999). A standardized policy is therefore mandatory to avoid these unnecessary practices. Likewise, the management of current complications must be anticipated and included as “FAQ” (frequently asked questions).

Applications to Other Conditions Management of Current Complications Pulmonary aspiration of regurgitated gastric content is the commonest risk and fear during enteral feeding (Ista et al. 2002; Montejo et al. 2010; Reignier et al. 2013). The monitoring of gastric residual volume is a common practice, although its physiological relevance is doubtful. In medical ICU patients, two recent large-scale studies (Montejo et al. 2010; Reignier et al. 2013) consistently reported that the use of a threshold of 200 ml to define an impairment in gastric emptying requiring the cessation of enteral feeding was useless. In one of these studies (Reignier et al. 2013), the absence of monitoring of gastric residual volume was safe, as the incidence of aspiration pneumonia did not increase, and the total amount of enteral nutrition was higher than the standard care group. Importantly, in both studies, the elevation of the head of bed

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was carefully checked and the use of promotility agents was frequent (Montejo et al. 2010; Reignier et al. 2013). In spite of these recent findings, a “high” gastric residual volume is still often used to justify the interruption of enteral nutrition, as it is considered as a major risk factor of aspiration pneumonia (Cahill et al. 2010). Hence, decision trees must consider and anticipate these complications by the inclusion of preventive measures (head-of-bed elevation) and by the incorporation of promotility agents and/or postpyloric tube in the algorithms. The effectiveness of the two latter options is mostly dependent on the experience of the team, implying that no general recommendation can be made for the design of a decision tree. In the out center, we incorporated in our own decision tree promotility agents, as the staff is familiar with their use. The issue of diarrhea during enteral feeding is another major concern (Wiesen et al. 2006). The commonly reported presence of diarrhea during enteral infusion of feeds can be explained by the composition of enteral formulas, as well as by the characteristics of administration, including the site and the mode of infusion. Interestingly, in a recent meta-analysis comparing the risks of parenteral and enteral nutrition, enteral feeding was not found to increase the risk of diarrhea (Marshall et al. 2012). In fact, in comparison with total parenteral nutrition, enteral nutrition can actually reduce the incidence of diarrhea via a better preservation of the gastrointestinal mucosal structure and function, even in the case of circulatory compromise. The use of fiber-enriched formulas and of probiotics or synbiotics could help to prevent both enteral nutrition-associated diarrhea and constipation, but a large-scale validation is still missing.

Guidelines and Protocols Design of Decision Trees The use of decision trees is probably the easiest and most efficient way to implement a systematic approach to nutrition care, especially when the enteral route is predominantly used. The high incidence of predictable and preventable

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complications as well as the involvement of each caregiver further support a multidisciplinary (nurses, dieticians, physicians, pharmacists) approach (Marshall et al. 2012). In order to achieve awareness and active involvement from each category of caregivers, the benefits of an adequate nutrition management should be widely disseminated and reminded. The translation of updated recommendations and guidelines to meet the local constraints probably represents the best way to improve and to harmonize the nutrition care (Kattelmann et al. 2006). The complexity of the decision trees will be adapted to meet local variables, including the type of patients, the current staffing, the available material (pumps, type and size of the feeding tubes, availability of postpyloric tubes), and the enteral feeding formulas. The identification of current concerns and problems is another key issue to record before designing any decision tree. In one study (Adam 1997), the two main problems preventing the delivery of feed were the presence of gut dysfunction and elective stoppage for procedures. Interestingly, ICUs with well-defined feeding protocols delivered significantly greater volumes of feed than those without (Heyland et al. 1995). Likewise, McClave et al. analyzed the factors impeding the adequate delivery of enteral feeds in 44 ICUs and found that sixty-six percent of the enteral tube feeding cessations were judged to be attributable to avoidable causes (McClave et al. 1999). Heyland et al. (1995) also analyzed the causes of delayed initiation and of cessation or decreases of enteral feeding rate and reported that gastrointestinal dysfunction causing intolerance to enteral nutrition is a common reason for not starting, or discontinuing, feedings. As the practices and features of enteral feeding largely differ between ICUs (Cahill et al. 2010), similar local surveys are required to identify the actual impediments and to design a locally applicable algorithm.

Experiences of the Implementation of Systematic Decision Trees The results of the implementation of decision trees must be communicated to the staff, and rooms for

J.-C. Preiser and M. De Ryckere

improvement must be identified to adjust the algorithm according to this feedback. Several teams, including ourselves reported significant improvements following the diffusion and use of decision trees. We carried out a “before-and-after” study (De Ryckere et al. 2012) two months before and two months after the diffusion of a simple decision tree (Fig. 1). The data of the consecutive adult patients exclusively fed by the enteral route for at least 4 days were recorded. We observed the following major differences during the “after” period (122 patient/ days) in comparison to the “before” period (204 patient/days) (Table 1): (1) a shorter time interval between admission and the initiation of enteral feeding; (2) the prescription of a precise target rate; (3) a smaller difference between the actual prescription and the current recommendation of 25 kcal/kg/day; (4) a faster increase in the rate of infusion, when the gastric residual volume was below the predefined threshold; and (5) the use of promotility agents when the residual volume was higher than the threshold on two consecutive measurements. It is also likely that an earlier institution of enteral nutrition partially prevents delays in gastric emptying (Nguyen et al. 2008). Besides the effects directly attributable to the use of the decision tree, a larger awareness and interest of the caregivers toward nutritional issues have also contributed to these improvements. Such improvements following changes in practice must be shown to the caregivers to increase and maintain the adherence to these changes (Fig. 2). Several similar improvements have been reported by others: an Australian team (Clifford et al. 2010) compared the characteristic of nutrition support before and after implementation of a detailed feeding algorithm that included commencement of nutrition support, progression to goal nutrition rates, and management of gastric residual volumes in 2005 (pre-intervention) and 2007 (post-intervention). The results indicate that the introduction of a detailed feeding algorithm resulted in an earlier commencement of nutrition and increased number of patients reaching goal rates in less time although the difference was not statistically significant.

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Enteral Decision Tree in Critical Illness

Fig. 1 Decision tree used for the infusion of enteral nutrition. The first step is the definition of the target rate. By default, a target rate corresponding to the delivery of 25 kcal/kg/day and of 1.5 g proteins/kg/day is selected. The infusion rate of the enteral formula is calculated to match these targets. The second step is the adaptation of the actual infusion rate to meet this target within a delay determined by the tolerance of the patient to the enteral feeds

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1 - Define target rate : 25 non-protein kcal/kg/day –1.5 g/kg/day proteins. 2 - Start infusion at half target rate Gastric residual volume /6h

< 250 ml

> 250 ml

Decrease infusion rate by half

Keep infusion rate or multiply it by a factor 2 to achieve target

Gastric residual volume /6h

< 250 ml

Keep infusion rate or multiply it by a factor 2 to achieve target

Table 1 Effects of the implementation of a systematic decision tree on the delivery of enteral nutrition (Adapted from De Ryckere et al. 2012) Time interval between admission and initiation of enteral nutrition (hours) Difference between recommended and actual caloric prescription (kcal) Time to reach target rate (hours) Difference between target and actual caloric intake (kcal)

Pre 40  60

Post 27  23

1,069  812

690  950

33  30

12  10

3,346  3,950

551  600

> 250 ml

Decrease infusion rate by half Consider pro-motility agent

Another Australian team (Doig et al. 2008) performed a randomized trial in ICUs of 27 communities and tertiary hospitals in Australia and New Zealand. Between November 2003 and May 2004, 1,118 critically ill adult patients expected to remain in the ICU longer than 2 days were enrolled. All participants completed the study. The goal of the study was to determine whether evidence-based feeding guidelines improve feeding practices and reduce mortality in ICU patients. The results show that using a multifaceted practice change strategy, ICUs successfully developed and introduced an evidencebased nutritional support guideline that promoted earlier feeding and greater nutritional adequacy.

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Identification of rooms for improvement in current practice

Change in practice

Outcome to be Improved

Improved outcome

Patient And caregivers

Fig. 2 Conceptual pattern for changes in practice. Changes in practices are justified by the findings and identification of rooms for improvement of outcomes by caregivers and/or patients. Once changes have been successfully implemented, the effect on the selected outcome

variable must be shown and must be displayed and discussed with the caregivers and the patient, to maintain the adherence to the new practice and/or to further improve it

However, the use of the guideline did not improve mortality or hospital or ICU length of stay. Another recent study carried out in Australia (Williams et al. 2013) confirmed that the implementation of a systematic policy reduced by half the number of interruptions of enteral feeding. In several other studies performed elsewhere (Barr et al. 2004; Mackenzie et al. 2005; Wøien and Bjørk 2006), using a protocol for enteral nutrition improved the proportion of enterally fed ICU patients meeting their calculated nutrition requirements. Such improvement can be quantified by several indices, including the percentage of patients who received at least 80 % of their estimated energy requirements during their ICU stay (Mackenzie et al. 2005).

In conclusion, a widespread implementation and use of decision trees for the management of enteral nutrition in critically ill patients is highly desirable. These decision trees must comply with current professional recommendations and must be adapted to the local environment. Such practice will improve the quality of care at a very low cost. From an educational standpoint, it will also increase the awareness of each category of healthcare providers.

Conclusions Altogether, the use of a decision tree for enteral feeding improved the delivery of nutrients to critically ill patients. Hence, several boards of experts endorsed by professional societies (MacClave et al. 2009; Heyland et al. 2003) all recommend the use of systematic decision trees and also regular audits to improve the daily practice of enteral nutrition in critically ill patients.

Summary Points – The implementation of early enteral nutrition as soon as possible is recommended for each critically ill patient. – Several obstacles impede the delivery of the prescribed amount of enteral nutrition. – Several reasons for the interruption of feeding can be anticipated. – The use of systematic decision trees including the management of predictable obstacles has been found to increase the awareness of the staff and to improve the delivery of nutrients. – The decision trees must be designed by all healthcare professionals involved in the management of enteral nutrition.

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Enteral Decision Tree in Critical Illness

– The decision trees must comply with available updated recommendations and with the local constraints.

References Adam S, Batson S. A study of problems associated with the delivery of enteral feed in critically ill patients in five ICUs in the UK. Intensive Care Med. 1997;23:261–6. Barr J, Hecht M, Flavin KE, Khorana A, Gould MK. Outcomes in critically ill patients before and after the implementation of an evidence-based nutritional management protocol. Chest. 2004;125:1446–57. Cahill NE, Dhaliwal R, Day AG, Jiang X, Heyland DK. Nutrition therapy in the critical care setting: what is “best achievable” practice? An international multicenter observational study. Crit Care Med. 2010;38:395–401. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365:506–17. Clifford ME, Banks MD, Ross LJ, Obersky NA, Forbes SA, Hegde R, Lipman J. A detailed feeding algorithm improves delivery of nutrition support in an intensive care unit. Crit Care Resusc. 2010;12:149–55. De Jonghe B, Appere-De-Vechi C, Fournier M, Tran B, Merrer J, Melchior JC, Outin H. A prospective survey of nutritional support practices in intensive care unit patients: what is prescribed? What is delivered? Crit Care Med. 2001;29:8–12. De Ryckere M, Maetens Y, Vincent JL, Preiser JC. Impact de l’utilisation systématique d’un arbre décisionnel pour la nutrition entérale en réanimation. Nutr Clin Metab. 2012;27:5–9. Doig GS, Simpson F, Finfer S, Delaney A, Davies AR, Mitchell I, Dobb G, Nutrition Guidelines Investigators of the ANZICS Clinical Trials Group. Effect of evidence-based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. JAMA. 2008;17(300):2731–41. Gramlich L, Kichian K, Pinilla J, Rodych NJ, Dhaliwal R, Heyland DK. Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? A systematic review of the literature. Nutrition. 2004;20:843–8. Heyland D, Cook DJ, Winder B, Brylowski L, Van de Mark H, Guyatt G. Enteral nutrition in the critically ill patient: a prospective survey. Crit Care Med. 1995;23:1055–60. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for

1419 nutrition support in mechanically ventilated, critically ill adult patients. J Parenter Enteral Nutr. 2003;27: 355–73. Ista P, Jassin S, No€el F, Preiser JC. Management and knowledge of enteral nutrition in intensive care units in a city in Belgium. Nutr Clin Pract. 2002;17:32–7. Kattelmann KK, Hise M, Russell M, Charney P, Stokes M, Compher C. Preliminary evidence for a medical nutrition therapy protocol: enteral feedings for critically ill patients. J Am Diet Assoc. 2006;106:1226–41. Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, Nitenberg G, van den Berghe G, Wernerman J, DGEM (German Society for Nutritional Medicine), Ebner C, Hartl W, Heymann C, Spies C. ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr. 2006;25:210–23. MacClave SA, Sexton LK, Spain DA, Adams JL, Owens NA, Sullins MB, Blandford BS, Snider HL. Enteral tube feeding in the intensive care unit: factors impeding adequate delivery. Crit Care Med. 1999;27:1252–6. McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, Ochoa JB, Napolitano L, Cresci G, A.S.P.E.N. Board of Directors; American College of Critical Care Medicine; Society of Critical Care Medicine. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nutr. 2009;33: 277–316. Mackenzie SL, Zygun DA, Whitmore BL, Doig CJ, Hameed SM. Implementation of a nutrition support protocol increases the proportion of mechanically ventilated patients reaching enteral nutrition targets in the adult intensive care unit. J Parenter Enteral Nutr. 2005;29:74–80. Marshall AP, Cahill NE, Gramlich L, MacDonald G, Alberda C, Heyland DK. Optimizing nutrition in intensive care units: empowering critical care nurses to be effective agents of change. Am J Crit Care. 2012;21: 186–94. Miller KR, Kiraly LN, Lowen CC, Martindale RG, McClave SA. CAN WE FEED? A mnemonic to merge nutrition and intensive care assessment of the critically ill patient. J Parenter Enteral Nutr. 2011;35: 643–59. Montejo JC, Miñambres E, Bordejé L, Mesejo A, Acosta J, Heras A, Ferré M, Fernandez-Ortega F, Vaquerizo CI, Manzanedo R. Gastric residual volume during enteral nutrition in ICU patients: the REGANE study. Intensive Care Med. 2010;36:1386–93. Nguyen NQ, Fraser RJ, Bryant LK, Burgstad C, Chapman MJ, Bellon M, Wishart J, Holloway RH, Horowitz M. The impact of delaying enteral feeding on gastric emptying, plasma cholecystokinin, and peptide YY concentrations in critically ill patients. Crit Care Med. 2008;36:1469–74. Preiser JC, Berré J, Carpentier Y, Jolliet P, Pichard C, Van Gossum A, Vincent JL. Management of nutrition in

1420 European intensive care units: results of a questionnaire. Working Group on Metabolism and Nutrition of the European Society of Intensive Care Medicine. Intensive Care Med. 1999;25:95–101. Reignier J, Mercier E, Le Gouge A, Boulain T, Desachy A, Bellec F, Clavel M, Frat JP, Plantefeve G, Quenot JP, Lascarrou JB, Clinical Research in Intensive Care and Sepsis (CRICS) Group. Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial. JAMA. 2013;309:249–56. Villet S, Chiolero RL, Bollmann MD, Revelly JP, Cayeux RNMC, Delarue J, Berger MM. Negative impact of

J.-C. Preiser and M. De Ryckere hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin Nutr. 2005;24:502–9. Vincent JL. Give your patient a fast hug (at least) once a day. Crit Care Med. 2005;33:1225–9. Wiesen P, Van Gossum A, Preiser JC. Diarrhoea in the critically ill. Curr Opin Crit Care. 2006;12(2): 149–54. Williams TA, Leslie GD, Leen T, Mills L, Dobb GJ. Reducing interruptions to continuous enteral nutrition in the intensive care unit: a comparative study. J Clin Nurs. 2013. doi:10.1111/jocn.12068. Wøien H, Bjørk IT. Nutrition of the critically ill patient and effects of implementing a nutritional support algorithm in ICU. J Clin Nurs. 2006;15:168–77.

Part X Enteral Aspects: Specific Nutrients and Formulations

Inadequate Vitamin B-6 Status in Critical Care

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Yi-Chia Huang and Chien-Hsiang Cheng

Abstract

Contents

Vitamin B-6 is required by the body for a wide variety of cellular process. It serves as a coenzyme in the synthesis of nucleic acids and is involved in the production of cytokines and other polypeptide mediators, as well as the synthesis of glutathione, and plays a role in the transsulfuration pathway of homocysteine metabolism. Critically ill patients are under severe stress, inflammation, and severe clinical conditions, and thus their utilization and metabolic turnover of plasma PLP may increase. A higher vitamin B-6 intake than that of the general population might therefore be required for critically ill patients. Supplementation of vitamin B-6 might be warranted for critically ill patients to decrease inflammatory responses and oxidative stress, to increase immune function, and to correct hyperhomocysteinemia during critical illness to prevent subsequent or worsening clinical deterioration.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1423 Vitamin B-6 and Immune in Critical Care . . . . . . 1424 Vitamin B-6 and Inflammation in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425 Vitamin B-6 and Oxidative Stress in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425 Vitamin B-6 and Homocysteine in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1426 Vitamin B-6 Status in Critical Care . . . . . . . . . . . . . 1427 Vitamin B-6 Intake and Requirement in Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428 Applications to Critical or Intensive Care . . . . . . 1428 Applications to Other Conditions . . . . . . . . . . . . . . . . 1429 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1429 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429

List of Abbreviations

PL Pyridoxal PLP Pyridoxal 50 -phosphate

Y.-C. Huang (*) School of Nutrition, Chung Shan Medical University, Chung Shan Medical University Hospital, Taichung, Taiwan e-mail: [email protected]; [email protected]

Introduction

C.-H. Cheng The Intensive Care Unit, Critical Care and Respiratory Therapy, Taichung Veterans General Hospital, Taichung, Taiwan e-mail: [email protected]

Vitamin B-6 is a collective term for the metabolically and functionally related pyridoxine, pyridoxal (PL) and pyridoxamine, as well as their

# Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_23

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Y.-C. Huang and C.-H. Cheng

Fig. 1 Chemical structure with vitamin B-6

phosphorylated forms, pyridoxine 50 -phosphate, pyridoxal 50 -phosphate (PLP), and pyridoxamine 50 -phosphate (Fig. 1). The physiological active coenzyme form of vitamin B-6, PLP, is required for normal nucleic acid and protein synthesis; acts as a coenzyme for the production of cytokines and other polypeptide mediators during the inflammatory response, playing a crucial role in protecting cells from oxidative stress; and is involved in the transsulfuration pathway of homocysteine metabolism. Therefore, vitamin B-6 deficiency alone can have far more profound effect on immune system functions, can cause greater inflammation and oxidative stress, and results in worse dysfunction of homocysteine metabolism compared with effects seen in deficiencies of other vitamins. During the acute phase of illness, stress, inflammation, and overproduction of free radicals may increase the utilization and metabolic turnover of vitamin B-6 and lower the body’s pool of vitamin B-6. Although vitamin B-6 deficiency is rare in healthy humans, critically ill patients may be sensitive to vitamin B-6 deficiency. In the last few decades, however, little research has been conducted on vitamin B-6 status in critical care settings.

Vitamin B-6 and Immune in Critical Care Inadequate plasma PLP status has been observed to impair both humoral and cell-mediated immunity (Axlerod 1971; Ha et al. 1984; Kumar and Axelrod 1968; Rall and Meydani 1993; Sergeev et al. 1978; Willis-Carr and St Pierre 1978). Although the mechanism of vitamin B-6 involvement in immune responses has not yet been fully ascertained, it has been postulated that PLP acts as a coenzyme in the utilization of a one-carbon unit from serine for the synthesis of nucleic acids (Chen et al. 1989; Rall and Meydani 1993; Trakatellis et al. 1992). Inadequate plasma PLP, therefore, would impair the synthesis of DNA and RNA and further compromise immune responses. Thus, immune responses could be depressed in critically ill patients with compromised vitamin B-6 status. It has been observed that critically ill patients have significantly lower and abnormal immune responses than those of healthy controls, and plasma PLP was found to be significantly associated with immune responses after adjustment for potential confounders (Huang et al. 2005).

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A number of studies have investigated whether the immune responses of critically ill patients benefit from vitamin B-6 supplementation. Several authors reported that 50–300 mg/day vitamin B-6 supplementation in either healthy elderly or hemodialysis patients significantly improved immune responses of subjects (Casciato et al. 1984; Talbott et al. 1987; Folkers et al. 1993). To the best of authors’ knowledge, only one study to date has been conducted on critically ill patients. The results showed that 50 mg or 100 mg/day of vitamin B-6 (pyridoxine-HCl) via IV injection could compensate for the lack of responsiveness of plasma PLP to vitamin B-6 intake and further increase immune responses of critically ill patients (Cheng et al. 2006). Although more research is needed to conclusively demonstrate the effects of vitamin B-6 supplementation on critically ill patients, improvements in immune response appear to occur with high doses of vitamin B-6 supplementation (>50 mg/day pyridoxine), even in subjects with no evidence of vitamin B-6 deficiency.

Vitamin B-6 and Inflammation in Critical Care Plasma PLP is thought to act as a coenzyme in the production of cytokines and other polypeptide mediators during the inflammatory response (Friso et al. 2001). Therefore, plasma PLP might be depleted under inflammatory conditions. Deficient plasma PLP has been observed to be associated with increased levels of pro-inflammatory cytokine [e.g., tumor necrosis factor-α] and inflammatory markers [e.g., C-reactive protein, erythrocyte sedimentation rate] in animal models (Doke et al. 1998; Chiang et al. 2005); general population subjects (Friso et al. 2001; Morris et al. 2010; Sakakeeny et al. 2012); patients with rheumatoid arthritis (Roubenoff et al. 1995; Chiang et al. 2003), coronary artery disease (Friso et al. 2004), and ischemic stroke (Kelly et al. 2004); and critically ill patients (Huang et al. 2005). However, in terms of the cause-effect relationship, it is not clear whether plasma PLP concentration is lowered by

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inflammatory responses or low plasma PLP increases the risk of inflammation. Critically ill patients who are under particularly severe stress and who have persistent inflammation may in turn increase their utilization and metabolic turnover of vitamin B-6, thereby decreasing the body’s pool of vitamin B-6. However, critically ill patients experience persistent inflammation which increases the release of cytokines, so there may be enhanced uptake of PL by red blood cells (erythrocyte) through passive diffusion, and accumulation in the cells is a result of binding of PLP and PL to hemoglobin and metabolic trapping by phosphorylation of the free forms of vitamin B-6 (Ink et al. 1982; Louw et al. 1992). If PLP is taken up into tissues, this might result in a redistribution of PLP from plasma to erythrocyte during the systemic inflammatory response (Talwar et al. 2003; Gray et al. 2004; Quasim et al. 2005; Vasilaki et al. 2008). In fact, the result of one study indicated that redistribution of PLP from plasma to erythrocyte may not have occurred in critically ill surgical patients (Hou et al. 2011). Rather than being involved in redistribution, PLP is probably maintained more stably in erythrocytes than in the plasma. Therefore, supplementation of vitamin B-6 could be beneficial for critically ill patients suffering from systemic inflammation.

Vitamin B-6 and Oxidative Stress in Critical Care Vitamin B-6 may play a crucial role in protecting cells from oxidative stress because the vitamin has been shown to exhibit antioxidant activity that even exceeds that of vitamin C and E (Bilski et al. 2000). Although the exact mechanism by which vitamin B-6 exerts its effects as an antioxidant nutrient remains unclear, it might act as an antioxidant, directly or indirectly. The possible direct mechanism might be the substitution of hydroxyl (-OH) and amine (-NH2) groups on a pyridine ring in vitamin B-6 compounds which can react with the peroxy radicals and thereby scavenge radicals and lipid peroxidation (Bilski et al. 2000; Kannan and

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Fig. 2 Possible indirect antioxidant defense mechanism of vitamin B-6

Homocysteine Vitamin B-6 Cystathionine Vitamin B-6 Cysteine GSH-X

NADP+

Reduced glutathione (2GSH) glutathione reductase

NADPH+H+

Jain 2004; Ohta and Foote 2002). The indirect mechanism of the antioxidant effect of vitamin B-6 might be through the glutathione antioxidant system. Plasma PLP serves as a coenzyme for cystathionine β-synthase and cystathionine γ-lyase, both of which are required for the synthesis of cysteine. Cysteine then contributes to glutathione synthesis (Fig. 2). It is therefore reasonable to hypothesize that inadequate levels of PLP indirectly affect cysteine and glutathione synthesis and, as a consequence, they influence the entire glutathione-dependent antioxidant defense system. In recent decades, vitamin B-6 status and oxidative stress responses were mostly studied in vitro or using animal models. Vitamin B-6 could prevent the oxygen radical generation and lipid peroxidation caused by hydrogen peroxide in U937 monocytes (Kannan and Jain 2004). Supplementation of vitamin B-6 to a folic acid-deficient diet with excess methionine prevented the elevation of oxidative stress markers [e.g., serum thiobarbituric acid-reactive substances and advanced oxidation protein product levels] in homocysteinemic rats (Mahfouz and Kummerow 2004). Very few data on the association of vitamin B-6 and oxidative stress in humans, especially in critically ill patients, have been reported. Higher oxidative stress has been shown to correlate with lower vitamin B-6

glutathione S-transferase H2O2

glutathione peroxidase

Oxidized Glutathione (GSSG)

2H2O

status in older individuals (Shen et al. 2010), which might suggest the potent antioxidant ability of vitamin B-6 in humans. Critically ill patients are susceptible to various insults during the acute phase of illness. Increased free radical production and lipid peroxidation and decreased antioxidant capacity may occur during critical illness, the combination of which would result in multiple organ failure (Goode et al. 1995; Motoyama et al. 2003). Thus, if critically ill patients have an inadequate vitamin B-6 status, the normal processes of scavenging radicals and lipid peroxidation may be compromised, and therefore, patients’ antioxidant defense capacity would be deleteriously affected. To date, there are few data on the association between vitamin B-6 and oxidative stress in critically ill patients. Critically ill patients may benefit from receiving vitamin B-6 supplementation, if only to maintain adequate vitamin B-6 status while they are under severe oxidative stress.

Vitamin B-6 and Homocysteine in Critical Care Homocysteine, a sulfur-containing amino acid, is either remethylated to form methionine or transsulfurated to form cysteine (Fig. 3). When

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Fig. 3 Homocysteine metabolism

methionine is in negative balance, homocysteine is remethylated to form methionine by a methionine-conserving remethylation pathway; this process requires methyltetrahydrofolate as a cosubstrate, methionine synthase, and vitamin B-12 as a cofactor. When methionine is in excess, homocysteine is directed to the transsulfuration pathway. During the transsulfuration reaction, homocysteine is irreversibly sulfoconjugated to serine by cystathionine β-synthase and cystathionase to convert to cystathionine and then cysteine by the PLP-dependent enzymes. Therefore, deficiencies of folate, vitamin B-12, and vitamin B-6 (called B-vitamins) may account for mild to moderate hyperhomocysteinemia, a well-known risk factor for cardiovascular disease (Wald et al. 2002; Vasan et al. 2003; Finch and Joseph 2010), which can increase the overproduction of oxygen free radicals through homocysteine oxidation (Wu and Wu 2002) and has been shown to be associated with increased inflammatory markers (e.g., interleukin-6, C-reactive protein) (Rohde et al. 1999; Gori et al. 2005). The high prevalence of hyperhomocysteinemia (plasma homocysteine concentration >12 or >15 μmol/L) in critically ill patients at admission is a particularly challenging problem. The prevalence rate of hyperhomocysteinemia has been reported to be approximately 12–55 % in critically ill patients (Schindler et al. 2002; Abilés et al. 2008; Ploder et al. 2010; Hou et al. 2012). Hyperhomocysteinemia might be due, at least in

part, to compromised B-vitamin status and may cause and further exacerbate oxidative stress and inflammatory responses in critically ill patients. However, studies on the association between plasma homocysteine and status of B-vitamins have yielded conflicting results (Schindler et al. 2002; Abilés et al. 2008; Hou et al. 2012). Maintenance of an adequate vitamin B-6 status is warranted for critically ill patients, regardless of whether or not lower plasma PLP significantly contributes to increased plasma homocysteine concentration in this patient population.

Vitamin B-6 Status in Critical Care The vitamin B-6 status (i.e., plasma PLP) of critically ill patients was shown to be significantly lower than that of healthy controls and decreased during their stay in the intensive care unit (Huang et al. 2002; Huang et al. 2005). Pyridoxal 50 -phosphate and PL are both bound to serum albumin, with the PLP binding more tightly, while being transported by the blood. The binding of PLP to serum albumin in the circulation serves to protect it from hydrolysis and allows for the delivery of PLP to other tissues. Critically ill patients often have a compromised albumin concentration (Bassili and Deitel 1981; Larca and Greenbaum 1982; Christman and McCain 1993; Huang et al. 2000; Kan et al. 2003; Hou et al. 2012); therefore, low serum albumin levels

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(12 months) Maternal milk plus 2.0 g of non-hydrolyzed cow’s milk-based protein supplement Infant formula plus 1.0 g of non-hydrolyzed cow’s milk-based protein supplement

Protein, g 1.1 1.6 2.6 2.6 2.9 2.5

Carbohydrate, g 7.0 7.2 10.3 17.0 7.0 7.2

Lipid, g 3.8 3.6 5.4 4.7 3.8 3.6

Calories, Kcal 70 70 100 122 78 74

Content per 100 mL

high, and protein catabolism is increased in these patients, leading to a negative net protein balance and loss of body mass.

Recommendations for Protein Supplementation Diets and formulas for infants and children generally contain an appropriate protein concentration as long as they receive a full age-specific caloric intake, but it may be insufficient when a restricted caloric intake is given as it usually occurs in the critically ill patient (usually requiring between 50 % and 60 % of calories in relation to their age). For this reason, it is necessary to use high-protein nutritional products or to add protein supplements to the existing ones. See Table 1.

Favorable Effects of a High-Protein Diet Metabolic response of critically ill children to injury is characterized by a variable energetic requirement, usually proportionally lower than the need of proteins (Coss-Bu et al. 2001). It has been observed that infants have a 25 % increase in protein degradation after surgery and a 100 % increase in urinary excretion of nitrogen if suffering a bacterial sepsis (Keshen et al. 1997). No studies have analyzed which the most suitable diet for critically ill children is, nor are there any specifically designed products for them.

Although it is generally accepted that the nutrients that critically ill children need differ from those required by healthy ones, children under 1 or 2 years of age are usually fed with breast milk or infant formulas in most units because of its availability, digestibility, excellent tolerance, and low osmolarity, and older children usually receive full enteral diets. This practice can be due to the limited evidence on which international recommendations are based (Mehta et al. 2009). The amount of protein to be administered to a critically ill child must be oriented to balance catabolism, allowing continued growth and the development of various processes such as protein synthesis optimization, tissue repair and inflammatory response facilitation, and skeletal muscle protein mass preservation. The administration of an adequate protein supply may not be enough to achieve a proper balance between the synthesis and degradation of proteins, but an adequate intake of calories must be ensured (Hulst et al. 2004b). This is due to two main reasons: protein synthesis is a process with high energy requirements, and the coexisting caloric deficit contributes to negative protein balance (Calloway 1954). Some studies have found that enriched protein diets increase protein synthesis, improve NB (Botran and López-Herce 2011; Van Waardenburg et al. 2009), and increase protein synthesis biochemical parameters (such as prealbumin, retinol-binding protein (RBP), and transferrin) (Botran and López-Herce 2011). Also a greater availability of essential and

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branched AA in plasma is observed (Van Waardenburg et al. 2009). This may allow to achieve a positive NB if protein synthesis is greater than the rate of degradation, even if it is also high (De Betue et al. 2011). Table 2 summarizes the benefits of protein supplementation in the critically ill child. Only two prospective randomized controlled trials have compared the administration of standard versus enriched protein diets to critically ill children. In the first double-blind, controlled study, 18 children with bronchiolitis and respiratory failure admitted to the PICU were included. They were randomized either to receive a protein and caloric enriched diet (3.1  0.3 protein/Kg/day

Table 2 Advantages of nutrition with protein-enriched diets in critically ill children Advantages Promotes and increases the rate of protein synthesis Improves nitrogen balance Increases the availability of essential and branched amino acids in circulation Facilitates tissue repair Preserves skeletal muscle mass Allows continuance of body’s growth

Fig. 2 Rates of protein kinetics (g/kg/24 h) in both study groups on day 5. Data are presented as mean  SD. *p < 0.05. PE-group protein- and energy-enriched formula-fed group, S-group standard formula-fed group, WbPB whole body protein breakdown, WbPBal whole body protein balance, WbPS whole body protein synthesis. WbPS and WbPB were significantly higher in the PE-group than in the S-group. Consequently, a positive WbPBal was achieved in the PE-group, which was

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and 119  25 kcal/Kg/day) or to receive a standard diet (1.7  0.2 protein/Kg/day and 84  15 kcal/ Kg/day). Higher protein balance from increased protein synthesis was observed during the first days in the enriched diet group, despite higher protein breakdown (De Betue et al. 2011; Van Waardenburg et al. 2009; Fig. 2). In the second study, 41 patients admitted to the PICU completed the study. Of these, 21 patients received standard formula and 20 received a protein-enriched formula. There was a greater positive trend in levels of prealbumin, transferrin, RBP, and total protein in the protein-enriched diet group. These differences were significant only for RBP. The positive NB trend was also higher in the protein-enriched diet group; however, this difference did not reach statistical significance. No adverse effects and hyperproteinemia were detected in the protein-enriched diet group (Botran and López-Herce 2011). Both studies demonstrate that the proteinenriched diet is well tolerated and improves some parameters of protein metabolism in the critically ill child. However, broader studies are needed to assess the impact of diets supplemented with proteins in anthropometric, biochemical, and clinical parameters in critically ill children.

significantly higher than in the S-group (Reproduced from Archives of Disease in Childhood. De Betue CT, van Waardenburg DA, Deutz NE, van Eijk HM, van Goudoever JB, Luiking YC, Zimmermann LJ, Joosten KF. Increased protein-calorie intake promotes anabolism in critically ill infants with viral bronchiolitis: a doubleblind randomised controlled trial; 96:817–822; 2011; with permission from BMJ Publishing Group Ltd)

1440 Table 3 Disadvantages of nutrition with protein-enriched diets in critically ill children Disadvantages Azotemia secondary to increased amino acid oxidation and urea formation Metabolic acidosis Neurodevelopmental disorders Increased energy requirements

Adverse Effects of Protein Supplementation A protein-enriched diet promotes protein anabolism, but may lead to an increased oxidation of AA with urea formation, as has been observed in infants when the supplementation exceeds amino acid needs (Rivera et al. 1993; Reynolds et al. 2008; van den Akker et al. 2006) or in children with impaired renal or hepatic function. A contribution of 4–6 g/Kg/day of protein in the diet has been associated with adverse effects such as azotemia, metabolic acidosis, and neurological disorders (Premji et al. 2006). Table 3 summarizes the disadvantages and side effects of protein supplementation in critically ill children. Moreover, protein supplementation stimulates protein synthesis, and this may increase resting metabolic requirement. It is very important to provide an adequate energy intake and to measure energy requirements frequently. A higher incidence of diarrhea onset has been described in association with the use of an adult immunomodulatory diet in critically ill children (Briassoulis et al. 2005), but this was probably not related to its higher protein content.

J. Urbano et al.

Anthropometric Measurements Anthropometric evaluation is the simplest method: it is applicable to all patients, is noninvasive, and is not expensive (Sánchez et al. 2005). Weight is a good parameter, though it is difficult to measure in the critically ill child on mechanical ventilation and with numerous catheters. Furthermore, it has low sensitivity in the short term and can be affected by edema or dehydration. Measurement of the skinfolds is a useful, cheap, and relatively easy technique for studying the protein and fat components of the body (Fleta et al. 1988). However, they have significant limitations as edema increases the thickness of the fold, leading to overestimation of the nutritional status. In addition, skinfold parameters have a low sensitivity for short-term changes in the nutritional status. Some studies have suggested that mid-arm or calf circumference could be used to assess the nutritional deficit within 2 weeks of admission to the intensive care unit (Hulst et al. 2004a), but others have not confirmed these findings (Sánchez et al. 2000), because the arm circumference can be affected by hydration status. Therefore, extensive studies are needed to confirm these findings. The creatinine/height index is able to detect malnutrition on admission, but its value as a variable for monitoring patients is an unresolved issue and is not useful in renal failure (Acosta 2008). Some studies suggest that a fall in the creatinine/height index could be an indicator of a risk of death, though other studies have not confirmed these findings (Sánchez et al. 2005).

Indirect Calorimetry

Evaluation of the Effects of Protein Supplementation and Protein Balance Measurement Techniques The objectives of monitoring nutrition in the critically ill child must be to evaluate its effect on nutritional status and to detect adverse effects.

Indirect calorimetry is the best method for measuring EE, and together with the NB – which is easy to calculate and allows protein catabolism to be determined – and an analysis of administered nutrition, the balance between delivery and utilization of energy and immediate substrates can be calculated (Mehta et al. 2009; Kyle et al. 2012).

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Nitrogen Balance NB is not useful as a parameter to detect malnutrition but is adequate in evaluating the effect of protein intake and may have a prognostic value (Acosta 2008). It must be taken into account that there are different formulas for NB calculation, because there are different correction factors for skin and feces losses, and different ways to calculate nitrogen loss in urine (Bechard et al. 2012).

Biochemical Parameters Certain serum proteins (albumin, prealbumin, transferrin, and retinol-binding protein) can be good nutritional indicators in the critically ill patient. Albumin is a widely used parameter in nutritional evaluation due to its high specificity. However it has a low sensitivity to acute changes as it has a long plasma half-life (20 days) (Acosta 2008). Other body proteins with shorter halflives are better alternatives for evaluating protein nutritional status in the critically ill patient. Prealbumin, with a short half-life of 2 days and a small volume of distribution, is very sensitive and specific to acute changes. Variations in its plasma levels can be observed in less than 7 days after changes in the diet, and some studies report a good correlation between the levels of this protein and the NB (Sánchez et al. 2005; Botran and López-Herce 2011; Yoder et al. 1987; Church and Hill 1987). Prealbumin is therefore a useful parameter for monitoring nutritional status or re-nutrition in the severely ill patient. Moreover, it is the only valid parameter for evaluation of the nutritional status in renal failure (Acosta 2008). Transferrin, the iron transporting protein, has a short half-life of 8–10 days and a small volume of distribution. However, its value as a nutritional indicator is lower than that of prealbumin due to its low sensitivity and specificity when analyzed individually since its levels may be altered in liver disease, iron deficiency anemia, nephrotic syndrome and after multiple blood transfusions or the administration of aminoglycosides and cephalosporins. The rapid increase in transferrin and

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prealbumin on starting enteral nutrition supports the hypothesis that when energy and protein delivery is adequate in the critically ill child, hepatic synthesis of body proteins is rapidly stimulated, leading to a rise in their serum concentrations (Sánchez et al. 2005; Botran and López-Herce 2011). RBP is also a good marker of nutritional status follow-up and re-nutrition as it has a very short half-life of 12 h. However, its levels also fall with liver disease, infection, or intense stress, and it is not useful in patients with renal failure (Acosta 2008). Fibronectin is synthesized in endothelial cells, hepatocytes, macrophages, and fibroblasts, and it has a short half-life of between 4 and 24 h. During fasting and in patients with malnutrition, fibronectin levels fall earlier than those of other proteins that are synthesized in the liver. Its levels also increase rapidly after restoration of an adequate energy delivery. It is considered to be a good marker of nutritional status, although its concentration also falls in sepsis, burns, and in the postoperative period (Tilden et al. 1989; Sánchez et al. 2005).

Determination of Protein Balance Using Labeled Amino Acid Techniques Stable AA isotopes can be used to determine protein balance (Engelen et al. 2005). During enteral feeding, there are two sources of circulatory AA: degradation of endogenous proteins and exogenous AA from enteral nutrition that are not retained in the splanchnic area. Protein synthesis during the feed can be calculated from the clearance of the essential amino acids (EAA) from the circulation (De Betue et al. 2011). Several methods have been described to estimate tracer and protein oxidation to the whole body level. Methods based on leucine isotopes are considered reference. The advantages of methods based on the addition of tracers to organ balance studies is that they allow the simultaneous estimation of protein synthesis and protein breakdown, and provide information on whether changes in net protein balance are primarily caused by a change in

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protein synthesis or in protein breakdown (Wagenmakers 1999). The limitations are its high cost, invasiveness, and need for clinical stability of the patient, additional resources, and staff expertise. Quantification of stable isotopes of protein metabolism has been used only sporadically in some infant studies (Keshen et al. 1997; Agus et al. 2006; Shew et al. 1999) and in the study conducted on 18 patients with bronchiolitis comparing protein-enriched diet versus the standard diet (De Betue et al. 2011). In this study the method of marked phenylalanine/tyrosine was used, and a general increase in phenylalanine kinetics (increased synthesis, increased degradation, and increased balance of proteins) in the protein-rich diet was observed, compared to the standard diet group (Fig. 2).

Early Enteral Nutrition: Caloric and Protein Intake Effect Several studies in adults and children have shown that enteral nutrition is the best method to feed the critically ill patient (Sánchez et al. 2005; Sánchez et al. 2000; Sánchez et al. 2003; Sánchez et al. 2007). This route may contribute to reduce septic complications and can even improve prognosis (Skillman and Wischmeyer 2008; Zamberlan et al. 2011; Mehta et al. 2009; Marik and Zaloga 2001; Sánchez et al. 2005). TEN (total enteral nutrition) is more physiological than TPN (total parenteral nutrition); it has a trophic effect on the intestinal mucosa, it stimulates the immune system by decreasing intestinal overgrowth and bacterial translocation, and it reduces the incidence of sepsis and multiple organ failure. TEN also produces less hepatic and metabolic complications than TPN, it is less expensive, and it does not require special preparation and can be started and modified at any time. For these reasons, TEN should be the initial method of nutrition in pediatric patients (Mehta et al. 2012; Skillman and Wischmeyer 2008; Zamberlan et al. 2011; Mehta et al. 2009). Even though most critically ill children tolerate TEN (Skillman and Wischmeyer 2008;

J. Urbano et al.

Zamberlan et al. 2011; Mehta et al. 2009; Sánchez et al. 2005; Sánchez et al. 2007) and that it is known that tolerance is similar when started earlier or later in evolution (Gurgueira et al. 2005), many critically ill children start nutrition very late and do not fully receive what was prescribed (usually because of the need for fluid restriction, interruptions due to procedures, poor tolerance, or mechanical problems (the feeding tube becomes obstructed or misplaced)). A recent study found that even though 93 % of critically ill children received nutrition on the third day after admission, the prescribed energy delivery was only achieved on the fifth day (De Neef et al. 2008). In an international study 71 % of patients suffered interruptions in nutrition leading to low caloric and protein intake (Mehta et al. 2012). It is important to start enteral nutrition within the first 24–48 h of admission and to increase nutrition quickly to achieve the caloric and protein goals as soon as possible (Campos and Sasbón 2009).

Proposals for the Future The goal of nutrition should be to provide individualized nutrition and protein-calorie intake, adapted to the specific characteristics of each patient and being continuously adjusted according to metabolic changes and nutritional status. It is therefore important to develop studies evaluating sensitive methods of nutrition assessment and, more specifically, the protein component that is more suitable for most critically ill children. High scientific quality clinical studies are needed to assess the effects of the administration of protein-enriched enteral diets compared to unsupplemented diets.

Applications to Critical Care Early enteral nutrition enriched with proteins can potentially meet the caloric and protein goals of critically ill children and thus improve NB, optimize protein synthesis, facilitate tissue repair and inflammatory response, and preserve muscle mass (Mehta et al. 2009).

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Applications to Other Conditions Even though most patients recover nutritional status 6 months after discharge from the PICU (Kondrup et al. 2003), there are some groups of patients at a particularly higher risk of malnutrition. Patients with complex congenital heart disease requiring admission at birth and major palliative cardiac surgery such as hypoplastic left heart syndrome have a high incidence of protein-calorie malnutrition which may be severe. This is of particular interest since they need to maintain an optimal nutritional status in order to tackle the following surgeries after only a few months following the initial admission. Parenteral nutrition and aggressive enteral nutrition during PICU hospitalization are associated with better nutritional status (Kelleher et al. 2006). These patients may benefit from the evaluation and optimization of their nutrition by a multidisciplinary nutrition team (Miller et al. 2007; Sánchez et al. 2007), and protein-enriched diets may be useful. Children who have suffered extensive burns have an important nutritional risk. It has been observed that the reduction of body mass continues until 1 year after the occurrence of burns, associating a linear growth delay up to 2 years afterwards (Hart et al. 2000; Rutan and Herndon 1990). There is no evidence that protein-enriched enteral nutrition has beneficial effects in patients suffering from chronic diseases that have an increased protein catabolism, such as pre- and postoperative heart failure, patients with severe burns after admission to the PICU, or patients with cystic fibrosis or other chronic respiratory conditions with increased work of breathing.

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Table 4 ASPEN daily protein intake recommendations for the critically ill children Age range (years) 0–2 2–13 13–18

Protein intake (g/Kg/24 h) 2–3 1.5–2 1.5

The protein intake must be accompanied by an adequate intake of calories (Mehta et al. 2009). Early enteral nutrition should be started with a rapid increase in the caloric and protein intake to rapidly meet these objectives. The use of proteinenriched diets can help to achieve these objectives, always taking into account liver and kidney function in each patient to avoid toxicity. It is necessary to periodically monitor the effect of nutrition using NB, IC, and biochemical parameters (urea, prealbumin, and RBP).

Summary Points • Protein malnutrition is common among critically ill children at the time of admission to the pediatric intensive care unit and during admission, and it often persists after discharge. • These patients present a hypercatabolic state, especially in the early stages of the disease. • Protein-enriched diets may be more suitable than normoproteic diets since they counteract hypercatabolism and may reduce the loss of body mass and the incidence of complications. • There are few studies that have examined the effects of protein-enriched diets in critically ill children. • The nutritional effects on the patient should be evaluated by a combination of nitrogen balance, biochemical parameters, and indirect calorimetry.

Guidelines and Protocols References Recommended protein amounts for critically ill children rely on limited data. ASPEN recommendations of protein intake in children are: 0–2 years, 2–3 g/Kg/day; 2–13 years, 1.5–2 g/Kg/day; and 13–18 years, 1.5 g/Kg/day (see Table 4).

Acosta JA. Valoración del Estado Nutricional en el Paciente Grave. In: Libro Electrónico Medicina Intensiva. Madrid; 2008. Available online: http:// intensivos.uninet.edu/06/0601.html. Accessed 16 Nov 2011.

1444 Agus MS, Javid PJ, Piper HG, Wypij D, Duggan CP, Ryan DP, et al. The effect of insulin infusion upon protein metabolism in neonates on extracorporeal life support. Ann Surg. 2006;244:536–44. Bechard LJ, Parrott JS, Mehta NM. Systematic review of the influence of energy and protein intake on protein balance in critically ill children. J Pediatr. 2012;161:333–9. Botran M, López-Herce J. Malnutrition in the critically ill child: the importance of enteral nutrition. Int J Environ Res Public Health. 2011;8:4353–66. Botrán M, López-Herce J, Mencía S, Urbano J, Solana MJ, García A, Carrillo A. Relationship between energy expenditure, nutritional status and clinical severity before starting enteral nutrition in critically ill children. Br J Nutr. 2011a;105:731–7. Botrán M, López-Herce J, Mencía S, Urbano J, Solana MJ, García-Figueruelo A. Enteral nutrition in the critically ill child: comparison of standard and protein-enrich diets. J Pediatr. 2011b;159:27–32. Briassoulis G, Filippou O, Hatzi E, Papassotiriou I, Hatzis T. Early enteral administration of immunonutrition in critically ill children: Results of a blinded randomized controlled clinical trial. Nutrition. 2005;21:799–807. Butte NF. Energy requirements of infants. Public Health Nutr. 2005;8:953–67. Calloway DH, Spector H. Nitrogen balance as related to caloric and protein intake in active young men. Am J Clin Nutr. 1954;2:405–12. Campos S, Sasbón JS. The Latin-American survey on nutrition in pediatric intensive care (ELAN-CIP). An Pediatr (Barc). 2009;71:5–12. Church JM, Hill GL. Assessing the efficacy of intravenous nutrition in general surgical patients-dynamic nutritional assessment using plasma proteins. JPEN J Parenter Enteral Nutr. 1987;11:135–40. Chwals WJ, Lally KP, Woolley MM, Mahour GH. Measured energy expenditure in critically ill infants and young children. J Surg Res. 1988;44:467–72. Coss-Bu JA, Jefferson LS, Walding D, David Y, Smith EO, Klish WJ. Resting energy expenditure in children in a pediatric intensive care unit: comparison of HarrisBenedict and Talbot predictions with indirect calorimetry values. Am J Clin Nutr. 1998;67:74–80. Coss-Bu JA, Klish WJ, Walding D, Stein F, Smith EO, Jefferson LS. Energy metabolism, nitrogen balance, and substrate utilization in critically ill children. Am J Clin Nutr. 2001;74:664–9. De Betue CT, van Waardenburg DA, Deutz NE, van Eijk HM, van Goudoever JB, Luiking YC, Zimmermann LJ, Joosten KF. Increased protein-calorie intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial. Arch Dis Child. 2011;96:817–22. De Klerk G, Hop WC, de Hoog M, Joosten KF. Serial measurements of energy expenditure in critically ill children: useful in optimizing nutritional therapy? Intensive Care Med. 2002;28:1781–5.

J. Urbano et al. De Neef M, Geukers VGM, Dral A, Lindeboom R, Sauerwein HP, Bos AP. Nutritional goals, prescription and delivery in a pediatric intensive care unit. Clin Nutr. 2008;27:65–71. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics. 2001;107:270–3. Engelen MP, Rutten EP, De Castro CL, et al. Altered interorgan response to feeding in patients with chronic obstructive pulmonary disease. Am J Clin Nutr. 2005;82:366–72. Fenton TR, McMillan DD, Sauve RS. Nutrition and growth analysis of very low birth weight infants. Pediatrics. 1990;86:378–83. Fitch CW, Neville J. Nutrient intake of infants hospitalized with lower respiratory tract infections. J Am Diet Assoc. 2001;101:690–2. Fleta J, Sarriá A, Bueno-Lozano M, Perez-Choliz V. Nutritional obesity. An Esp Pediatr. 1988;29:7–12. Gurgueira GL, Leite HP, Taddei JA, de Carvalho WB. Outcomes in a pediatric intensive care unit before and after the implementation of nutrition support team. JPEN J Parenter Enteral Nutr. 2005;29:176–85. Hart DW, Wolf SE, Mlcak R, et al. Persistence of muscle catabolism after severe burn. Surgery. 2000;128:312–9. Hulst J, Joosten K, Zimmermann L, Hop W, van Buuren S, B€ uller H, Tibboel D, van Goudoever J. Malnutrition in critically ill children: from admission to 6 month after discharge. Clin Nutr. 2004a;23:223–32. Hulst JM, van Goudoever JB, Zimmermann LJ, Hop WC, Albers MJ, Tibboel D, Joosten KF. The effect of cumulative energy and protein deficiency on anthropometric parameters in a pediatric ICU population. Clin Nutr. 2004b;23:1381–9. Kelleher DK, Laussen P, Teixeira-Pinto A, et al. Growth and correlates of nutritional status among infants with hypoplastic left heart syndrome (HLHS) after stage 1 Norwood procedure. Nutrition. 2006;22:237–44. Keshen TH, Miller RG, Jahoor F, Jaksic T. Stable isotopic quantitation of protein metabolism and energy expenditure in neonates on- and post-extracorporeal life support. J Pediatr Surg. 1997;32:958–63. Kondrup J, Allison SP, Elia M, Vellas B, Plauth M. ESPEN guidelines for nutrition screening 2002. Clin Nutr. 2003;22:415–21. Kyle UG, Arriaza A, Esposito M, Coss-Bu JA. Is indirect calorimetry a necessity or a luxury in the pediatric intensive care unit? JPEN J Parenter Enteral Nutr. 2012;36:177–82. López-Herce J, Sánchez C, Mencía S, Santiago MJ, Carrillo A, Bellón JM. Energy expenditure in critically ill children: correlation with clinical characteristics, caloric intake, and predictive equations. An Pediatr (Barc). 2007;66:229–33. Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients. A systemic review. Crit Care Med. 2001;29:2264–70.

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Meert KL, Daphtary KM, Metheny NA. Gastric vs. smallbowel feeding in critically ill children receiving mechanical ventilation: a randomized controlled trial. Chest. 2004;126:872–8. Mehta NM, Duggan CP. Nutritional deficiencies during critical illness. Pediatr Clin North Am. 2009;56:1143–60. Mehta NM, Compher C, ASPEN Board of directors. ASPEN clinical guidelines: nutrition support of the critically ill child. JPEN J Parenter Enteral Nutr. 2009;33:260–76. Mehta NM, Bechard LJ, Cahill N, Wang M, Day A, Duggan CP, Heyland DK. Nutritional practices and their relationship to clinical outcomes in critically ill children–an international multicenter cohort study. Crit Care Med. 2012;40:2204–11. Miller TL, Neri D, Extein J, Somarriba G, Strickman-Stein N. Nutrition in pediatric cardiomyopathy. Prog Pediatr Cardiol. 2007;24:59–71. Oosterveld MJ, Van Der Kuip M, De Meer K, De Greef HJ, Gemke RJ. Energy expenditure and balance following pediatric intensive care unit admission: a longitudinal study of critically ill children. Pediatr Crit Care Med. 2006;7:147–53. Pérez-Navero JL, Dorao P, López-Herce Cid J, de la Rosa I, Pujol M, Hermana MT. Nutrition working group of the Spanish Society for Pediatric Critical Care Medicine. Artificial nutrition in the pediatric intensive care units. An Pediatr (Barc). 2005;62:105–12. Phillips R, Ott L, Young B, Walsh J. Nutritional support and measured energy expenditure of the child and adolescent with head injury. J Neurosurg. 1987;67:846–51. Pollack MM, Ruttimann UE, Wiley JS. Nutritional depletion in critically ill children: association with physiologic instability and increase quantity of care. JPEN J Parenter Enteral Nutr. 1985;9:309–13. Premji SS, Fenton TR, Sauve RS. Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane Database Syst Rev. 2006;25, CD003959. Prentice AM, Paul AA. Fat and energy needs of children in developing countries. Am J Clin Nutr. 2000;72 (5 Suppl):1253S–65. Reynolds RM, Bass KD, Thureen PJ. Achieving positive protein balance in the immediate postoperative period in neonates undergoing abdominal surgery. J Pediatr. 2008;152:63–7. Rivera Jr A, Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life. Pediatr Res. 1993;33:106–11.

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Rutan RL, Herndon DN. Growth delay in postburn pediatric patients. Arch Surg. 1990;125:392–5. Sánchez C, López-Herce J, Moreno De Guerra M. The use of transpyloric enteral nutrition in the critically ill child. J Intensive Care Med. 2000;15:247–54. Sánchez C, López-Herce J, Carrillo A, Bustinza A, Sancho ZL, Vigil D. Transpyloric enteral nutrition in critically ill children (I) technics and indications. An Pediatr (Barc). 2003;59:19–24. Sánchez C, López-Herce J, García C, Rupérez M, García E. The effect of enteral nutrition on nutritional status in the critically ill child. Clin Intensive Care. 2005;16:75–8. Sánchez C, López-Herce J, Carrillo A, Mencía S, Vigil D. Early transpyloric enteral nutrition in critically ill children. Nutrition. 2007;23:16–22. Shew SB, Keshen TH, Jahoor F, Jaksic T. The determinants of protein catabolism in neonates on extracorporeal membrane oxygenation. J Pediatr Surg. 1999;34:1086–90. Skillman HE, Wischmeyer PE. Nutrition therapy in critically ill infants and children. JPEN J Parenter Enteral Nutr. 2008;32:520–34. Tilden SJ, Watkins S, Tong TK, Jeevanandam M. Measured energy expenditure in pediatric intensive care patients. Am J Dis Child. 1989;143:490–2. van den Akker CH, te Braake FW, Wattimena DJ, et al. Effects of early amino-acid administration on leucine and glucose kinetics in premature infants. Pediatr Res. 2006;59:732–5. Van Waardenburg DA, de Betue CT, Goudoever JB, Zimmermann LJ, Joosten KF. Critically ill infants benefit from early administration of protein and energyenriched formula: a randomized controlled trial. Clin Nutr. 2009;28:249–55. Venugopalan P, Akinbami FO, Al-Hinai KM, Agarwal AK. Malnutrition in children with congenital heart defects. Saudi Med J. 2001;22:964–7. Wagenmakers AJ. Tracers to investigate protein and amino acid metabolism in human subjects. Proc Nutr Soc. 1999;58:987–1000. Yoder MC, Anderson DC, Gopalakrishna GS, Douglas SD, Polin RA. Comparison of serum fibronectin, prealbumin and albumin concentrations during nutritional repletion in protein-calorie malnourish infants. J Pediatr Gastroenterol Nutr. 1987;6:84–8. Zamberlan P, Delgado AF, Leone C, Feferbaum R, Okay TS. Nutrition therapy in a pediatric intensive care unit: indications, monitoring and complications. JPEN J Parenter Enteral Nutr. 2011;35:523–9.

Enteral Support and N-3 Fatty Acids in Critically Ill Elderly Patients

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Karina V. Barros, Ana Paula Cassulino, and Vera Lúcia Flor Silveira

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1448 Polyunsaturated Fatty Acids . . . . . . . . . . . . . . . . . . . . . 1449 Inflammation, Ageing and Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1451 Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453 Applications to Critical or Intensive Care . . . . . . 1455 Applications to Other Conditions . . . . . . . . . . . . . . . . 1459 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1459 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1460 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1460

K.V. Barros • A.P. Cassulino Departamento de Fisiologia, Universidade Federal de São Paulo-Campus São Paulo, São Paulo, SP, Brazil e-mail: [email protected]; [email protected]; [email protected]; [email protected] V.L.F. Silveira (*) Departamento de Ciências Biológicas, Universidade Federal de São Paulo-Campus Diadema, Eldorado, Diadema, SP, Brazil e-mail: vera.fl[email protected]; verafl[email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_55

Abstract

Ageing is characterized by a series of physiological and psychological changes that are related, in turn, with alterations in the nutritional status. The human immune system progressively deteriorates with age, leading to a greater incidence or the reactivation of infectious diseases, as well as to the development of autoimmune disorders and cancer. The critically ill elderly are more likely to suffer an exacerbated inflammatory response increasing the susceptibility of infection, sepsis, septic shock and multiple organ failure development, which are related to a longer hospitalization period and elevated risk of mortality. The relationship between inflammatory response and polyunsaturated fatty acids (PUFA)–enriched diets has been investigated in last years. Several studies have shown that PUFA can modify immunological and inflammatory reactions and can be used as a complementary therapy in chronic diseases. Enteral formulas supplied with specific pharmaconutrients can help offset tissue damage and moderate the inflammation. In this sense, n-3 PUFA intake can alter the fatty acid composition in membranes of cells involved in immune inflammatory responses and leading to better outcomes. Several clinical studies have shown that the administration of n-3 PUFA can blunt the inflammatory response in critically ill patients. 1447

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Although n-3 PUFA as pharmaconutrition appears to exert beneficial effects with no side effects, enteral supplementation of this fatty acid has presented conflicting data in the literature. These discordant data are most likely due to different routes of administration (enteral or parenteral), dose, duration of administration, timing of onset in relation to stage of the inflammatory response and differences in the nutrient combinations used. Further researches are necessary before any definitive recommendations can be made about enteral n-3 PUFA supplementation in critically ill patients, mainly in special populations, such as the elderly. This chapter will focus on the literature review about the critically ill elderly, inflammation, fatty acids and n-3 PUFA supplementation in enteral nutrition. List of Abbreviations

AA ALA APC ASPEN

Arachidonic acid α-linolenic acid Antigen presenting cells American society of parenteral and enteral nutrition CVD Cardiovascular disease D5D Delta-5-desaturases enzyme D6D Delta-6-desaturases enzyme DHA Docosapentaenoic acid EFSA European Food and Safety Authority (EFSA) EPA Eicosapentaenoic acid ESPEN European society of parenteral and enteral nutrition FA Fatty acids FDA Food and Drug Administration GLA Gamma linolenic acid ICAM Intercellular adhesion molecule ICU Intensive care unit IL Interleukin LA Linoleic acid NHF National heart foundation NHMRC National Healthy of Medical Research Council (NHMRC) PC Plasma phosphatidylcholine PUFA Polyunsaturated fatty acids ROS Reactive oxygen species

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SNP TNF

Single nucleotide polymorphism Tumor necrose factor

Introduction The increase in the elderly population has also been related to the higher demand for elderly beds in the intensive care unit (ICU), representing around 42 to 52 % of ICU hospitalization and 60 % of hospital costs (Marik 2006). The critically ill elderly are more likely to suffer an exacerbated inflammatory response increasing the susceptibility of infection, sepsis, septic shock and multiple organ failure development, which are related to a longer hospitalization period and elevated risk of mortality (Chan et al. 2009; Marik 2006). Ageing is characterized by a series of physiological and psychological changes that are related, in turn, with alterations in the nutritional status (Wick et al. 2000). The prescription of multiple drugs is often used in elderly people, and this practice can influence food intake, absorption and utilization of various nutrients, which may compromise the health and nutritional requirements (Chernoff 1990). Therefore, physiological alterations related to ageing are extremely common and often not recognized, such as atrophic gastritis, hypochlorhydria, gastric emptying, salivary gland atrophy, abnormal dentition, changes in gustatory, olfactory, visual dysphagia and functional disability, which may impact on the nutritional status (Graf 2006). Making up this population is considered as being in nutritional risk. The routine identification of nutritional risk screening is important as the first stage in nutritional treatment of the elderly. Despite this knowledge, inadequate feeding practices in ICU patients, elderly or not, have been observed, and the implementation of practice guidelines and nutritional prescription by an expert team is important and can influence cost-effective and improved outcome, especially in the elderly population (Bottoni et al. 2008). If oral intake is not possible or sufficient, the use of enteral nutrition is indicated (McClave et al. 2009; Kreymann et al. 2006).

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Nutrition in critical patients currently represents not only a simple supply of energy, macronutrients and micronutrients to ensure the target nutrition and avoid intra-hospital malnutrition (Simopoulos 2002). Following the advances in nutrigenetic and nutrigenomic studies, scientists have shown that some nutrients are capable of influencing inflammatory response and also the time of disease cure (Simopoulos 2008; Heller et al. 2006; Weiss et al. 2002).

Polyunsaturated Fatty Acids Fatty acids (FA), lipid constituents, are carboxylic acids that can be represented by the form RCO2H. Most often, the group R is a long carbon chain, unbranched, with an even number of carbon atoms and may be saturated or contain one (monounsaturated) or more double bonds

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(polyunsaturated) (Calder 2011). Fatty acids are often referred to by their common names but are correctly identified by a systematic nomenclature. This nomenclature indicates first the number of carbon atoms in the hydrocarbon chain, followed by the number of double bonds and the position of the first double bond from the terminal methyl group, which is indicated by n-9, n-7, n-6 or n 3 (Fig. 1). There are two main families of polyunsaturated FA (PUFA), n-6 (or w-6) and n-3 (or w-3) (Sala-Vila et al. 2008). Triacylglycerols (TAG), formed by three FA esterified to glycerol, are the main form of fat present in the human diet. The TAG of animal origin are rich in saturated fatty acids and are characterized by being solid at ambient temperature (fats); those of vegetable origin are rich in unsaturated FA and liquid at room temperature (oils). The TAG act as reserve lipids found in the form of oily microdroplets, emulsified in the cytosol.

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Fig. 1 Structure of some fatty acids

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1450 Fig. 2 Biosynthesis of some fatty acids

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linoleic acid (18:2n-6)

Δ15-desaturase

Δ6-desaturase γ-Linolenic acid (GLA, 18:3n-6) Elongase Dihomo-γ-Linolenic acid (GLA, 18:3n-6) Δ5-desaturase Arachidonic acid (ARA, 20:4n-6)

α-Linolenic acid (18:3n-3) Δ6-desaturase Stearidonic acid (18:4n-3) Elongase 20:4n-3 Δ5-desaturase

Eicosapentaaenoic acid (EPA, 20:5n=3) Elongase Docosapentaenoic acid (DPA, 20:5n-3) Elongase Δ6-desaturase β-oxidation Docosahexaenoic acid (DHA, 22:6n-3)

In addition to the TAG, other lipids are present in small amounts in the diet, such as phospholipids, cholesterol, cholesterol esters and traces of free FA. Phospholipids are the major lipid components of the cell membrane, acting as structural elements and precursors of second messengers and affecting the activity of some enzymes such as phospholipase A2 and protein kinase C. Thus, the lipids, besides being a source of energy (immediate or reserve), act as key components of our body, both in terms of structural (cellular) and functional constituents (Burr and Burr 1973). Mammals synthesize saturated fatty acids from non-lipid precursors and unsaturated n-9 series and n-7; normally, the diet provides adequate amounts of these fatty acids. However, the cell membrane also needs unsaturated FA of n-3 and n-6 families to maintain their structure, fluidity and function measures. As mammals lack the enzyme delta-12 desaturase and delta-15 (found in most plants) that inserts double bonds at positions 3 and 6, they do not synthesize n-3 or n-6 PUFA. Then, these FA have to be consumed in the diet and are therefore called essential fatty acids (Burr and Burr 1973). The PUFA most commonly consumed are the linoleic acid (LA, 18:2 n-6) and the α-linolenic acid (ALA, 18:3 n-3). These two FA can be converted to other unsaturated derivatives. Linoleic acid can be converted to γ-linolênic (18:3 n-6), dihomo-γ-linolenic (20:3 n-6) and

arachidonic acid (AA, 20:4 n-6) sequentially. Similarly, the α-linolenic acid (18:3 n-3) is converted into eicosapentaenoic acid (EPA, 20:5 n-3) and docosapentaenóico acid (DHA, 22:5 n-3) (Calder 2010) (Fig. 2). The main dietary sources of acids LA and ALA are oils rich in polyunsaturated fats. The PUFA of n-6 series are derived from plants, found, for example in soybean, sunflower and evening primrose oils. The PUFA of n-3 series are predominantly found in fish oils and marine mammals in deep cold water, such as mackerel, sardines, trout, salmon and tuna (Calder 2010). This occurs because many marine plants, especially phytoplankton algae, also synthesize EPA and DHA from α-linolenic acid (Fig. 2). This synthesis of long-chain PUFA n-3 by marine algae and their transfer through the food chain to fish explains its abundance in some fish oils and marine mammals (Semplicini and Valle 1994). Up to 1929, the FA were viewed exclusively as an efficient energy storage. In 1929 and 1930, George and Mildred Burr published articles reporting the essentiality of PUFA. The authors found that administration of diets completely devoid of fat in rats caused severe changes in relation to growth and physiological functions of various organs, which were attributed to the lack of long-chain PUFA. Similar changes were observed in newborns undergoing a diet based on skimmed milk and reversed by the

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Enteral Support and N-3 Fatty Acids in Critically Ill Elderly Patients

administration of whole milk. These findings led to a systematic study carried out by Hensen et al. (1958). This study found that the administration of skimmed milk to infants was associated with diarrhoea and skin abnormalities, among others. The supplementation of milk with linoleic acid reversed all symptoms. These observations therefore characterize the effects of PUFA deficiency in humans (Hensen et al. 1958; Holman 1998). With the development of parenteral nutrition, which initially did not contain essential fatty acids, it became evident that a deficiency of n-type PUFA-6 (PUFA n-6) caused the death of patients. This led the Food and Drug Administration (FDA) in 1982 to approve the supplementation of parenteral nutrition with PUFA n-6 (Holman 1998). The essentiality of PUFA n-3 took longer to be characterized mainly by having been demonstrated in humans only when parenteral diets supplemented with PUFA n-6 began to be used. Patients undergoing these various diets had neurological changes that were reversed when the diet was increased with PUFA n-3 (Innis 1991; Holman 1998).

Inflammation, Ageing and Immune Response The relationship between inflammatory response and PUFA-enriched diets has been investigated in last years. Several studies show that PUFA can modify immunological and inflammatory reactions and can be used as a complementary therapy in chronic diseases (Kinsella 1990; Serhan 2006). Inflammation is a body's response to tissue injury, which can be triggered by mechanical stimuli or chemical or microbial invasion or due to hypersensitivity reactions. This response includes complex processes that involve the immune system cells and biological mediators (Rankin 2004). The acute phase response is characterized by increased blood flow and vascular permeability and increased accumulation of fluid, leukocytes and inflammatory mediators, while the chronic phase is characterized by the development of specific humoral immune responses against pathogens present at the site of

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injury (Calder 2012). Inflammation is characterized by redness, swelling, heat and pain. These signs occur primarily due to vasodilation, allowing increased blood flow to the affected area, increased vascular permeability, which facilitates the diffusion of molecules such as antibodies, cytokines and other plasma proteins to the site of injury, and cellular infiltration, which occurs by chemotaxis and diapedesis, direct movement of inflammatory cells through the vessel wall towards the site of inflammation. In addition, during the inflammatory response, catabolic and metabolic changes and biosynthetic activation in various organs, enzyme systems and cells of the immune system occur (Calder 2012). The inflammatory response begins the process of immune elimination of invading pathogens and toxins for the repair of damaged tissue. The non-specific inflammatory response that occurs, regardless of the cause, involves phagocytosis of bacteria or leftover tissue, secretion of proteolytic enzymes, production of reactive oxygen species and secretion of molecular modulators. It can also turn in immune-mediated response when there is the participation of lymphocytes and antigenpresenting cells. This second type is closely associated with the onset and maintenance of chronic inflammation. The inflammatory process is controlled by cellular and molecular components. Among the cellular components are neutrophils, monocytes, lymphocytes, fixed macrophages, dendritic cells, mast cells and eosinophils. These cells accumulate in inflamed tissues and interact with the endothelial cells of the microcirculation. Different adhesion molecules, including selectins, integrins and intercellular adhesion molecule (ICAM), participate in these interactions. Neutrophils constitute 60 % of circulating leukocytes and act as the first line of cellular defense and may participate in both reactions as non-specific defence reactions as specific antigens (Calder 2011). Monocytes represent approximately 3–6 % of circulating leukocytes in human blood and migrate to different tissues where they differentiate into macrophages in response to different stimuli. These cells participate in a variety of functions related to host defence, being the most well known in the

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phagocytosis of microorganisms and cell debris and cytotoxic activity against microorganisms, virus-infected cells and tumour cells (Calder 2011). The molecular components of inflammation include vasoactive substances (kinins, histamine), pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6, anti-inflammatory cytokines such as IL-4, IL-10 and IL-13, chemokines, acute-phase proteins, bioactive lipids such as eicosanoids derived from AA, platelet-activating factor, diacylglycerol, ceramides, cAMP, inositol triphosphate, among others (Calder 2007). Ageing is the central link between inflammation, chronic stimulation and immune exhaustion (Fig. 3). The human immune system progressively deteriorates with age, leading to a greater

Fig. 3 Connection between age-related inflammation, loss of immune functions and chronic stimulation of immune system

incidence or the reactivation of infectious diseases, as well as the development of autoimmune disorders and cancer (Rymkiewicz et al. 2012). Immunosenescence is the term used for loss of immune function caused by age, which involves many changes in the innate and adaptive responses (Makinodan and Kay 1980). Age-dependent modifications in adaptive response as a declined number of naïve T cells in peripheral blood and lymphoid tissues is frequently observed in the elderly. These alterations can also affect CD4+ T-cell function including cell proliferation and cytokine production (Rymkiewicz et al. 2012). There are also changes in the other parts of the immune system; however, the changes in the T and B cells, especially in decreasing antigenpresenting cells (APC), are observed (Fig. 4) (F€ulöp et al. 2007). Advanced age is known to be accompanied by low-grade, chronic up-regulation of inflammatory responses, evidence for which is provided by increased serum levels of pro-inflammatory cytokines (IL-6, IL-15, IL-8), coagulation factors and reactive oxygen species (ROS) (F€ulöp et al. 2007). Lifestyle factors such as nutrition and physical activity practice daily are related to the reduced overall inflammation in ageing. Considering the increased inflammatory response in critically ill patients, the reduced immunological response caused by ageing, the increased risk of infections and the prolonged period of hospital stay observed in older patients, several studies have

Thymic involution

Decrease of naive T-cells

Change in T-cell subpopulations

Increase of CD4+ suppressive regulatory T-cells

replicative senescent cells T-cells exhaustion

Fig. 4 Alterations in the immune system caused by aging

Filling of the immunological space

Increase of memory T-cells

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Enteral Support and N-3 Fatty Acids in Critically Ill Elderly Patients

suggested that n-3 PUFA supplementation can be prescribed as a complementary therapy in the treatment of critically ill patients in order to modulate the inflammatory response and aiming to optimize immune response, to reduce the days of mechanical ventilation and length of ICU stay.

Enteral Nutrition Nutrition therapy in critically ill patients has been considered essential for clinical recovery and improved outcomes (McClave et al. 2009). Many critically ill patients admitted to the ICU are affected by negative energy balance during the first 3–4 days of hospitalization, due to haemodynamic stabilization and gradual onset of the diet offered, either enteral or parenteral nutrition (Calder et al. 2009). Other factors contribute to the energy deficit including increased metabolism, delay in the onset of diet and inappropriate caloric intake. Furthermore, studies have shown that the optimum energy requirement is achieved in only 50–75 % of patients in the ICU, and approximately 25 % of patients receive only 1,000–1,500 kcal/day (Calder et al. 2009). Critically ill patients often require either enteral or parenteral nutrition support. Enteral nutrition is the preferential route for preserving the physiological characteristics of the patient (Jeejeebhoy 2007), especially in the elderly. It is known that catabolic stress and systemic inflammatory response can alter morphology and function of the gastrointestinal tract (Peuhkuri et al. 2010) causing inadequate caloric intake. Up to 60 % of ICU patients are affected by impaired gastrointestinal motility, digestion or absorption problems such as gastro-oesofageal reflux, vomit, diarrhoea, gastroparesis and abdominal distension, leading to energy deficit and loss of lean body mass (Singer and Cohen 2010; Hegazi and Wischmeyer 2011). Providing at least 80 % of prescribed amounts of protein and calories is associated with improved clinical outcomes (Heyland et al. 2011), with provision of enteral nutrition within 24–48 h from admission to the ICU via a standardized feeding protocol being consistent

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with best practices and associated with improved nutrition delivery (McClave et al. 2009). The low nutritional supply and poor nutritional status impairs the immune system and respiratory function, speeding up the muscle loss, with dependence on mechanical ventilation and gastrointestinal complications (Heyland et al. 2003). Many of these patients can develop sepsis, multi-organ failure and even death (McClave et al. 2009). Until recently, enteral nutrition included only basic macronutrients to sustain patients through periods of metabolic stress. Nowadays, enteral feeds are formulated with active nutrients that may help reduce oxidative damage to cells and tissues, modulate inflammation, enhance beneficial stress responses and improve feeding tolerance (Hegazi and Wischmeyer 2011). Enteral formulas with specific pharmaconutrients can help offset tissue damage and moderate the inflammation. Dietary intake of certain oils alters the fatty acid composition in membranes of cells involved in immune inflammatory responses (Fig. 5; Hegazi and Wischmeyer 2011). The possibility of treatment with n-3 PUFA in chronic inflammatory diseases has increased its use in enteral nutrition. The use of this antiinflammatory feeding formulation significantly reduced time on ventilator, length of ICU stay and incidence of new organ failure (PontesArruda et al. 2008). It is well known that not all individuals respond to nutritional therapy in the same way. For any nutrient used in nutritional therapy, it is possible to find individuals with good response or poor response or non-responders (Paoloni-Giacobino et al. 2003). Due to the considerable individual variability, a large number of patients is necessary in studies of nutritional intervention (PaoloniGiacobino et al. 2003). The variation in the intensity of the inflammatory response in chronic diseases, including sepsis, and also the longevity of life in the elderly have been associated with single-nucleotide polymorphisms (SNPs) (Visentainer et al. 2003; Nakada et al. 2005; Mira et al. 1999; Cederholm et al. 2007). These polymorphisms that are present in regulatory regions of genes encoding pro-inflammatory

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K.V. Barros et al. ICU admission

Hemodynamic stabilization

Early nutrition prescription (within 24-48h of admission) choosing the enteral formula according to the aging alterations

Nutrition status classification and risk of malnutrition

Calculation of nutritional requirements

Clinical parameters improvement

Necessity of improve immune response (sepsis, septic shock, acute lung injury, trauma and surgery)

Standard enteral formulation Immune nutrients prescription

Cell membrane modulation using at least 0.2g/kg/day of n-3 PUFA

Nutritional requirements achieved by enteral nutrition after 3-4 days of admission

Yes Success of nutritional therapy

No Identification of intercurrences and sort out to avoid nutritional deficit

Fig. 5 Algorithm for choosing enteral formula to achieve nutritional target

cytokines may affect the transcription rate and synthesis of cytokines (Visentainer et al. 2003), altering the immunological and inflammatory responses. Differences in frequency of alleles in genes that encode cytokines may contribute to the incidence of different diseases (Carvalho-Silva et al. 2001). Regarding this, some studies have shown that genetic variability in the FADS1FADS-2 gene cluster encoding delta-5 (D5D) and delta-6 (D6D) desaturases has been associated with plasma long-chain PUFA levels in

adults (Bokor et al. 2010). Desaturases and elongases catalyse the conversion of PUFAs in humans. The D5D and D6D desaturases are known to be the key enzymes of this pathway. Both desaturases are expressed in a majority of human tissue, with the highest levels in liver but also with major amounts in brain, heart and lungs. The hypothesis that these desaturases play a key role in inflammatory diseases is strengthened by functional studies in mice, where selective D5D and D6D inhibitors showed an antiinflammatory effect (Cormier et al. 2012).

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Enteral Support and N-3 Fatty Acids in Critically Ill Elderly Patients

Several SNP in FADS genes were reported in humans, and some studies showed association between FADS SNPs and fatty acids in serum or plasma phospholipids, erythrocyte membrane and adipose tissue (Rzehak et al. 2009) demonstrating that the FA amounts in blood and tissues are influenced not only by diet but to a large extent also by genetic variants common in the world population (Glaser et al. 2011).

Applications to Critical or Intensive Care Despite advances in intensive medicine, the mortality in critically ill patients, especially in the elderly, remains high. The pharmacological treatments used, aiming to reduce exacerbated inflammatory response, have been shown ineffective in mortality reduction (Wang et al. 2007; Shimaoka and Park 2008). In this sense, nutrition, as a complementary therapy, has revealed to be important and essential. Several clinical studies have shown that the administration of n-3 PUFA can blunt the inflammatory response in critically ill patients (Table 1), and due to heterogeneity in ICU population, few studies have been developed mainly with the elderly and using only omega-3 PUFA as pharmaconutrition. However, enteral supplementation of n-3 PUFA has presented conflicting data in the literature. These discordant data are most likely due to different routes of administration (enteral or parenteral), dose of n-3, duration of administration, timing of onset in relation to stage of the inflammatory response and subtle differences in the nutrient combinations used. Enteral formula containing immunemodulating nutrition, such as arginine, nucleotides and n-3 FA, has been recommended with effects superior to standard formula by European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines, as grade A of recommendation in some situations as elective upper GI surgical patients and surgical trauma. For critically ill patients and patients with severe sepsis, the grade of recommendation is B (Kreymann et al. 2006).

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As well as ESPEN recommendation, the American Society of Enteral and Parenteral Nutrition (ASPEN) also recommends as grade A immune-modulating enteral formulations for appropriate patient populations such as major elective surgery, trauma, burns, head and neck cancer and critically ill patients with mechanical ventilation. The grade B recommendation is for medical ICU patients. Enteral formula supplied not only with EPA but also with gamma-linolenic fatty acid (GLA) and other antioxidant micronutrients has shown better results than only n-3 PUFA supplementation in case of enteral route. Despite three classic studies using EPA, gamma-linolenic acid and antioxidants, associated with clinical benefits in acute lung injury, gas exchange and respiratory dynamics improved with decreased requirements of mechanical ventilation and length of ICU hospitalization (PontesArruda et al. 2008; Singer et al. 2006; Gadek et al. 1999), Stapleton et al. 2010, in an attempt to confirm beneficial effects of n-3 PUFA alone in a enteral diet, failed in demonstrating any improvement on pulmonary or systemic biomarkers. Besides difficulty to attribute the beneficial effect to only one nutrient, the dose and onset time of supplementation were seen as important targets. Heller et al. (2006) found lower rates of infection and a short length of ICU stay in patients who received more than 0.05 g fish oil/kg/day and a reduced mortality in those who received more than 0.2 g/fish oil/kg/day. However, it is important to note that in this study, fish oil was prescribed in parenteral nutrition. Cytokine profile can also be affected by fish oil lipid emulsion. Barros et al. (2014), analyzing 40 critically ill elderly, between 60 and 80 years, receiving a standard enteral nutrition and supplied with fish oil lipid emulsion, dose 0.2 g/kg/day for 3 days, observed a higher energy intake, lower serum TNF-α and IL-8 concentrations and higher serum IL-10 concentration in the supplemented group compared to the control group. These differences occurred around 7–9 days of ICU stay at the time of the patient’s extubation, suggesting an anti-inflammatory effect. Moreover, no alterations in ICU stay and mortality was observed.

Population or setting Severe sepsis and septic shock, ICU

Sepsis and sepsis shock, ICU

Study PontesArruda et al. (2008)

GrauCarrmona et al. (2011)

132

Sample Size 103

Table 1 Comparison among clinical studies

Control: 71

Study: 61

Control: 48

Age (years) Study: 55

Enteral nutrition enriched with EPA, GLA (commercial formula)

Intervention Enteral nutrition enriched with EPA, GLA (commercial formula)

Standard enteral nutrition

Control group Standard enteral nutrition

11 days

Supplementation period At least during 4 days

48 h of admission

Time of onset 36 h after stabilization and clinical diagnosis of sepsis

Dose Ratio n6:n3: 1.85:1 N3: 10 g/L EPA: 4.5 g/L GLA: 4.3 g/L DHA: 2.0 g/L Ratio n6:n3: 1.85:1 N3: 10 g/L EPA: 4.5 g/L GLA: 4.3 g/L DHA: 2.0 g/L

No difference in gas exchange and also in incidence of organ failures, but decreased the length of hospitalization

Outcome Reduced mortality, improved gas exchange and reduced lengh of mechanical ventilation and ICU stay

1456 K.V. Barros et al.

Acute lung injury, ICU

Early acute lung injury, ICU

Sepsisinduced acute respiratory distress syndrome, ICU

Theilla et al. (2007)

Rice et al. (2011)

Gadek et al (1999)

102

108

119

Control: 51

Study: 51

Study: 55 Control: 53

Control: 62

Study: 57

Enteral nutrition enriched with EPA, GLA (commercial formula)

Enteral nutrition enriched with EPA, GLA (administered twice-daily bolus)

Enteral nutrition enriched with EPA, GLA (commercial formula)

Standard enteral nutrition

Standard enteral nutrition

Standard enteral nutrition

7 days

21 days

7 days

In 24 h

Within 48 h of acute lung injury and mechanical ventilation requirement

After randomization

Ratio n6:n3: 1.85:1 N3: 10 g/L EPA: 4.5 g/L GLA: 4.3 g/L DHA: 2.0 g/L EPA: 6.84 g GLA: 5.92 g DHA: 3.40 g Ratio n6:n3: 1.85:1 N3: 10 g/L EPA: 4.5 g/L GLA: 4.3 g/L DHA: 2.0 g/L (continued)

Reduction of new organ failures

No alteration in clinical response, outcomes or inflammatory biomarkers

Reduced occurrence of new pressure ulcers

110 Enteral Support and N-3 Fatty Acids in Critically Ill Elderly Patients 1457

Population or setting Acute lung injury, ICU

Acute lung injury, ICU

Study Stapleton et al. (2010)

Singer et al. (2006)

Table 1 (continued)

95

Sample Size 90

Control: 62

Age (years) Study: 41 Control: 49 Study: 57 Enteral nutrition enriched with EPA, GLA (commercial formula)

Intervention Enteral fish oil

Standard enteral nutrition

Control group Saline placebo

14 days

Supplementation period 14 days

24 h of ICU admission

Time of onset 48 h of admission and diagnosis of acute lung injury

Dose EPA: 9.75 g DHA: 6.75 g Ratio n6:n3: 1.85:1 N3: 10 g/L EPA: 4.5 g/L GLA: 4.3 g/L DHA: 2.0 g/L

Improve in gas exchange and reduced requirements for mechanical ventilation

Outcome No alterations on inflammatory biomarkers

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Enteral Support and N-3 Fatty Acids in Critically Ill Elderly Patients

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The clinical supplementation of n-3 PUFA in critically ill patients appears to be safe and beneficial; however, further research is necessary before any definitive recommendations can be made about enteral omega-3 FA supplementation in critically ill patients, mainly in special populations, such as the elderly. It is important to look at the dose, time of onset supplementation and route of administration; all these variables can change the outcome. It is known that many of the anti-inflammatory effects of n-3 PUFA are linked to their incorporation into inflammatory cell membranes (Calder 2010, 2011) When these fatty acids are supplied orally, their incorporation into inflammatory cell membranes occurs over a period of days to weeks, and perhaps slow modification of inflammatory cell membranes by oral n-3 PUFA is not likely to be useful in more acute settings or where rapid relief of inflammation is required. Barros et al. (2012) showed that the critically ill elderly in the ICU had a lower proportion of one n-3 FA, EPA, in their plasma phosphatidylcholine (PC) than seen in healthy elderly subjects. This lower status of EPA may be important in predisposing to a poor outcome. Furthermore, amongst the critically ill patients, survivors had a higher amount of another n-3 FA, DHA, in their plasma PC than non-survivors. By last, the authors demonstrated that administering n-3 FA parenterally in the elderly receiving enteral nutrition resulted in an improvement in gas exchange that was not seen in the control group and this was associated with a trend towards a reduction in number of days of ventilation that were required. Pharmaconutrition appears to exert beneficial effects with no side effects. Although the supplementation of some nutrients is related to better outcome, it is important to note that first, the target of energy and protein supply should be achieved to guarantee the nutritional status maintenance.

disease, ulcerative colitis, diabetes mellitus, cardiovascular events and cancer cachexia (Simopoulos 2002; Calder 2012). For the last years, several organizations around the world have established dietary recommendations and guidelines for daily n-3 FA intake, in particular for EPA and DHA for chronic disease. The intake of 1–5 g/day of fish oil has been used in preventing and treating cardiovascular disease (CVD), and the American Heart Association recommend 1 g/day for CDV. For the prevention of CVD, the National Heart Foundation (NHF) of Australia (2008) recommends a dietary intake of 500 mg/day EPA + DHA, the equivalent of two to three servings (150 g) of oily fish per week. For adults with diagnosed CVD, a combined dosage of 1,000 mg EPA + DHA per day is recommended, which is best achieved by fish oil supplementation. The National Health and Medical Research Council (NHMRC) in Australia and New Zealand suggest a consumption of 610 and 430 mg/day DHA + EPA for males and females respectively, in case of preventing chronic disease, while European Food and Safety Authority (EFSA 2010) recommend 3 g/day. However, despite n-3 PUFA being likely to reduce risk of CVD, due to the long carbon chain of these fatty acids, an increased lipid peroxidation can occur. Some studies have shown that up to 3–4 g of n-3 long-chain-PUFA per day, no apparent effects on lipid peroxidation have been observed (Rangel-Huerta et al. 2012). In relation to vascular side effects, the n-3 PUFA supplementation is safe, and even the concerns about antithrombotic properties of n-3 PUFA, particularly in an older adult population, such as implication bleeding, stroke or bruising, are not observed in clinical trials. Villani et al. (2013) in a review study did not find any adverse effect related to prolonged n-3 PUFA supplementation in older adults.

Applications to Other Conditions

Guidelines and Protocols

N-3 PUFA can also be used to prevent some diseases, specially those related to chronic inflammation including rheumatoid arthritis, Crohn’s

The preference and benefits of choosing enteral nutrition as a preferential nutrition route are well established for critical patients. The addition of

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specialized nutrients as a component of enteral formulas in the ICU patients is a reality and should be prescribed for a multidisciplinary team aiming anti-inflammatory, immune-modulating and tolerance-promoting nutrients. Each hospital should develop its nutrition protocol based on reality, group of patients attended and international guidelines. The continued education of teams and the knowledge about protocol used is a crucial point for a success of therapy and the patient’s outcomes. The elderly should be classified as a risk population, and the nutrition has to be prescribed according to their limitation. Omega-3 PUFA seems to enhance immune response and restored EPA and DHA in cell membranes that is deficient in critical patients. The dose, time of onset supplementation and route of administration should be established by the protocol used to avoid side effects.

Summary Points – Critically ill patients are affected by traumatic insults, which involve excessive inflammation and an immunosuppressed state. – This process becomes more critical with ageing, which is associated with exhaustion of immune response and poor outcome. – Although several studies have shown beneficial effects of n-3 PUFA in acute and chronic disease, more studies are necessary to get the final recommendation of its supplementation in enteral nutrition in these patients.

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Glaser C, Lattka E, Rzehak P, et al. Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health. Matern Child Nutr. 2011;7 Suppl 2:27–40. Graf C. Functional decline in hospitalized older adults. Am Nurs J. 2006;106(1):58–67. Grau-Carmona T, Morán-García V, García-de-Lorenzo A, et al. Effect of an enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid and antioxidants on the outcome of mechanically ventilated, critically ill, septic patients. Clin Nutr. 2011; 30(5):578–84. Hegazi RA, Wischmeyer PE. Clinical review: optimizing enteral nutrition for critically ill patients-a simple datadriven formula. Crit Care. 2011;15(6):234. Heller AR, Rossler S, Litz RJ, et al. Omega-3 fatty acids improve the diagnosis-related clinical outcome. Crit Care Med. 2006;34:972–9. Hensen AE, Haggard ME, Boelsche NA, et al. Essential fatty acids in infant nutrition. J Nutr. 1958;66:565–76. Heyland DK, Schroter-Noppe D, Drover JW, et al. Nutrition support in the critical care setting: current practice in Canadian ICUs-opportunities for improvement? J Parenter Enteral Nutr. 2003; 27(1):74–83. Heyland DK, Cahill N, Day AG. Optimal amount of calories for critically ill patients: depends on how you slice the cake! Crit Care Med. 2011; 39(12):2619–26. Holman RT. The slow discovery of the importance of n-3 essential fatty acids in human health. J Nutr. 1998;128:427S–33. Innis SM. Essential fatty acids in growth and development. Prog Lipid Res. 1991;30:39–108. Jeejeebhoy KN. Enteral nutrition versus parenteral nutrition–the risks and benefits. Nat Clin Pract Gastroenterol Hepatol. 2007;4(5):260–5. Kinsella JE. Lipids, membrane receptors, and enzymes: effects of dietary fatty acids. J Parenter Enteral Nutr. 1990;14(5 Suppl):200S–17. Kreymann KG, Berger MM, Deutz NEP, et al. ESPEN guidelines on enteral nutrition. Intensive care. Clin Nutr. 2006;25:210–23. Makinodan T, Kay MM. Age influence on the immune system. Adv Immunol. 1980;29:287–330. Marik PE. Management of the critically ill geriatric patients. Crit Care Med. 2006;34(9S):S176–82. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). Board of Directors and the American College of Critical Care Medicine. J Parenter Enteral Nutr. 2009;33:277–316. Mira JP, Cariou A, Grall F, et al. Association of TNF2, a TNF-α promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999;282(6):561–68.

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Nakada T, Hirasawa H, Oda S, et al. Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukine10 gene polymorphisms on clinical outcome in Japanese critically ill patients. J Surg Res. 2005;129:322–8. National Heart Foundation of Australia. Position statement on Fish, fish oils, n-3 polyunsaturated fatty acids and cardiovascular health, 2008. http://www.heartfoundation.org. au/SiteCollectionDocuments/Fish-position-statement.pdf Paoloni-Giacobino A, Grimble R, Pichard C. Genomic interactions with disease and nutrition. Clin Nutr. 2003;22(6):507–14. Peuhkuri K, Vapaatalo H, Korpela R. Even low-grade inflammation impacts on small intestinal function. World J Gastroenterol. 2010;16(9):1057–62. Pontes-Arruda A, Demichele S, Seth A, Singer P. The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. J Parenter Enteral Nutr. 2008;32(6):596–605. Rangel-Huerta OD, Aguilera CM, Mesa MD, Angel GA. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomarkers: a systematic review of randomized clinical trials. Br J Nutr. 2012;107:S159–70. Rankin JA. Biological mediators of acute inflammation. AACN Clin Issues. 2004;15(1):3–17. Rice TW, Wheeler AP, Thompson BT, NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574–581. Rymkiewicz PD, Heng YX, Vasudev A, Larbi A. The immune system in the aging human. Immunol Res. 2012;53(1–3):235–50. Rzehak P, Heinrich J, Klopp N, et al. Evidence for an association between genetic variants of the fatty acid desaturase 1 fatty acid desaturase 2 (FADS1 FADS2) gene cluster and the fatty acid composition of erythrocyte membranes. Br J Nutr. 2009;101(1):20–6. Sala-Vila A, Miles EA, Calder PC. Fatty acid composition abnormalities in atopic disease: evidence explored and role in the disease process examined. Clin Exp Allergy. 2008;38(9):1432–50. Semplicini A, Valle R. Fish oils and their possible role in the treatment of cardiovascular diseases. Pharmacol Ther. 1994;61(3):385–97. Serhan CN. Novel chemical mediators in the resolution of inflammation: resolvins and protectins. Anesthesiol Clin. 2006;24:341–64. Shimaoka M, Park EJ. The compensatory antiinflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008;29:617–27. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002;21:495–505. Simopoulos AP. The importance of the Omega-6/Omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med. 2008;233:674–88. Singer P, Cohen J. Nutrition is metabolism. J Parenter Enteral Nutr. 2010;34(5):471–2.

1462 Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and gammalinolenic acid in ventilated patients with acute lung injury. Crit Care Med. 2006;34:1861. Stapleton RD, Martin JM, Mayer K. Fish oil critical illness: mechanisms and clinical applications. Crit Care Clin. 2010;26:501–14. Theilla M, Singer P, Cohen J, Dekeyser F. A diet enriched in eicosapentanoic acid, gamma-linolenic acid and antioxidants in the prevention of new pressure ulcer formation in critically ill patients with acute lung injury: a randomized, prospective, controlled study. Clin Nutr. 2007;26(6):752–7. Villani AM, Crotty M, Cleland LG. Fish oil administration in older adults: is there potential for adverse events?

K.V. Barros et al. A systematic review of the literature. BMC Geriatr. 2013;13(1):41. Visentainer JEL, Lieber SR, Persoli LBL, et al. Serum cytokine levels and acute graft-versushost disease after HLA-identical hematopoietic stem cell transplantation. Exp Hematol. 2003;31: 1044–50. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency departments. Crit Care Med. 2007;35:1928–36. Weiss G, Meyer F, Mathies B, et al. Immunomodulation by preoperative administration of n-3 fatty acids. Br J Nutr. 2002;87:S89–94. Wick G, Jansen-D€ urr P, Berger P, et al. Diseases of aging. Vaccine. 2000;18:1567–83.

Viscosity Thickened Enteral Formula

111

Satomi Ichimaru and Teruyoshi Amagai

Contents

Applications to Critical or Intensive Care . . . . . . 1475

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1464

Applications to Other Conditions . . . . . . . . . . . . . . . . 1475

History of TEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1464

Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1475

Types of TEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Type 1: Intragastric Thickened Enteral Formula (IG-TEF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Type 2: TEF Prepared by Mixing Liquid Enteral Formula and Thickener (LT-TEF) . . . . . . . . . Type 3: Ready-to-Use TEF (RTU-TEF) . . . . . . . . . . .

Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475

1465 1465

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1476

1465 1468

Potential Advantages of TEF . . . . . . . . . . . . . . . . . . . . . Prevention of GER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention of Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention of Leakage Around the PEG Puncture Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects on Glucose Metabolism . . . . . . . . . . . . . . . . . . . . Improvement of Quality of Life (QOL) in Patients and Caregivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1468 1468 1470

Unresolved Issues with TEF . . . . . . . . . . . . . . . . . . . . . . Ideal Viscosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk of Bacterial Contamination . . . . . . . . . . . . . . . . . . . Ideal Feeding Tube Type . . . . . . . . . . . . . . . . . . . . . . . . . . . Ideal Volume and Timing of Additional Water . . . . Nutrient Interactions: Malabsorption of Dietary Minerals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1474 1474 1474 1474 1474

1473 1473 1473

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S. Ichimaru (*) Department of Nutrition Management, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan e-mail: [email protected] T. Amagai Department of Food Science and Nutrition, School of Human Environmental Sciences, Mukogawa Women’s University, Nishinomiya, Japan e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_27

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Abstract

List of Abbreviations

Thickened enteral formula (TEF) is a formula in which viscosity is intentionally increased by adding thickener to prevent enteral nutritionrelated complications, such as diarrhea, nausea, vomiting, and gastroesophageal reflux (GER). Three types of TEFs are available at present: intragastric TEF, TEF prepared by mixing liquid enteral formula and thickener, and ready-to-use type. The positive effects of TEF are considered to be based on its high viscosity, which reduces the outflow rate of gastric contents and thereby helps to prevent diarrhea and GER. While several studies have been conducted on TEF with viscosity ranging from 900 to 20,000 mPa
s, the mechanisms of TEF have not been fully demonstrated. TEF efficacy with regard to reducing complications of EN should not be determined based solely on quantitative viscosity data, as modalities for measuring viscosity and assessing complications subsequent to administration have not been standardized. Potential advantages of TEF include prevention of GER, diarrhea, skin trouble around the percutaneous endoscopic gastrostomy puncture site, and improvement of blood glucose levels and quality of life for both patients and caregivers. However, most previous studies of TEF have been empirical in nature, with little scientific evidence available supporting the efficacy of TEF in preventing complications of EN. TEF administration is only successful when functions of gastric motility, enterokinesis, digestion, and absorption are all normal. When applying TEF, bacterial contamination, feeding tube shape, timing and volume of administered water, and nutrient interactions should be considered. Given the present findings, TEF appears more suitable for use in patients in long-term care hospitals, nursing homes, or home medical care settings than acute care hospitals. Establishing a solid base of evidence supporting the usage of TEF will require more large-scale randomized controlled trials.

EN GER IG LT PEG QOL RTU TEF

Enteral nutrition Gastroesophageal reflux Intragastric Liquid and thickener Percutaneous endoscopic gastrostomy Quality of life Ready to use Thickened enteral formula

Introduction Thickened enteral formula (TEF) – defined here as a formula in which the viscosity is intentionally increased using thickener – is administered to prevent enteral nutrition (EN)-related complications, such as nausea, vomiting, and gastroesophageal reflux (GER). As no official definition of TEF has yet been proposed, it is also referred to as semi- or half-solid formula. Several studies have been conducted thus far in an attempt to describe the efficacy of TEF with viscosity ranging from 900 mPa
s (similar to pancake syrup) to 20,000 mPa
s (similar to tomato paste) (Ichimasa and Ichimaru 2010). Despite an incomplete understanding of precisely how TEF inhibits EN-related complications, its administration in place of liquid formula is becoming common practice in Japan. This chapter provides an overview of TEF, including its history, types available, suggested mechanism, and potential benefits.

History of TEF Enteral formulas are generally liquid in phase to allow administration through small-diameter tubes (e.g., 8–12 Fr). Liquids flow relatively easily, a property which may be responsible in part for observed EN-related complications. The usage of TEF was initially proposed to reduce the outflow of gastric contents by increasing the viscosity of enteral formula. Since its introduction by Inada et al. in 1998, TEF has been the subject of a

111

Viscosity Thickened Enteral Formula

number of clinical case studies presented at nutritional academic meetings. Improvements in EN-related complications, such as diarrhea and GER, have been reported with TEF compared with wholly liquid enteral formula. In addition, TEF has been reported able to be safely administered via intermittent or bolus methods. In chronic-stage patients, intermittent or bolus feeding is preferred to continuous feeding, as these methods avoid prolonging the immobility of patients, reduce the risk of pressure ulcers, and increase the time available for rehabilitation. While the positive effects of TEF on preventing diarrhea and GER are considered to be due to its high viscosity, which reduces the outflow of gastric contents, two studies have reported an increased gastric emptying rate following intake of a TEF compared with a liquid enteral formula (Shimoyama et al. 2007; Nagasawa 2009). These findings suggest that any improvement in preventing complications of EN observed with TEF is likely associated not only its high viscosity to resist the flow but also its effects on gastric motility. The mechanism of such inhibition of EN-related complications by TEF is still being investigated, with results of previous studies on the efficacy of TEF summarized in Table 1.

Types of TEF Three types of TEFs have been developed for clinical use, and their properties are described below.

Type 1: Intragastric Thickened Enteral Formula (IG-TEF) With IG-TEF, liquid thickener is administered through a feeding tube in advance, and the viscosity of the formula is later increased inside the stomach (Fig. 1). This type of TEF is primarily administered in patients with both nasogastric and gastrostomy tubes. The only type of thickener

1465

commercially available at present is REF-P1 ® (Kewpie Corporation, Tokyo, Japan). Pectin in REF-P1 ® forms a gel by binding divalent metal cations such as calcium. The ultimate viscosity of the TEF therefore depends on the calcium concentration in the liquid formula. For example, while the viscosity of an elemental formula (K-3S ®; Kewpie Corporation) is only 8 mPa
s, the value increases to 900 mPa
s within 10 min of adding 90 g of REF-P1 ® to 400 mL of the elemental formula (Inada et al. 1998).

Type 2: TEF Prepared by Mixing Liquid Enteral Formula and Thickener (LT-TEF) With LT-TEF, liquid formula is mixed with powder or liquid thickener and then manually administered through a feeding tube using a syringe (Fig. 2). This type of TEF is primarily administered in patients with gastrostomy tubes, which have a wide internal diameter to prevent tube occlusion. Thickening enteral formulas using the standard thickener for dysphagia patients to drink liquids often proves difficult, as EN formulas are higher in protein and fat than water, fruit juices, and other typical beverages. As such, several special thickeners for TEF have been developed which increase viscosity by reacting with the protein included in enteral formulas. Common thickeners for TEF available on the market are listed in Table 2. Most thickeners include dextrin or a polysaccharide thickener. Dextrin is made up of any of a number of various polysaccharides obtained by hydrolysis of starch and used as thickener not only in food manufacturing but also in pharmaceuticals. Polysaccharide thickener is the name given to a food additives mixture of two or more thickeners, such as pectin, carrageenan, guar gum, and xanthan gum, the blending ratio of which depends on each product. Cooking agar can also be used as a TEF thickener, but the need to dissolve the compound in boiling water before mixing with liquid formula renders it more troublesome to use than other agents. Gelatin is not used to thicken TEF

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S. Ichimaru and T. Amagai

Table 1 Previous studies evaluating the effectiveness of thickened enteral formula Subjects

Effectiveness of TEF

Study design

Viscosity

GER

Diarrhea

Fever

Mean, 72.5 range, 55–90 Mean, 21

Before after

800–900a

9/15

2/4

4/8

Crossover

900a

+

Mean, 79.9  10.5

Crossover

ND

+

Mean, 84.3  9.9 range, 57–101

Before after

2,000b–20,000a

30/ 50

Author year

n

Profile

Age

Inada et al. (1998)

15

Tabei et al. (2003)

4

Cerebrovascular disease, brain injury Healthy volunteer

Kanie (2004b)

17

Yoshida et al. (2008)

50

Cerebrovascular disease, dementia Aspiration pneumonia Intractable diarrhea Leakage around the PEG tube Cerebral palsy

15 7 Miyazawa et al. (2008)

18

Nishiwaki et al. (2009)

15

Cerebrovascular disease, dementia Cerebrovascular disease

Adachi et al. (2009)

14

Shizuku et al. (2011)

32

Cerebrovascular disease

Goda (2006a)

15

ND

Leakage

12/15 4/7

Mean, 11.7  4.4

Crossover

1,200a

3,000a

+ +

+ +

Mean, 82.7  6.8

Crossover

Pudding-like

Mean, 83.1

Crossover

2,000b

Mean, 85.8 range, 56–100 ND

Crossover

2,000b

Stepwise intervention

20,000a 10,000a 2,000a

+

14/ 15 9/14 7/9

B B-type viscometer; CT computed tomography; GER gastroesophageal reflux; IG intragastric thickened enteral formula; LT thickened enteral formula prepared by adding thickener to liquid formula; ND not described; NGT nasogastric tube; PEG percutaneous endoscopic gastrostomy; RTU ready-to-use thickened enteral formula; TEF thickened enteral formula. “+” means present and “ ” means absent in statistical analysis. aMeasured by the author, bMeasured by the manufacturer

111

Viscosity Thickened Enteral Formula

1467

Condition of viscosity measurement

Temperature ( C)

Amount of formula administered at a time

Type of TEF

Type of viscometer

Rotational speed (rpm)

Symptoms

IG

ND

ND

20

Esophageal pH monitoring CT

IG

B

ND

LT

ND

LT or RTU

Modality to assess complication

Statistical analysis

+

Symptoms

Duration of administration

Feeding route

400 ml

56 (20–90) min

PEG or NGT

20

400 ml

3 min

Oral

ND

ND

400 ml

Bolus

PEG

B

6

25

ND

ND

PEG or NGT

Esophageal pH monitoring Symptoms Esophageal pH monitoring Symptoms Scintigraphy

+

IG

B

20

23

ND

30 min

NGT

+

LT

ND

ND

ND

200 ml

Bolus

PEG

Esophageal pH monitoring Symptoms

+

RTU

ND

ND

25

150 g

10 min

PEG

+

RTU

ND

ND

25

150 or 200 g

10 min

PEG

Thickened barium

ND

ND

ND

400 ml

5–15 min

PEG

X-ray

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S. Ichimaru and T. Amagai

because it melts at human body temperature and loses its viscosity easily. While the amount of thickener required to obtain an expected viscosity differs by product, the ultimate viscosity of LT-TEF can be additionally influenced by formula energy density, stirring time, and time elapsed since preparation (Wakita et al. 2012).

Type 3: Ready-to-Use TEF (RTU-TEF) Pre-thickened TEF is packed into a pouch with a spout that connects to the feeding tube and is

administered by manually squeezing the pack (Fig. 3). Like LT-TEF, this type of TEF is also primarily administered in patients with gastrostomy tubes. RTU-TEF does not require a delivery container or administration set and is administered in a closed system. Given that elderly caregivers with a weak grip may find the pouch difficult to squeeze, a pressure bag similar to an arterial line pressure bag is sometimes used instead of manual squeezing. Common commercially available RTU-TEFs are listed in Table 3. The viscosity, energy density, and water concentrations of RTU-TEFs vary widely. The lack of a standardized method of measuring the viscosity is one drawback to using this type of TEF, with viscosity presently measured based on each manufacturer’s own conditions. As such, efficacy of RTU-TEF should not be based solely on quantitative viscosity data.

Potential Advantages of TEF

Thickened

1. Liquid thickener is administered. 2. Liquid enteral formula is administered. 3. Formula is thickened in the stomach. Fig. 1 IG-TEF. Liquid thickener is administered through a feeding tube in advance, and the viscosity of the formula is later increased inside the stomach. This type of TEF is primarily administered in patients with both nasogastric and gastrostomy tubes. IG-TEF intragastric thickened enteral formula

Fig. 2 LT-TEF. Liquid formula is mixed with powder or liquid thickener and then manually administered through a feeding tube using a syringe. This type of TEF is primarily administered in patients with gastrostomy tubes. LT-TEF thickened enteral formula prepared by mixing liquid enteral formula and thickener

Liquid formula

While several advantages in using TEF have been reported, factors preventing EN-related complications are not fully understood, with further investigation yet needed to clarify just how TEF improves upon liquid formula administration. The following section addresses, at least in part, details of these factors.

Prevention of GER Aspiration pneumonitis induced by GER is a serious problem for patients on tube feeding, and

Thickener

Thickened

Maltodextrin, pectin, sodium citrate, sodium metaphosphate, pH control chemicals, calcium lactate Dextrin, polysaccharide thickener Dextrin, polysaccharide thickener

Powder

Liquid

Liquid Powder

a

NA not available Okada (2007)

Reflunon® Reflunon Powder PG ®

Dextrin polysaccharide thickener pH control chemicals Dextrin, polysaccharide thickener, sodium gluconate

Powder

Tsururinko for Liquid Diet ® Faset Powder ® Toromi perfect EN ® Easygel ®

Powder

Dextrin, xanthan gum, carrageenan, sodium citrate

Powder

Softia ENS ®

Contents Dextrin, polysaccharide thickener, potassium chloride Dextrin, agar polysaccharide thickener

Form Powder

Product Pegmelin ®

1.0 11.1

4.8

23.3

10.8

12.9

27.3

Fiber content g/100 g 1.5–3

13–38 1.3–4

27

1.5–2

1–2

1.5–4.5

2.8

Dosage to 100 mL of liquid formula (g) 3

Table 2 Examples of commercially available thickeners for thickened enteral formula

B B

B

620–41,000a

5,000–10,000 1,000–10,000

NA

B

B

B

12 12

12

NA

12

12 6 12

25 25

20

NA

20

20

20

Condition of viscosity measurement Rotational Type of speed Temperature viscometer (rpm) ( C) B 12 20

4,500–9,000

900–12,000

8,900 15,970 800–13,000

Expected viscosity (mPas) 2,000–10,000

Healthy food Healthy food

Otsuka

Nisshin OilliO

Food Care

Clinico

Manufacturer Sanwa Kagaku NUTRI

111 Viscosity Thickened Enteral Formula 1469

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S. Ichimaru and T. Amagai

Fig. 3 RTU-TEF. Pre-thickened TEF is packed into a pouch with a spout that connects to the feeding tube and is administered by manually squeezing the pack. This type of TEF is primarily administered in patients with gastrostomy tubes. RTU-TEF ready-to-use thickened enteral formula

several studies examining TEF with viscosity ranging from 900 to 20,000 mPa
s have shown the efficacy of TEF in preventing GER in this range (Table 1). Findings in a study using thickened noncaloric barium suggest that higher viscosity is thought to be more effective in preventing GER (Goda 2006a). However, the impact of the thickened noncaloric barium on the gut may differ from that of TEF, possibly due to the fact that noncaloric barium’s lack of fat and protein may not allow it to effectively stimulate the secretion of gut hormone, unlike TEF. Inada et al. (1998) and Tabei et al. (2003) reported on a population of patients on tube feeding for whom recurrent aspiration pneumonitis due to GER and incidence of pyrexia due to respiratory infections were ameliorated by administration of TEF with viscosity of 800–900 mPa
s (no statistical analysis conducted). In contrast, however, Adachi et al. (2009) reported that TEF with viscosity of 2,000 mPa
s had no positive effect on GER and in fact tended to increase incidence of acidic GER in patients with percutaneous endoscopic gastrostomy (PEG) feeding using the esophageal pH monitoring method. These controversial findings may be due to a lack of standardization in modalities for measuring viscosity and assessing complications. Compounding the confusion aroused by these conflicting findings is the fact that the mechanism by which TEF reduces GER is unclear. A study conducted on 11 healthy adult volunteers suggested that gastric emptying was accelerated by orally administered TEF with viscosity of 900 mPa
s compared with standard liquid

formula (Shimoyama et al. 2007). Findings showed that while the liquid formula initially entered the duodenum more rapidly from the stomach than TEF, once a certain volume was reached, gastric emptying was inhibited compared with that in subjects administered TEF. The authors stated that the mechanism of this inhibition of gastric emptying may have been the so-called “duodenal brake” triggered by increased blood levels of cholecystokinin. This early gastric emptying of TEF may contribute to preventing GER. However, conflicting results were reported in another study involving healthy subjects, which found that higher viscosity (16,000 and 128,000 mPa
s) was associated with slower gastric emptying (Kawasaki et al. 2010). Similarly, a crossover study conducted on 15 post-PEG patients with history of aspiration pneumonia or vomiting noted no significant differences in gastric emptying time between those fed liquid formula and those receiving TEF, although GER was significantly decreased in those receiving the puddinglike viscosity TEF (Nishiwaki et al. 2009). These authors further suggested that TEF may prevent GER by improving its transition from the proximal to distal stomach. Further studies will be needed to more clearly understand this mechanism.

Prevention of Diarrhea Several clinical case studies have been published on prevention of diarrhea using TEF with

0.55 kcal/g 0.75 kcal/g

1.0 kcal/g

1.5 kcal/g

1.5 kcal/g

2,000 2,000

2,000

5,000

5,000

F2 Shot EJ ®

Recovery Nutreat ® ACURE ® VF-5

Hine Jerry ®

1.0 kcal/g

1.8 kcal/g

2.5 kcal/g

2,000

5,000 10,000 6,000

2.0 kcal/g

2,000

Product ACURE ® VF-1 MEDIF ® PUSH CARE ® MEDIF ® PUSH CARE ® 2.5 F2 Light 55 ® F2 Light ®

Act Through ®

Energy density 1.5 kcal/g

Viscosity (mPas) 1,000

76

31

41.2

42

77

150 110

17

27.1

Water content (ml/100 kcal) 41.2

1.2

2

2.3

1.5

1.5

2.1 1.6

1.2

1.2

Fiber content (g/100 kcal) 2.3

Agar, guar gum

Agar, polysaccharide thickener Polysaccharide thickener

Agar

Pectin, agar

Pectin, agar Pectin, agar

None

Thickener Polysaccharide thickener None

Table 3 Examples of commercially available ready-to-use thickened enteral formulas

B

B

B

B

B

B B

B

B

Type of viscometer B

12 6 12

12

12

6

6 6

6

6

Rotational speed (rpm) 12

20

20

20

25

25

25 25

25

25

Temperature ( C) 20

Condition of viscosity measurement

300 g

167 g, 222 g

545 g 400 g, 533 g 200 g, 300 g, 400 g 200 g, 267 g 200 g, 267 g

120 g, 160 g

150 g, 200 g

Volume per pack 200 g

Otsuka Pharmaceutical Factory (continued)

CLINICO

Asahi Kasei

Sanwa Kagaku

TERUMO

TERUMO TERUMO

AJINOMOTO

AJINOMOTO

Manufacturer Asahi Kasei

111 Viscosity Thickened Enteral Formula 1471

NA not available

Semi Solid Support ®

PG Soft EJ ®

Calm Solid 500 ®

Calm Solid 400 ®

Calm Solid 300 ®

Product Hine Jerry AQUA ®

20,000

0.75 kcal/mL

10,000 20,000 10,000 20,000 10,000 20,000 20,000

2.0 kcal/mL

1.5 kcal/g

1.25 kcal/mL

1.0 kcal/mL

Energy density 0.8 kcal/g

Viscosity (mPas) 6,000

Table 3 (continued)

33

44

62.6

83.3

116.3

Water content (ml/100 kcal) 101

1.9

0.37

1.3

1.3

1.3

Fiber content (g/100 kcal) 1.2

Agar

Pectin, agar

Gelatinizer (hydrocolloids)

Gelatinizer (hydrocolloids)

Gelatinizer (hydrocolloids)

Thickener Agar, guar gum

B

B

B

B

B

Type of viscometer B

6

12 6 12 6 12 6 6

Rotational speed (rpm) 12

20

25

20

20

20

Temperature ( C) 20

Condition of viscosity measurement

200 g, 267 g 200 mL, 250 mL

436 g (400 mL)

428 g (400 mL)

420 g (400 mL)

Volume per pack 250 g

Nestle Japan

TERUMO

NUTRI

NUTRI

Manufacturer Otsuka Pharmaceutical Factory NUTRI

1472 S. Ichimaru and T. Amagai

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Viscosity Thickened Enteral Formula

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viscosity ranging from 3,000 to 20,000 mPa
s (Ito et al. 2006; Murabayashi et al. 2006; Nakayama et al. 2010). For example, improvement of intractable diarrhea was reported in 12 of 15 patients on liquid enteral nutrition after the introduction of TEF with viscosity of 6,000–20,000 mPa
s (Yoshida et al. 2008). In contrast, however, a crossover study conducted on 32 post-PEG patients found no significant difference in the percentage of days with diarrhea between patients receiving RTU-TEF with viscosity of 2,000 mPa
s and those on liquid formula (Shizuku et al. 2011). This discrepancy may be due to differences in study design and definition of diarrhea. Some of the benefits observed with TEF may be attributable in part to the soluble fiber content of the formula, which may delay small intestine transit time and help control diarrhea by increasing sodium and water absorption (Klosterbuer et al. 2011). Further research will be needed to confirm this effect or clarify some alternate mechanism.

diabetes mellitus on receiving TEF (Akatsu et al. 2005). In another study, 10 post-PEG patients showed significant reductions in blood glucose level at 60 and 120 min after initiation of feeding when administered TEF for 15 min than when fed liquid formula for 60 min (Goda 2006b). Dietary fibers in thickener may increase the viscosity of the chyme, thereby slowing the rate of intestinal glucose absorption (Hallfrisch and Behall 2000). In contrast, however, plasma glucose levels in healthy subjects were significantly higher after oral intake of TEF than with liquid formula (Shimoyama et al. 2007), a discrepancy in findings which may be due to inconsistencies in feeding manner and nutritional makeup between studies. Accurate comparison of the effects on glucose metabolism between TEF and liquid formula will require ensuring that the nutrient components and feeding manner are uniform.

Prevention of Leakage Around the PEG Puncture Site

TEF is generally administered by bolus method. In a home care setting, 354  131 mL of TEF was administered once over 16.6  8.8 min (Okada and Ogawa 2011). Continuous feeding is often recommended with liquid enteral formula in order to minimize the incidence of EN-related complications during nutritional support. However, this method increases the time patients must remain in a sitting position, which may cause potential problems such as pressure ulcers or insufficient time allocated for rehabilitation. TEF allows for rapid administration of nutrients, potentially helping prevent the occurrence of pressure ulcers (Miyamoto 2009; Nakayama et al. 2010). TEF can also reduce the workload of nursing stuff and caregivers who typically must carefully observe patients during EN feeding. Time required for preparing and delivering formula, administering nursing care, and keeping an eye on patients receiving TEF was significantly reduced compared with time required to care for patients on liquid formula (Shizuku et al. 2011;

One of the late complications following PEG tube placement is leakage from the tube insertion site. A case report of an 85-year-old woman reported that nutrient leakage from the PEG insertion site was resolved immediately after starting TEF feeding (Kanie et al. 2004a). Similarly, Yoshida et al. (2008) found that the replacement of liquid formula with TEF suppressed leakage of gastrointestinal fluid in 4 of 7 patients. While logic suggests that leakage would naturally be reduced or resolved completely with TEF administration because of increased viscosity, helping to stem the flow, few clinical studies have been conducted to prove this effect.

Effects on Glucose Metabolism One case report described improvement of high blood glucose levels in a bedridden patient with

Improvement of Quality of Life (QOL) in Patients and Caregivers

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Okada and Ogawa 2011). Cost expenditures may be reduced as well by using RTU-TEF, which requires no delivery container or administration set.

S. Ichimaru and T. Amagai

such mixing, these two types of TEF have comparatively low risk for bacterial contamination.

Ideal Feeding Tube Type

Unresolved Issues with TEF Ideal Viscosity The optimum viscosity of TEF remains unclear. In a clinical study conducted on post-PEG patients comparing those receiving one of two TEFs with viscosities of 4,000 of 10,000 mP
s (viscosity measured under the same conditions), no significant differences were observed in length of hospital stay or respiratory or gastrointestinal complications (Ichimaru et al. 2012). Several studies of TEF have been performed with viscosities ranging from 900 to 20,000 mP
s; however, the efficacy of TEF should not be evaluated based solely on quantitative viscosity values, as modalities for measuring viscosity and assessing complications have not been standardized among studies (Table 1). A study evaluating the physical property of TEFs in artificial gastric juice found that when the isoelectric point of the constituent proteins was lower or higher than the pH of TEF, its viscosity tended to increase or decrease, respectively (Takemura et al. 2011). Maruyama et al. (2008) also reported that the properties of TEF depend on the acidity of gastric juice, which can be altered by H2 blockers. Changes in physical properties of TEF after administration into the stomach need to be considered to accurately compare the effectiveness of TEF.

Risk of Bacterial Contamination LT-TEF preparation involves mixing liquid formula with thickener and pouring the subsequent product into a syringe, a process which raises the risk of bacterial contamination. The environment in which thickener is added to TEF should therefore be controlled in order to reduce this risk. Of note, because IG-TEF and RTU-TEF need no

Two important points to consider when administering TEF through a feeding tube include the tube diameter and shape. IG-TEF can be used for a small-diameter nasogastric tubes, as the liquid thickener and liquid formula are administered into the stomach separately and the viscosity increases subsequent to administration. In contrast, LT-TEF and RTU-TEF are administered mainly via gastrostomy tubes because these formulas are thickened before administration and wide-internal-diameter tubes are necessary to prevent tube occlusion. Patients with low-profile PEG require extension tubes for bolus feeding with straight adaptors to administer TEF; an extension tube for continuous feeding with a 90 adaptor is not appropriate for TEF.

Ideal Volume and Timing of Additional Water Water content of RTU-TEF varies widely (Table 3). Energy-dense RTU-TEFs are not intended to meet the patient’s total fluid needs, and additional water should therefore be provided through a feeding tube for adequate hydration. However, if water is given immediately after TEF, the viscosity of TEF may be lowered in the stomach, thereby reducing the formula’s effectiveness. To ensure TEF efficacy, supplemental water is administered either more than 2 h before or more than 2 h after TEF administration. When additional fluid needs to be given immediately after TEF, thickened water should be administered via the feeding tube not to decrease the viscosity of TEF. Pre-thickened water packed into a pouch with a spout to connect to gastrostomy tubes is also available commercially. In addition, as little water as possible should be used when flushing the feeding tube to avoid decreasing the viscosity of TEF.

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Nutrient Interactions: Malabsorption of Dietary Minerals Miura et al. (2008) examined the mineral concentration in the urine, excrement, and blood from rats following 2-week administration of liquid formula containing the same mineral composition as a TEF. Absorption of zinc, copper, iron, calcium, magnesium, sulfur, and potassium was lower in animals receiving TEF than in those on a liquid enteral formula. Although these authors’ conclusions need to be confirmed in humans, this potential negative effect of TEF should be kept in mind.

Applications to Critical or Intensive Care No data have yet been generated on the effects of TEF administration in critically ill patients. Generally, TEF is not suitable for this population, as pump-assisted continuous feeding is preferred in these patients and enhances gastrointestinal tolerance. Almost all kind of TEFs include fiber as a thickener, and data supporting the routine use of fiber in enteral feeding in critically ill patients are insufficient at present. The American Society of Enteral and Parenteral Nutrition (ASPEN) has stated that both soluble and insoluble fiber should be avoided in patients at high risk for bowel ischemia or severe dysmotility (McClave et al. 2009).

Applications to Other Conditions TEF administration is only successful with optimal gastric motor function and normal enterokinesis, digestion, and absorption. Indications of TEF reported as expert opinion are shown in Table 4 (Goda 2011). TEF appears to be most suitable for administration in patients with gastrostomy tubes in long-term care hospitals, nursing homes, or home medical care settings rather than acute care hospitals. Bolus feeding of TEF is contraindicated for patients with jejunostomy.

1475 Table 4 Indications for application of thickened enteral formula TEF should be considered for use in patients who 1. Want to reduce time required for feeding to reserve time for rehabilitation 2. Repeat aspiration or vomiting 3. Repeat diarrhea without malabsorption 4. Have trouble with leakage from the PEG puncture site in the stomach 5. Have a gastrostomy tube due to head-and-neck cancer 6. Are stable but chronically ill and want to reduce the time required for feeding because they cannot stay in bed Reference: Goda (2011)

Guidelines and Protocols Few studies attempted to establish guidelines for TEF, nor is TEF cited in any guidelines published by major nutritional associations such as the European Society for Clinical Nutrition and Metabolism or American Society for Parenteral and Enteral Nutrition. At present, TEF is used based on expert opinions or practical experience. Most previous studies on TEF have been empirical, with little scientific evidence available supporting the efficacy of TEF. Compounding this dearth of supportive data is the fact that design characteristics such as viscosity of TEF, methods of assessing complications, and type of thickener used vary among studies, hampering understanding the mechanism of TEF. More large-scale randomized controlled trials should be conducted to clearly explain how TEF works, who benefits from its usage, and which viscosity is optimal.

Summary Points • Thickened enteral formula (TEF) is a formula in which viscosity is intentionally increased to prevent EN-related complications. • Three types of TEF are available at present: intragastric TEF, TEF prepared by mixing liquid formula and thickener, and ready-touse TEF.

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• Potential advantages of TEF are the prevention of gastroesophageal reflux, diarrhea, and skin trouble around the PEG puncture site and improvement of blood glucose levels and quality of life for both patients and caregivers. • However, the mechanism by which TEF exerts its effects and the optimum viscosity of TEF remain unclear. • When applying TEF, bacterial contamination, shape of a feeding tube, the timing and volume of additional water, and nutrient interactions should be considered. • At present, TEF can be used only in stable chronically ill patients with optimal gastric motor function, normal enterokinesis, digestion, and absorption. • Additional research is needed to identify the effectiveness, mechanism, and indications of TEF.

References Adachi K, Furuta K, Morita T, et al. Half-solidification of nutrient does not decrease gastro-esophageal reflux events in patients fed via percutaneous endoscopic gastrostomy. Clin Nutr. 2009;28:648–51. Akatsu H, Yamamoto T, Suzuki Y, Kanie J. Better control of blood sugar with treatment using half-solid nutrients: a case report [in Japanese]. Nihon Ronen Igakkai Zasshi. 2005;42:564–6. Goda F. The method of and evidence of short time gastrostomy tube feeding of semi-solid enteral nutrient. In: Goda F, editor. Guidebook for short time gastrostomy tube feeding of semi-solid enteral nutrient – towards the quality of good life for gastrostomy patients [in Japanese]. 1st ed. Tokyo: Ishiyaku Publishers; 2006a. p. 19–26. Goda F. The evidence for effectiveness of short time gastrostomy tube feeding of semi-solid enteral nutrient. In: Goda F, editor. Guidebook for short time gastrostomy tube feeding of semi-solid enteral nutrient – towards the quality of good life for gastrostomy patients [in Japanese]. 1st ed. Tokyo: Ishiyaku Publishers; 2006b. p. 27–34. Goda F. Short time gastrostomy tube feeding of semi-solid enteral nutrient [in Japanese]. In: PDN lectures. PEG doctors network; 2011. http://www.peg.or.jp/lecture/ enteral_nutrition/05-02-01.html. Accessed 29 Apr 2013. Hallfrisch J, Behall KM. Mechanisms of the effects of grains on insulin and glucose responses. J Am Coll Nutr. 2000;19:320–25S.

S. Ichimaru and T. Amagai Ichimasa A, Ichimaru S. Review of mechanism, current evidence and practice of enteral semi-solid formula use to prevent gastroesophageal reflux, diarrhea, and to improve patient care [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2010;25:1207–16. Ichimaru S, Amagai T, Wakita M, Shiro Y. Which is more effective to prevent enteral nutrition-related complications, high- or medium-viscosity thickened enteral formula in patients with percutaneous endoscopic gastrostomy?: a single-center retrospective chart review. Nutr Clin Pract. 2012;27:545–52. Inada H, Kaneda K, Yamagata N. Prevention of aspiration pneumonia in patients with gastroesophageal reflux using REF-P1 (pectin gel) [in Japanese]. Jpn J Parenter Enteral Nutr. 1998;20:1031–6. Ito Y, Imataka T, Kobayashi K, et al. Comparison of the thickening agent and agar to use to prepare half solid enteral nutrition for the purpose of prevention of gastroesophageal reflux [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2006;21:77–83. Kanie J, Suzuki Y, Akatsu H, Kuzuya M, Iguchi A. Prevention of late complications by half-solid enteral nutrients in percutaneous endoscopic gastrostomy tube feeding. Gerontology. 2004a;50:417–9. Kanie J, Suzuki Y, Iguchi A, Akatsu H, Yamamoto T, Shimokata H. Prevention of gastroesophageal reflux using an application of half-solid nutrients in patients with percutaneous endoscopic gastrostomy feeding. J Am Geriatr Soc. 2004b;52:466–7. Kawasaki N, Urashima M, Odaira H, Noro T, Suzuki Y. Effects of gelatinization of enteral nutrients on human gastric emptying. Gastroenterol Res. 2010;3:106–11. Klosterbuer A, Roughead ZF, Slavin J. Benefits of dietary fiber in clinical nutrition. Nutr Clin Pract. 2011;26:625–35. Maruyama M, Hiroi J, Matsumura A, Hashimoto N, Yokoshima Y. Intra-gastric change of the semi-solid formula with pectin liquid, “REF-P1” [in Japanese]. Jpn J Cancer Chemother. 2008;35:29–31s. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nutr. 2009;33:277–316. Miura Y, Endo R, Ikeda K, Sera K, Suwabe A. Comparison of absorption of trace elements on liquid and partially solidified enteral nutrition consist of the same elements – Examination about receipt and disbursement balance of trace elements after partially solidified enteral nutrition administration to rats. Nishina Mem Cyclotron Center Annu Report [in Japanese]. 2008;15:128–34. Miyamoto H. Application of nutrition support using half solid diet in the oldest patients with tube feeding [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2009;24:807–9.

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Miyazawa R, Tomomasa T, Kaneko H, Arakawa H, Shimizu N, Morikawa A. Effects of pectin liquid on gastroesophageal reflux disease in children with cerebral palsy. BMC Gastroenterol. 2008;8:11. Murabayashi Y, Simizu A, Sakuma T, et al. Clinical experience with addition of polysaccharides thickening agent to liquid formula diets [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2006;21:85–9. Nagasawa K. Influence of semi-solid nutrient on gastric emptying in patients with gastrostomy. Jpn J Appl Physiol [in Japanese]. 2009;39:297–302. Nakayama T, Hayashi S, Okishio K, et al. Prompt improvement of a pressure ulcer by the administration of high viscosity semi-solid nutrition via a nasogastric tube in a man with tuberculosis: a case report. J Med Case Reports. 2010;4:24. Nishiwaki S, Araki H, Shirakami Y, et al. Inhibition of gastroesophageal reflux by semi-solid nutrients in patients with percutaneous endoscopic gastrostomy. J Parenter Enteral Nutr. 2009;33:513–9. Okada S. Gel-forming properties of “EASYGEL”, the food for making various enteral nutrients into jelly [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2007;22:41–51. Okada S, Ogawa S. Influence of using semi-solid diet to the burden of nursing care for family- caregivers

1477 [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2011;26:1399–406. Shimoyama Y, Kusano M, Kawamura O, et al. Highviscosity liquid meal accelerates gastric emptying. Neurogastroenterol Motil. 2007;19:879–86. Shizuku T, Adachi K, Furuta K, et al. Efficacy of half-solid nutrient for the elderly patients with percutaneous endoscopic gastrostomy. J Clin Biochem Nutr. 2011;48:226–9. Tabei I, Kubo H, Yano F, Inada H. The effect of viscosity regulating solution for enteral nutrition against gastro esophageal reflux [in Japanese]. Jpn J Gastroenterol Surg. 2003;36:71–7. Takemura Y, Yamashita S, Seiki M, Yamamoto T, Fukuda H. Changes in the physical properties of semisolid nutritional preparations in artificial gastric juice [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2011;26:1255–64. Wakita M, Masui H, Ichimaru S, Amagai T. Determinant factors of the viscosity of enteral formula – basic analysis of the thickened enteral formula. Nutr Clin Pract. 2012;27:82–90. Yoshida S, Minei K, Yoshimi Takenouch Y, Wakunami A. Nutrition support using semi-solid diet with tube feeding in hospitalized elder patients [in Japanese]. J Jpn Soc Parenter Enteral Nutr. 2008;23:43–9.

Part XI Enteral Aspects: Specific Conditions

Enteral Feeding and Infections in Preterm Neonates

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Gianluca Terrin, Maria Giulia Conti, and Antonella Scipione

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1482 Malnutrition and the Risk of Infections . . . . . . . . . Malnutrition in Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . Malnutrition and Intestinal Function . . . . . . . . . . . . . . . Malnutrition and Immune Response . . . . . . . . . . . . . . . Malnutrition and Intestinal Microflora . . . . . . . . . . . . .

1482 1482 1483 1484 1484

Specific Nutrient Malnutrition and Risk of Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1485 1485 1485 1487 1487 1487 1487

Nutritional Approaches Against Infections . . . . . Trophic Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Human Milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lactoferrin Supplementation . . . . . . . . . . . . . . . . . . . . . . . Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipid Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iron Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zinc Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1488 1488 1488 1490 1491 1491 1491 1492 1492 1492 1493

Application to Critical or Intensive Care . . . . . . . 1493 Enteral Feeding and Related Side Effects . . . . . . . . . . 1493 Application to Other Conditions . . . . . . . . . . . . . . . . . 1494 Malnutrition, Chronic Lung Disease, and Risk of Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1494 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1495 Enteral Nutrition Administration . . . . . . . . . . . . . . . . . . . 1495 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1496 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1496

G. Terrin (*) Department of Gynecology-Obstetrics and Perinatal Medicine, Sapienza University of Rome, Rome, Italy e-mail: [email protected]; gianluca. [email protected] M.G. Conti • A. Scipione Department of Pediatrics, Sapienza University of Rome, Rome, Italy e-mail: [email protected]; [email protected] # Springer Science and Business Media New York (outside the USA) 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_156

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Abstract

Infections are major morbidities in preterm neonates. They represent the main cause of death of these particular patients. Malnutrition increases the risk of infections. Immaturity of neonatal gut system limits the use of enteral nutrition in the early life of preterm neonates. Additionally, the risk of necrotizing enterocolitis frequently allows to enteral nutrition avoidance or suspension. Starvation produces modification in mucosal barrier integrity (favoring bacterial translocation), immune response, and microflora composition. Deficit of specific nutrients (i.e., amino acids, lipids, vitamins, microelements) reduces defenses against infections and increases the risk of inflammatory damage. On the other hand, adequate nutritional support may prevent occurrence of many infectious disease, by improvement of immune response, epithelial barrier integrity, and microflora composition. The use of minimal enteral feeding (10–20 ml/kg of body weight), during a period of feeding intolerance, could be considered an efficacious nutritional strategy against infections in neonates.

TNFα TPN VLBW

Tumor necrosis factor α Total parenteral nutrition Very low birth weight

Introduction Childhood malnutrition is associated with increased incidence and case fatality rate of common infectious disease worldwide. This malnutrition-attributable risk of infection accounts for more than half of global mortality. Malnutrition and infection represent a vicious cycle, with malnutrition inhibiting immune response, while infections impede adequate nutritional intake. Additionally, malnutrition may induce mucosal barrier alterations, leading to the translocation of pathogens from the intestinal lumen to the blood, with activation of local and systemic inflammatory response. Adequate nutritional support may reduce the risk of infections limiting malnutrition and promoting intestinal development and adequate function. This chapter focused on the role of nutrition on the risk of infections in neonates. We also explore the nutritional strategy useful to promote functional intestinal and immune system development in order to limit infectious diseases in neonate.

List of Abbreviations

ARA Arg BLF GALT Gln GLP-2 Glu HLF LCPUFAs LGG MCFA MCT MEF NEC SCFA TCR TLR

Arachidonic acid Arginine Bovine lactoferrin Gut-associated lymphoid tissue Glutamine Glucagon-like peptide 2 Glutamate Human lactoferrin Long-chain polyunsaturated fatty acids Lactobacillus rhamnosus GG Medium-chain fatty acids Medium-chain triglycerides Minimal enteral feeding Necrotizing enterocolitis Short-chain fatty acids T-cell receptor Toll-like receptor

Malnutrition and the Risk of Infections Malnutrition in Neonates Up to 90 % of infants born at the gestational age lower than 29 weeks do not achieve the median birth weight of the reference fetus at the same corrected gestational age at term of gestation (De Curtis and Rigo 2012). During the initial post-discharge period, the estimates of growth failure range from 30 % to 67 %. Major morbidities affecting very low-birth-weight (VLBW) infants contribute significantly to reduce extrauterine growth velocity. However, it remains unclear which postnatal nutritional regimen is appropriate to support postnatal growth and to minimize postnatal growth retardation (Agostoni et al. 2010);

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many evidences suggest that enteral nutrition should be introduced as early as possible to reduce the risk of malnutrition.

Malnutrition and Intestinal Function Fetal nutritional requirements are very high. Intrauterine growth is modulated by many aspects including maternal metabolic and endocrine factors, placental function, and nutrient availability. At birth, there is a significant demand to digest and adsorb nutrients efficiently to maintain rate of growth similar to the fetus also in the first weeks of extrauterine life. This aspect is particularly relevant for preterm neonates that should complete “intrauterine growth after birth.” Intestinal epithelial cell integrity is of prime importance considering that this single layer of epithelium is simultaneously responsible for nutrient absorption and protection against potentially noxious environment of the gut lumen (Fig. 1).

Alteration of epithelal barrier

Inflammatory infiltration

Bacterial translocation

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The intestinal epithelium is continuously exposed to a variety of commensal and pathogenic microbes and antigens. To contain this bacterial, viral, and antigenic load, features of the mucosal epithelium have evolved that allow it to function as an active participant in mucosal immune responses and a physical barrier to the uptake of noxious substances. The inability to tolerate enteral nutrition leads to further atrophy of the intestinal mucosa because of the absence of nutrient-stimulated local growth factor production such as glucagon-like peptide 2 (GLP-2), gastrin, cholecystokinin, peptide YY, and neurotensin. A lack of enteral nutrients also affects maturation of intestinal motility, at least in part responsible for the common problems of feed intolerance encountered in newborns (Berni Canani et al. 2008). Nutrient malabsorption deriving from breakdown of mucosal integrity may lead to further impairment of intestinal development, increase of aberrant inflammation, and alteration in intestinal microflora.

Modif ication of Microf lora

Reduced Immune response in submucosa

Reduced mucus and slgA

Loss of tight junction

Fig. 1 Pathophysiologic consequences of malnutrition and starvation at intestinal level in neonates

1484

Malnutrition and Immune Response Mucosal and systemic immune response against infectious agents is less developed in the neonatal period. The ontogeny of the gut-associated lymphoid tissues is structurally incomplete at birth and its further development is highly dependent on microbial colonization in the early postnatal period (Berni Canani et al. 2008). Several factors compromise the neonatal innate immune system’s response to pathogenic challenge. Circulating levels of complement proteins are low, and neutrophils display impaired chemotactic, phagocytic, and microbicidal capabilities. Macrophage activation by cytokines and toll-like receptor (TLR) ligands is also impaired, although innate immune response seems at least in part well developed. Neonatal antimicrobial peptide secretion by innate immune cells is similar to that observed in older ages (Terrin et al. 2008). NK cells, which are present in large numbers in cord blood samples, express high levels of activating receptors, implying effector functions that may be in excess of adult levels (Sundström et al. 2007). Low baseline expression of T-cell receptor (TCR), adhesion molecules, and CD40L and inefficient cytokine generation certainly diminish T-cell responsiveness; neonatal T cells are able to demonstrate a relatively complete repertoire of effector functions (Holt and Jones 2000). As early as 28 weeks of gestation, the fetus is able to mount an antigen-specific CD8+ response to intrauterine viral infection. The inadequate response to pathogenic challenge is partly explained by a bias towards Th2-type responses at the expense of Th1 effector mechanisms important in fighting infection. This bias is crucial for continued maternal acceptance of the fetus and is partly mediated by placental factors. It also helps to facilitate the proper acquisition of tolerance to innocuous antigens and resolves gradually through infancy and childhood, as the adaptive immune system becomes more competent at fighting infection. Th2 dominance is supported by differences in antigen presentation and in the balance of regulatory lymphocytes. Antigen presentation by circulating cells is inefficient at birth, with cord blood monocytes, macrophages,

G. Terrin et al.

and dendritic cells expressing low levels of costimulatory molecules and demonstrating inefficient TLR-mediated signaling alongside abnormalities in maturation and cytokine production. Additionally, the fetal blood, thymus, and lymphoid organs contain large numbers of functional Treg cells, which exert a suppressant effect over the fetal immune system (Micha€elsson et al. 2006). In this context early nutrition is essential to promote adequate innate immune response and Th1/Th2 balance during adaptive immunity development. Malnutrition inhibits complement activation, phagocytic cell activity, antibody production, circulating lymphocyte proliferation, T-cell expression of activation markers, and memory T-cell production. The number of circulating dendritic cells is also reduced, and a recent study demonstrated reduced dendritic cell IL-12 production in half of a cohort of severely malnourished children (Hughes et al. 2009). Cohort studies have demonstrated that malnutrition is associated with reduced thymic size and function with elevated levels of CD8+ ve T cells and NK cells that persist through the first year independent of current nutritional status and is strongly associated with risk of death from infection in adolescence and early adulthood (Moore et al. 1999).

Malnutrition and Intestinal Microflora Soon after delivery, the semi-sterile infant intestinal tract becomes colonized by bacteria. The balance of this colonization is affected by the mode of delivery and the infant’s diet. In breastfed babies, Bifidobacteria and Lactobacilli quickly become dominant, whereas in formula-fed babies, Bacteroides species are present in large numbers, alongside other bacteria known to be enteric pathogens (Harmsen et al. 2000). Breast milk contains high concentrations of oligosaccharides, which ferment in the bowel and promote the growth of Bifidobacterium gut commensals. Other nutrients have similar prebiotic effects, including casein, alpha-lactalbumin, lactoferrin, and nucleotides (Mountzouris et al. 2002). Nonpathogenic commensal bacteria are protective against infection

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via a number of mechanisms including competitive inhibition of epithelial binding by enteropathogenic bacteria and effects on tight junctions and on the immune system (Berni Canani et al. 2008; Terrin et al. 2012a). In the neonate, a healthy gut flora may also be critical to the development of a properly functioning mucosal immune system. By approximately 10 days of life, a term breastfed infant GI tract becomes colonized with Bifidobacterium and Lactobacillus species. In a formula-fed infant, the colonization is less diverse and is composed of only ~50 % of the Bifidobacterium organisms observed in breastfed infants. The colonization of preterm infants is not only delayed but is more likely to be dominated by pathogenic bacteria such as members of the Enterobacteriaceae family and Clostridium species. Cross talk between enteric bacteria and TLRs in the intestinal mucosa can modulate the level of immune activation in the gut and direct towards either Th1- or Th2-type responses (Forchielli and Walker 2005). Lactobacilli prime dendritic cells to drive the development of Treg cells and to promote mucosal tolerance to nonpathogenic antigens (Berni Canani et al. 2012a, b). Alteration of luminal environment induced by malnutrition modifies microflora composition and consequently the immune system development and activation.

Specific Nutrient Malnutrition and Risk of Infections Specific nutrient deficiency has been associated with an increased risk of infectious diseases. In this chapter, we focus only on macro- and micronutrients with a significant burden of evidences in neonatal age (Table 1). Other nutrients have important effects on the developing immune system. Selenium deficiency is associated with poor cell-mediated immunity including increased risk of viral infections and rapid progression of HIV (Fawzi et al. 2005). We address to specific lectures to study in deep the additional important role of copper, antioxidant agents, vitamin C (Kim et al. 2013), and vitamin E (Gay et al. 2004) on immune response against infections.

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Amino Acids Arginine (Arg) is an essential amino acid in neonates synthesized by enterocytes and required for protein synthesis and maximum growth (Wu 2010). Injury to the intestinal mucosa increases amino acid requirements for growth and repair. Supplemental Arg in neonatal piglets improves intestinal integrity and function because it is the substrate for synthesis of nitric oxide (NO). Arg synthesis is decreased in total parenteral nourished piglets, with a significant reduction in NO production, contributing to the decrease in superior mesenteric blood flow and induction of mucosal atrophy. In weanling piglets, supplemental Arg decreases the mucosal injury by decreasing intestinal lesions and increasing cell proliferation. Arg is also an important component of intestinal immune response. Enteral Arg administration increases protein synthesis in rotavirusinfected piglets, but it has no effect on the severity of diarrhea (Corl et al. 2008). However, determining the correct supplementation level of dietary Arg is a key component of neonatal nutrition because dosing may determine its effectiveness. In addition to its function as a primary energy source for intestinal epithelial cells and leukocytes, glutamine (Gln) contributes to key metabolic processes from protein synthesis useful to the immune response and regulation of oxidant capacity (Li et al. 2007). Glutamate (Glu) is synthesized from Gln and is the precursor to glutathione, proline, and Arg. Its importance in the gut seems to be essential in neonatal intestinal growth and development because it is almost 100 % oxidized at the intestinal mucosal level. Despite the potential role of Gln and Glu on protection against infections, clinical efficacy of these amino acids remains controversial (Bertolo and Burrin 2008).

Lipids Medium-chain triglycerides (MCT), long-chain polyunsaturated fatty acids (LC-PUFAs), and shortchain fatty acids (SCFA) are essential components in providing energy and maintaining GI growth and development for neonates, but they have also immunomodulatory effects (Gottrand 2008).

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Table 1 Effects of different nutritional factors on the risk of infectious diseases in neonates Macronutrients Nutrients Arginine

Glutamine

Oligosaccharides

Effects on intestinal functions Substrate for synthesis of NO " Enterocyte migration " Enterocyte restitution Energy source for epithelium " Protein synthesis # Enterocyte apoptosis Antioxidant action None

Lactoferrin

" Differentiation of enterocytes " Enteric gap junction

Short-chain fatty acids

" Epithelial surface area " Enterocyte proliferation # Apoptosis " Nutrient transporters " Villous length # Crypt depth

Medium-chain fatty acids Long-chain polyunsaturated fatty acids

Micronutrients Iron

Influence of immune response " T-cell development " B-cell development

Modification of intestinal microflora None

" B-cell proliferation " T-cell differentiation " NK cell activation " Macrophage activation

None

" Cytokine expression " Circulating leucocytes " T cells " Cytokine expression " Circulating leucocytes " T cells " NK cell activation # Intraepithelial lymphocytes # Secretion of antiinflammatory factors

" Early development of microbiota " Bifidobacterium " Lactobacillus " Bifidobacterium " Lactobacillus

# Intraepithelial lymphocytes

Modulate microbial gastric and intestinal populations " Lactobacillus " Development of early microbiota " Lactobacillus

Components of intestine membranes " Intestinal glucose absorption " Cellular migration in damaged mucosa # Ischemia

" T-cell differentiation # Intraepithelial lymphocytes

None

" T-cell differentiation " T-cell proliferation " Macrophage activity " Neutrophil activity " NK cell activity " T-cell activity " T-cell differentiation " Phagocyte activity " NK cell activity " T-cell activity #Secretion of proinflammatory cytokines # Maturation of dendritic cells " Secretion of proinflammatory cytokines " Differentiation of monocytes " Phagocytic activity of macrophages " Product of antimicrobial peptide " Maturation of Th1 Th2

Zinc

" Villous length " Cellular proliferation " Metabolic function of epithelium

Vitamin A

Integrity of the epithelial cells Antioxidant action

Vitamin D

" Enterocyte proliferation " Metabolic function of epithelium " Intestinal barrier integrity

" Development of early microbiota

" Development of early microbiota " Development of early microbiota

" Development of early microbiota

" Early development of microbiota " Clearance of pathological microflora

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Medium-chain fatty acids (MCFA) are saturated 6–12 carbon fatty acids, which occur naturally as MCT in milk fat and other dietary nutritional supplements. MCFA and MCT have specialized nutritional and metabolic effects, including being readily digestible, passive absorption, and obligatory oxidation, making them of particular interest for neonatal nutrition. MCFA-fed weanling piglets have been shown to have increased villus length, decreased crypt depth, and decreased intraepithelial lymphocytes. Fatty acid supplementation may impact on the immune response to infection as well. LC-PUFAs contribute to normal perinatal growth and development. Modification of dietary LC-PUFA intake greatly affects membrane structure through incorporation into cellular membrane phospholipids in many tissues, including intestine (Hess et al. 2008). Membrane LC-PUFAs are synthesized from dietary essential fatty acids and then can be metabolized to produce prostanoids, which are essential in many cellular functions. Approximately 30–35 % of fatty acids comprising small intestine membranes is dietary essential fatty acids and cannot be synthesized de novo. The majority of these essential fatty acids are of the (n6) series, including linoleic acid and arachidonic acid (ARA). The n-6 PUFA have proinflammatory and n-3 PUFA antiinflammatory properties (REF).

Iron Iron is an essential nutrient for pathogens as well as humans. Bacterial proliferation could be favored by a condition of iron depletion. Iron level may influence the risk of developing infections through different ways as indicated in Table 1. In malaria only mild iron deficiency may be a protective factor against this type of infection (Nyakeriga et al. 2004).

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(i.e., protein synthesis, nucleic acid metabolism, immune functions, and organogenesis). Zinc is considered key for optimal functioning of both innate and acquired immunity. Impaired immune function may be a common cause of secondary immunodeficiency in humans because of inadequate zinc status. Zinc deficiency impairs cellular mediators of innate immunity. In addition its deficiency depresses lymphocyte proliferation and Th1 cytokine production (interleukin-2 and interferon-γ), causes Th1/Th2 imbalance, and depresses delayed-type hypersensitivity skin responses and antibody responses to T-cell-dependent antigens, and it also causes thymus involution. Zinc is required for the activity of thymulin, a hormone involved in T-cell differentiation and enhancement of T-cell and NK cell actions. Zinc plays also an antiinflammatory and an antioxidant effect (Taneja et al. 2009).

Vitamin A Vitamin A has a diverse range of roles in effective immune responses. Its actions on maintaining immunity are not focused through one specific mechanism, but affect multiple aspects of the immune system response. It is important in maintaining the integrity of mucosal surfaces, and deficient states are associated with increased rates of invasive respiratory, gastrointestinal, and ocular infections. Deficiency also interferes with phagocytic and NK cell function and with both Th1 and, especially, Th2 responses (Raverdeau and Mills 2014). The fetus accumulates vitamin A in the third trimester. For this reason preterm infants have lower serum concentrations of vitamin A compared with term infants. It is involved in the regulation and promotion of growth and differentiation of many cells and in maintaining the integrity of the epithelial cells (Peniche 2013). Vitamin A seems to play an important role in maintaining immunity.

Zinc Zinc is a structural component of hormones, nucleotides, and proteins (Terrin et al. 2013); it is required for the production of a wide variety of enzymes involved in essential metabolic patterns

Vitamin D An association has been established between low levels of vitamin D and upper respiratory and

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enteric infections, pneumonia, otitis media, Clostridium infections, vaginosis, urinary tract infections, sepsis, influenza, dengue, hepatitis B, hepatitis C, and HIV infections. It has long been recognized that children with rickets have increased susceptibility to respiratory tract infections, with several studies reporting increased pneumonia incidence associated with vitamin D insufficient intake (Walker and Modlin 2009). Subclinical vitamin D deficiency is probably very common in many preterm neonates. Fetal vitamin D stores are highly dependent on maternal nutritional sufficiency, and breast milk is poor in vitamin D even from vitamin replete mothers. Many body cells, including immunocompetent cells, such as dendritic cells, macrophages, and B and T cells, have vitamin D receptor and the enzymatic capability to synthesize 1,25(OH)2D from its precursor 25(OH)D (Walker and Modlin 2009). The 1,25(OH)2D is a potent modulator of acquired immunity and the immune balance between Th1 and Th2 cells (Das et al. 2014). Local or systemically produced vitamin D hormone inhibits the maturation of dendritic cells, among others, reduces Th1-mediated secretion of proinflammatory cytokines such as TNFα, and increases the differentiation of monocytes to macrophages and their rate of phagocytosis as well as the activity of lysosomal enzymes in macrophages. Recent evidence suggests that 1,25dihydroxyvitamin D3 exerts protective effects during infections by upregulating the expression of cathelicidin and β-defensin 2 in phagocytes and epithelial cells (Das et al. 2014).

Nutritional Approaches Against Infections Trophic Feeding Minimal enteral feeding (MEF), also called trophic feeding or gut priming, is adopted into clinical practice to start enteral nutrition in preterm neonates. MEF can be defined as the provision of small volume of enteral nutrition with the purpose of stimulating gastrointestinal function. The primary aim of trophic feeding is to accelerate gastrointestinal

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maturation. MEF mitigates intestinal mucosa atrophy and prevents bacterial translocation during periods of total parenteral nutrition. MEF can also decrease the duration of parenteral nutrition and related infection risk (Freitas BAC 2011). There is a significant relationship between the age when preterm newborn infants achieve full enteral nutrition and sepsis. Many evidences suggest that early achievement of full enteral nutrition will reduce the incidence of sepsis. In VLBW infants, the preferred early feeding regimen is human milk, which can be initiated, according to clinical conditions, even on the first days after birth in small quantities (e.g., 1–2 mL colostrum/milk every 6 h, and progressively increasing the volume and frequency). MEF could be adopted not only early in life to start enteral feeding but also during the periods of feeding intolerance, when signs of feeding intolerance are not specific nor systemic (Fig. 2), in order to reduce the duration of parenteral nutrition and to limit the risk of infections (Terrin et al. 2008).

Human Milk The benefits of human milk for gastrointestinal function and host defense are well known. Preterm infants fed with human milk have fewer infections than those fed on formula. This effect has been observed with both fresh and pasteurized human milk (Menon and Williams 2013). Other studies show a protective effect of breast milk on the incidence of NEC (Adamkin 2012). Feeding with donor human milk was also associated with a significantly reduced risk of NEC. In particular, infants who received donor human milk are three times less likely to develop NEC and four times less likely to have confirmed NEC. Most recently, it has been reported that preterm babies receiving mother’s own breast milk fortified with human milk-based product had significantly lower rates of NEC compared with those receiving conventional bovine milk fortifier or preterm formula.

Human Milk Composition The protective effect of human milk has been attributed to several factors, such as composition in macronutrients, content in immunoglobulin,

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Start with minimal enteral feeding (10-20 ml/kg/day) Presence of worrying symptoms of feeding intolerance∗ Avoiding enteral nutrition for at least 6-12 hours

Persistence of feeding intolerance in the absense of worrying symptoms∗

Minimal enteral feeding

No feeding intolerance

Worsening of general clinical condition associated with the presence of worrying symptoms∗

Restart enteral feeding at 50% of previous volume

Withdrawing enteral nutrition and checking for NEC (Rx every 6h)

Observation for at least 24 h Persistence or reappearing of feeding intolerance in absence of worrying symptoms∗

No feeding intolerance

Observation for at least 48-72 h∗∗

Increase enteral nutrition of 20-30 ml/Kg/day

No worrying symptoms∗

Persistence of feeding intolerance and worrying symptoms∗

Fig. 2 Flow diagram for the management of preterm newborns with feeding intolerance. Note: *erythematic abdominal wall, absence of bowel sounds, blood in the

stools or in aspirates, bile in the aspirate; or radiological marker of NEC-Bell stage > I. **In these conditions it is possible to start medical therapy for NEC

immune cells, enzymes, and growth factors (Table 1). Molecules with immunological, hormonal, enzymatic, trophic, and bioactive activities present in breast milk can offer passive protection against infections in neonatal period. Macronutrient composition of human milk has also a role in protection against infection. The amino acid composition of human milk is not suitable for the nutritional requirements of preterm infants who are at risk of developing a deficit or an overload of essential and semi-essential amino acids (De Nisi et al. 2012).

factors related to the mucosal or systemic immune response. Secretory IgA, present at high concentration in the colostrum (10 g/L) and in mature human milk (1 g/L), is particularly resistant to the peptic acidity of the stomach and to digestion by enteric enzymes and bacterial proteases. IgA concentration may be higher in milk from mothers delivering prematurely (Goldman et al. 1998). IgG and IgM are also present at lower concentrations and provide the infant with 10–100 mg/day. The distribution of specific antibodies within IgG subclasses in human milk may compensate for the reduced transplacental transfer of some antibodies, as those against pneumococci (Brandtzaeg 2003). The entero-broncho-mammary link of IgA1 B cells and mucosal immune system is considered a means of transfer of highly specific protection from a mother to her infant. When the nursing mother is exposed to antigenic material from environmental pathogens, M cells of Peyer’s patches in

Human Milk Transfer of Immunity Breast milk exerts a direct modulatory effect on the neonatal immune system (Table 1). Breast milk represents an important means of transmission of immune competence from the mother to infant. Most of the protective components of human milk may interact synergistically with each other or with

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the gut-associated lymphoid tissue (GALT) or tracheobronchial tree mucosa (BALT) acquire and present the antigen to B cells that become active to secrete IgA and migrate to local and regional lymph. The antimicrobial effects of IgA antibodies are related both to immune exclusion, by inhibition of epithelial adherence and penetration or microbial agglutination and neutralization, and immune elimination, by phagocytosis and cytotoxicity.

Human Donor Milk Despite the potential benefits, nutrients of human milk are not sufficient to cover the greater needs of VLBW infants and to ensure a growth similar to that of the fetus during the last period of gestation. In order to meet the unique nutritional requirements of VLBW infants and to preserve the singular benefit of human milk, human milk fortifiers, which increase the nutritional content of human milk, have been recommended (Ziegler 2014). Through a process of human milk lactoengineering, human milk can be fortified with skim and cream components derived from heattreated, lyophilized mature donor human milk to produce a “human milk formula.” Expressed donor milk can be, for milk or hind milk, obtained either before or after the donor’s own infant has fed from the breast; these two types of milk will have, respectively, lower or higher fat and energy contents than milk received by the breastfed infant. A Cochrane systematic review (Ramani and Ambalavanan 2013) suggested that infants fed with donor breast milk had a significantly reduced risk of NEC. However, providing, storing, and administering human donor milk is not an easy practice. The National Institute for Health and Clinical Excellence 2010 has recently issued guidance on donor breast milk banks, and further advice can be obtained from the United Kingdom Association for Milk Banking. Treatment of donor breast milk (i.e., collection, bacterial decontamination, store, froze, pasteurization, exposition to light) may induce qualitative alteration. Screening of breast milk donors from virus (HIV-1, HTLV, HBV, HCV) and syphilis is advised (National Institute for Health and Clinical Excellence). The risk of acquiring HIV1 from donor

G. Terrin et al.

breast milk is unknown, but there have been no reported cases of preterm infants infected in this way. Published evidence suggests that pasteurization destroys HIV (Prameela 2012). More recent studies reported that “flash-heat treatment of breast milk” can be used to inactivate HIV-1 in resource-poor settings. Some concerns about CMV infection in preterm infants receiving breast milk from seropositive mothers remain. However, the relative incidence of human milk-associated CMV infection is very low with no developmental abnormality at 24-month follow-up (Lanzieri et al. 2013). Differences in CMV acquisition from fresh or frozen milk have been suggested, and short-term high-temperature pasteurization techniques were found to prevent CMV transmission more effectively than freezing.

Lactoferrin Supplementation Lactoferrin is a glycoprotein that in all mammals is involved in the innate immune response to sepsis. It is the major whey protein being present in colostrum and mature milk and is highly concentrated in the former (7 mg/mL) and more diluted in the latter (1 mg/mL), with a decrease that is slower in milk of premature neonates’ mothers. Bovine lactoferrin (BLF) and human lactoferrin (HLF) have high (77 %) amino acid homology, with BLF exhibiting even higher in vitro antimicrobial activity than HLF. Both lactoferrins resist proteolysis in the digestive tract, bind to specific receptors on enterocytes, and are poorly absorbed in the gut. Lactoferrin is a potent inhibitor of viruses, gram-positive cocci, gram-negative bacilli, and fungi including Candida spp. (Bizzarro et al. 2010). The involved mechanisms include direct actions towards membrane components, immunomodulatory effects, and a synergistic action with anti-infective drugs. Lactoferrin also has prebiotic properties, creating an enteric environment for the growth of beneficial bacteria and reducing colonization with pathogenic species. It has also direct intestinal immunomodulatory and antiinflammatory actions by affecting cytokine expression, mobilizing leucocytes into the

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circulation, and activating T cells. Lactoferrin undergoes partial acid proteolysis in the stomach to form lactoferricins, peptides with enhanced antimicrobial activity. This may explain partly the link between exposure to H2-receptor antagonists and the risk of late-onset invasive infection in very preterm infants (Terrin et al. 2012b, c). At high concentration, as in colostrum, lactoferrin enhances proliferation of enterocytes and closure of enteric gap junctions. At lower concentrations, lactoferrin stimulates differentiation of enterocytes and expression of intestinal digestive enzymes. Given the high homology between HLF and BLF, it might be argued that supplemented BLF overlaps with maternal milk in protecting against sepsis. Very preterm infants have low lactoferrin intake exacerbated by the delay in establishing enteral feeding. Enteral lactoferrin supplementation may therefore compensate for this gestational immunodeficiency.

Probiotics Probiotic supplementation may have the ability to inhibit pathogenic colonization and stimulate antiinflammatory effects. Probiotics may compete with pathogenic bacteria but may also have direct antimicrobial effects. Lactobacilli have been shown to secrete lactic acid to lower local pH, which inhibits the growth of pathogenic bacteria. Lactobacillus organisms are also known to communicate directly with pathogenic bacteria to reduce the pathogenic bacteria’s gene expression for binding to host cells. Clinical centers with higher rates of NEC are more likely to observe a benefit with probiotic supplementation. Extremely low-birth-weight infants may not benefit to the extent observed in those with greater GA or BW. Although reports of probiotic-related sepsis are limited, caution should be used when considering probiotic supplementation in infants at greatest risk for an impaired mucosal barrier (e.g., GI anomalies). Policies regarding storage, preparation, distribution, administration, and documentation of probiotics to ensure patient safety should be adopted. In conclusion, recent evidences indicate no definitive conclusions

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on the efficacy of probiotics to reduce NEC and sepsis in neonates (Mihatsch et al. 2012).

Lipid Supplementation MCFA and LC-PUFA have been associated with antimicrobial and antiviral activity in gastric lining and proximal small intestine of mammalian neonates. The n-3 PUFA supplementation during late infancy led to increased production of IFNγ during lipopolysaccharide-stimulated whole blood culture, suggesting more efficient immune response (Damsgaard et al. 2007). Similar effects were seen when the lactating mother received supplements during early infancy, and these efficiency gains persisted for at least 2 years (Thienprasert et al. 2009). Most of the formulas in Europe and the USA are currently supplemented with long-chain PUFA (Table 2). However, as membranes enriched with PUFA are particularly susceptible to oxidative damage, concern over the use of long-chain PUFA in infant formulas might suggest the need for a higher vitamin E intake (Table 2).

Iron Supplementation In two large recent studies of routine iron and folate supplementation in children younger than 3 years, supplementation was associated with an increased risk of infections confined to those living in an area of intense malarial transmission (Tielsch et al. 2006). In preterm neonates routine supplementation has been associated with positive effects on the immune system and long-term outcomes (Table 2) (Prentice 2008). Neonates born prematurely have a scarce iron reserve, and, thus, they should be considered subjects at high risk of iron deficiency. In two trials, milk fortification reduced morbidity due to respiratory disease, but these results were not confirmed in three later fortification studies. No systematic studies report advantages of oral iron supplementation on infectious morbidity in breastfed infants in non-malarial regions.

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Table 2 Recommended enteral nutrient intakes for preterm infants Macronutrients Energy, kcal Protein, mg Lipids, g (of which MCT 55 (0.9 % of fatty acids) 12–30 18–42 11.6–13.2 Per kg/day 2–3 1.1–2; 10 100–132 5–10 30–1,230 0.3–5  27.5 11–55 Per kg/day 1,300–3,300 800–1,000 3.3–16.4 4.4–28 45–300 0.1–0.77 11–46 1.7–16.5 35–100 380–5,500 0.33–2.1 200–400 140–300

Notes: Modified by Agostoni et al. 2010 AA arachidonic acid; DHA docosahexaenoic acid a The linolenic acid to a-linolenic acid ratio is in the range of 5–15:1 (wt/wt) b The ratio of AA to DHA should be in the range of 1.0–2.0 to 1 (wt/wt), and eicosapentaenoic acid (20:5n-3) supply should not exceed 30 % of DHA supply

Zinc Supplementation Zinc supplementation in children with diarrhea is associated with a significant reduction in length of symptoms (Passariello et al. 2012).

Preterm neonates have lower zinc reserves than term infants as about 60 % of fetal zinc is acquired during the third trimester of pregnancy. Preterm are also less efficient at absorbing and retaining zinc for growth. Adequate absorption may be compromised by limited intake and immature digestive and absorptive processes, whenever excessive endogenous losses occur secondary to either poorly regulated secretion or interference with reabsorption. Thus, premature neonates have relatively high dietary zinc requirements. Recently, it has been demonstrated that dose of zinc higher than those recommended (Table 3) may reduce incidences of NEC, but not of infectious diseases in preterm neonates (Terrin et al. 2013). Other studies evaluating the role of zinc in preventing infections in the first months of life are summarized in Table 3.

Vitamin A Several studies in different areas of the world, where there is generally poor nutritional status, have suggested that vitamin A supplementation in infancy may be associated with decreased mortality and morbidity. Routine supplementation trials have demonstrated improvements in measles and diarrheal disease morbidity (Villamor and Fawzi 2005). Routine supplementation for infants 5 days were randomized to PN isonitrogenous and isocaloric PN providing 25 kcal/kg/day and 1.2 g AA/kg/day (without or with 0.5 g/kg/day alanylGLN dipeptide); intent-to-treat analysis showed no impact of GLN-PN on infections other than a reduction in urinary tract infections in the GLN group (Grau et al. 2011).

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In a double-blind RCT in which GLN dipeptide was given as a separate intravenous (IV) infusion (0.28 g GLN/kg/day) versus IV saline placebo for the entire ICU stay in 413 patients receiving separate enteral and/or parenteral nutrition support as indicated, the GLN group demonstrated no change in illness severity scores, a significant decrease in ICU mortality, but no change in 6-month mortality (Wernerman 2011). In a 2  2 factorial design RCT from 10 ICUs in Scotland, 502 critically ill adults requiring PN were randomized to receive either a standardized PN formulation with or without L-GLN (20.2 g/day) and with or without selenium (500 μg/day) (Andrews et al. 2011). Subjects receiving GLN, without or with selenium (n = 250), did not demonstrate a difference in clinical outcomes (infections, mortality, and length of ICU or hospital stay); however, the exact dose of GLN given was uncertain, and the study PN was given for a short period of time, generally 5 days (Andrews et al. 2011). In an RCT conducted in 5 American hospitals, 150 critically ill patients with intestinal failure and requiring PN after cardiac, vascular, or intestinal surgery received isonitrogenous (1.5 g/kg/ day) and isocaloric PN (25 kcal/kg/day) without or with alanyl-GLN dipeptide (0.5 g/kg/day; equivalent to 0.33 g GLN/kg/day) provided in complete PN formulations given for an average of 12 days in each group; subjects receiving GLN-supplemented PN did not demonstrate different rates of infection, mortality, or other clinical outcomes compared to patients receiving GLN-free PN (Ziegler 2012). In the first study demonstrating adverse effects of GLN administration in ICU patients, Heyland and colleagues enrolled 1,223 adult ICU patients with shock, multiple organ failure, and respiratory failure from 40 ICUs in Canada, Europe, and the United States in a 2  2 factorial study, the REDOXS trial (Heyland et al. 2013). Subjects received the highest dose of GLN yet administered to patients by a combination of enteral and parenteral routes (0.6–0.8 g/kg/day), without or with a combination of enterally administered antioxidants (vitamin C, selenium, zinc, vitamin E, and beta-carotene) plus IV selenium; results showed no impact of the antioxidants; however,

K. Gundogan and T.R. Ziegler

the subjects in the glutamine arms demonstrated a significantly higher in-hospital and 6-month mortality (6 % absolute increase), particularly if renal failure was present (Heyland et al. 2013). However enteral + parenteral GLN was given independent of nutrition support, and the mean energy/protein intake was 1.5 kg/day) and energy (>2.3 MJ/day) and an attenuated postprandial endogenous secretion of GLP-2 (Jeppesen et al. 2001). GLP-2 compliance was >99 %. Evaluated in metabolic balance studies, treatment with GLP-2 (400 400 μg mu;g BID s.c., corresponding to 0.013  0.020 mg/kg/day, range 0.011–0.017 mg/kg/day)

P.B. Jeppesen

significantly increased the intestinal absorption of energy from 49.9 to 53.4 % ( p = 0.04), wet weight (from 25 to 36 %), and nitrogen (from 47.4 to 52.1 %, p = 0.04). Fecal wet weight excretion decreased by 0.49  0.53 kg/day ( p = 0.04). Urine volume increased by 0.23  0.44 kg/day, but this did not reach statistical significance. Body weight increased (1.2  1.0 kg) and lean body mass increased (2.9  1.9 kg), whereas fat mass decreased (1.8  1.3 kg) significantly in relation to the treatment. The 24 h urine creatinine excretion increased 0.7  0.7 mmol/day from 8.6  1.2 to 9.3  1.9 mmol/day (p < 0.02). The time to 50 % gastric emptying of solids increased by approximately 30 min, whereas GLP-2 did not significantly affect the gastric emptying of fluids. Small bowel transit time was not changed. Crypt depth and villus height were increased in five and six patients, respectively. The overall mean increase in small bowel villus heights (10  19 %, p = 0.14) and crypt depths (18  42 %; p = 0.28) did not reach statistical significance. A negative correlation was found between the residual jejunal length and the effect of GLP-2 on the absolute (r = 0.85; p = 0.002) and relative wet weight absorption (r = 0.85; p = 0.002), indicating that patients with the shortest bowel benefitted more in wet weight absorption. Thus, when maintaining oral intake constant, treatment with native GLP-2 increased intestinal wet weight absorption and thereby diminished fecal wet weight excretions. Overall, the positive effects on the relative intestinal energy and macronutrient absorption were in the magnitude of 5 %, whereas effects on wet weight and electrolyte absorption were in the magnitude of 10 % in short-term studies employing a low GLP-2 dose. Results on the long-term effects treatment with native GLP-2 in SBS patients were published in 2009 (Jeppesen et al. 2009). Eleven SBS patients were treated with GLP-2 (400 μg, s.c., TID, corresponding to 0.018  0.020 mg/kg/day, range 0.014–0.020 mg/kg/day) for 2 years keeping parenteral support constant. Seventytwo-hour nutritional balance studies were performed at baseline, at Weeks 13, 26, and 52 during 2 years intermitted by an 8-week washout period. In addition, mucosal morphometrics,

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renal function (calculated by creatinine clearance), body composition and bone mineral density (by DEXA), biochemical markers of bone turnover (by s-CTX and osteocalcin, PTH, and vitamin D), and muscle function (NMR, lung function, exercise test) were measured. GLP-2 compliance was >93 %. In the eight patients who completed the study, GLP-2 treatment reduced fecal weight significantly by approximately 1.0 kg/day from approximately 3.0 to approximately 2.0 kg/day ( p < 0.001) and enabled the SBS patients to maintain their intestinal fluid and electrolyte absorption at equivalently lower oral intakes still maintaining the urinary weight constant. No significant changes were demonstrated in the oral energy intake or absorption, and GLP-2 did not significantly affect mucosal morphology, body composition, bone mineral density, or muscle function. Based on these findings, it seemed that providing GLP-2 at each meal (TID), and thereby in higher daily dose and for a longer period, had better effects compared to 35 days of GLP-2 given BID. If reductions in parenteral support were not performed in relation to treatment with GLP-2, the improved intestinal wet weight absorption translated into a reduction in oral fluid intake in the SBS patients. Findings from these pioneering native GLP-2 studies inspired the investigational plan for the conduction of the phase 2 and phase 3 teduglutide studies.

Teduglutide Teduglutide is a 33-amino-acid glucagon-like peptide 2 (GLP-2) analog created by substitution of alanine by glycine in the second position of the peptide. Teduglutide has a mean terminal half-life (t1/2) of approximately 2 h in healthy subjects and 1.3 h in SBS subjects (NPS Pharmaceuticals 2012) compared to the half-life of GLP-2 of only 7 min. Results from the first clinical pharmacology phase 2 study of teduglutide in SBS patients (referred to as Study 92001) were published in 2005 (Jeppesen et al. 2005). The effects of teduglutide on intestinal absorptive capacity and

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intestinal trophicity were evaluated in a metabolic balance study that assessed the wet weight (~weight of diet and beverages) and energy intake against output (as measured by fecal wet weight and urine output). The oral intake and parenteral support (PS) of energy and wet weight was required to be maintained constant to enable assessment of changes in intestinal absorption during each of three controlled inpatient admissions to a metabolic research unit. PS-dependent adult patients with stable SBS due to various underlying etiologies and with diverse intestinal remnant anatomies were enrolled. The participants were treated with teduglutide at doses of 0.03 (n = 3), 0.1 (n = 10), and 0.15 (n = 4) mg/kg/day for 21 days and were then followed for 21 days off treatment. Seventy-two hour nutrient balances were performed to evaluate effects of teduglutide administration on absolute and relative absorption as well as stomal or fecal output of gastrointestinal (GI) wet weight, sodium, potassium, energy, fat, and nitrogen during the three admissions (at baseline, last 3 days of treatment, and after 3 weeks of follow-up). Endoscopies were also performed to obtain intestinal biopsy samples for histopathological examination (Jeppesen et al. 2005). In the 17 patients completing the study, teduglutide decreased fecal wet weight, sodium, potassium, energy, fat, and nitrogen. The average effects of teduglutide on intestinal absorption are given in Table 1. On average, teduglutide decreased GI wet weight losses (fecal or ostomy output) by approximately 800 mL per day and increased absolute GI wet weight absorption by approximately the same amount (each p < 0.001 vs. baseline). This represented a 30 % reduction in fecal wet weight losses from baseline, which correlated with an increase in urine output of ~550 mL/day ( p < 0.001 vs. baseline). Teduglutide at the 0.10 and 0.15 mg/kg/day doses produced increases in fluid and nutrient absorption, but there was no difference between the doses. There was less evidence to determine an effect from the 0.03 mg/kg/day dose possibly due to the few patients studied. Providing the 0.10 mg/kg/day teduglutide dose BID in five jejunostomy SBS-IF patients did not significantly

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Table 1 Mean change from baseline to end of treatment of nutrient, electrolyte, and energy absorption and fecal excretion in Study 92001 Pooled groupsa (n = 17) Mean absolute absorption Fecal/stomal output

Fat, g/day 11.2 11.5*

Nitrogen, g/day 2.0* 1.7**

Sodium, g/day 0.6 0.6

Potassium, g/day 0.4* 0.4*

Calories, kcal/day 203 258.5**

*P < 0.05 **P < 0.01 a Pooled data from dosing groups: 0.03, 0.10, and 0.15 mg/kg daily and 0.05 and 0.075 mg/kg twice daily (NPS Pharmaceuticals 2012)

increase the effects. Effects were of the same magnitude in SBS patients with and without a colon in continuity (Jeppesen et al. 2005). Teduglutide increased villus height and crypt depth in the intestinal mucosa, thereby increasing the overall absorptive surface area of the intestine, in a manner similar to that observed in preclinical models using GLP-2 (Drucker et al. 1996). In patients with jejunostomies receiving teduglutide doses of 0.03 mg/kg/day (n = 2) and 0.10 mg/kg/ day (n = 6), respectively, the histologic changes were significant, with an increase in villus height of 38  45 %, p = 0.03; crypt depth of 22  18 %, p = 0.01; and mitotic index of 115  108 %, p = 0.01. In the group of five SBS patients with colon in continuity, crypt depth increased in four patients following teduglutide treatment, but the mean increase of 13  22 % did not reach statistical significance ( p = 0.330), and the increase in mitotic index was also nonsignificant (76  112 %; p = 0.170). Small bowel biopsies to determine villus height were not obtained in this patient group. Absorption of D-xylose at 2 h resulted in increases in plasma concentrations in 14 of 16 patients in relation to teduglutide treatment, but the increase did not quite reach statistical significance ( p = 0.06). The gains in absorption and in villus heights during treatment with teduglutide were reversed after teduglutide discontinuation, underscoring that the observed effects were teduglutide dependent (Jeppesen et al. 2005). In summary, the phase 2 study demonstrated that teduglutide decreased nutrient excretion, increased energy absorption (in a post hoc defined subpopulation of patients with a constant energy intake), decreased GI wet weight and

electrolyte losses, and thereby improved intestinal wet weight absorption. Teduglutide showed evidence for structural adaptation through an increase in villus height and crypt depth. These findings supported the use of the 0.10 mg/kg/day dose for the evaluation of teduglutide in phase 3 studies. However, since metabolic balance studies are complex and require inpatient admissions to a metabolic research unit, the phase 3 studies were conducted using a more practical but still clinically relevant outpatient design. The selection of endpoints in this setting took into account assessments that would be considered meaningful to SBS patients and clinicians. Thus, a reduction of at least 20 % in PS was selected as a key outcome measure since this would represent a 1-day-perweek reduction in the need for PS in most patients. The patient disposition of the phase 3 studies is given in Fig. 2. In Study 004, the primary endpoint was expanded beyond the percentage of patients who achieved response (i.e., 20 % reduction in PS volume at Weeks 20 and 24) to characterize more completely the reduction in PS volume: thus, the primary endpoint for this phase 3 study included a description of both intensity and duration of response (graded categorical response), beginning as early as Week 16 (Jeppesen et al. 2011). A 20 % or greater volume reduction responder definition was included as a key secondary endpoint. In the pivotal 020 study, which was designed as a confirmatory trial of the 0.05 mg/kg/day dose based on results from the 004 study, the primary endpoint was at least a 20 % reduction in PS volume achieved at both Week 20 and Week 24 (Jeppesen 2012). The graded categorical response that was

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Fig. 2 Patient disposition in phase 3 teduglutide studies. PS parenteral support

the primary endpoint in Study 004 was included as a secondary endpoint in Study 020. Additional secondary endpoints based upon PS volume at Week 24 included: mean percent change from baseline, mean absolute change from baseline, duration of response, and the number of patients with at least a 1-day reduction in PS infusion. Study 004 (Jeppesen et al. 2011) and Study 020 (Jeppesen 2012) were similar in many design elements (Fig. 2). Both were 24-week prospective, randomized, double-blind, placebocontrolled, parallel-group, multinational, and multicenter studies conducted in the United States, Canada, and Europe. Both enrolled adults (18 years of age) with SBS due to diverse causes (e.g., Crohn’s disease, vascular disease, volvulus, injury, and others) who were dependent on PS for at least 12 months and required PS at least 3 times per week. Study 004 included teduglutide doses of 0.10 and 0.05 mg/kg/day, while Study 020 included only the 0.05 mg/kg/day dose.

In both studies (Jeppesen et al. 2011; Jeppesen 2012), PS requirements were optimized and stabilized for up to 16 weeks before randomization to accurately establish baseline values for intake of fluid and nutrients and to achieve urine output of 1–2 l per day. Patients were asked to maintain stable oral intake so that increased intestinal fluid absorption would be reflected in increased urinary output. Fecal output was not measured in this outpatient study. During the treatment period, increased intestinal fluid absorption should have demonstrated increased urine output, allowing the investigator to reduce PS volume in those patients who were deemed clinically stable. Thus, the protocol specified consistent oral intake so that reductions in PS volume would reflect increases in fluid absorption. In both studies, the investigators followed a protocol-defined weaning algorithm that allowed PS volume adjustments based on 48 h urinary output and assessments of overall hydration and clinical status. However, there were important

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Fig. 3 Fluid composite effect in Study 004. Overall effects of placebo, teduglutide 0.10 mg/kg/day, and teduglutide 0.05 mg/kg/day at baseline and Weeks 4, 8, 12, 16, 20, and 24 on the composite effect, which is the sum

of the combined beneficial effects of reduction in oral fluid intake, increase in urine volume, and reduction in daily parenteral volume based on the 48 h measurements at home

differences between the algorithms used in each study. The Study 004 protocol limited the maximum amount by which PS volume could be reduced to 10 % beginning at Week 4 and then monthly. By contrast, in Study 020, PS volume reductions began at Week 2 and were as high as 30 % of the baseline level. Close monitoring of clinical status, including hydration, was required in both studies. The two phase 3 studies were followed by open-label extension studies, the 004 study by a 28-week study designated the 005 study and the 020 study by a 2-year study designated the 021 study (Fig. 2). In the 004 study, the graded categorical response rate, which was the primary study outcome, was not significantly different from placebo in the teduglutide 0.10 mg/kg/day group (8/32 vs. 1/16, p = 0.16) at Week 24, although a greater frequency of higher category responses was seen (Jeppesen et al. 2011). To gain further understanding about the effect of teduglutide, it was decided to explore the effect of the 0.05 mg/kg/day dose on the primary endpoint. These results showed a statistically significant improvement compared with placebo in the graded categorical response rate for the 0.05 mg/kg/day teduglutide dose group (16/35, p = 0.007). However, parenteral volume reductions at Week 24 were similar in both treatment groups (353  475 and 354  334 mL/day equivalent to 2.5 L/week). Therefore, one explanation for the observation that the higher

teduglutide dose did not reach the primary endpoint of the study was that baseline parenteral volume was somewhat higher in the 0.10 mg/kg/ day group compared with the 0.05 mg/kg/day group (1,816  1,008 vs. 1,374  639 mL/day equivalent to 12.9  6.7 vs. 10.5  5.3 L/week, p = 0.11). In addition, the oral fluid intake decreased by approximately 350 mL/day, and the parenteral volume decreased by approximately 350 mL/day in the 0.10 mg/kg/day teduglutide dose group. This decrease in oral intake was detrimental to the study outcome. It resembled the findings from the long-term native GLP-2 study (Jeppesen et al. 2009). It was believed that a more aggressive PS reduction could have alleviated this unintended effect. However, in the 0.05 mg/kg/ day teduglutide dose group, oral intake was constant, and urine volume even increased by approximately 350 mL/day, and the parenteral volume was decreased by more than 350 mL/day. Overall, by calculating the fluid composite effect (Fig. 3), which represents the sum of beneficial effects (reduction in oral intake + reduction in PS volume + increase in urine volume), it was estimated that the true effect of either teduglutide dose on intestinal wet weight absorption probably was around 700 mL/day (i.e., 4.9 L/week), closely reflecting the effects demonstrated in the phase 2 study (Jeppesen et al. 2005). At Week 24, there was a significant mean reduction in parenteral energy support in patients receiving the 0.05 mg/kg/day

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teduglutide dose from baseline (912  1,333 kJ/day = 218  318 kcal/day, p = 0.001). This reduction also closely matched improvements in energy absorption demonstrated in the phase 2 study. However, the reduction in PS energy was not significantly different between patients receiving the 0.05 mg/kg/day teduglutide dose and those receiving placebo (243  450 kJ/day = 58  107 kcal/day, p = 0.11). In addition, findings from intestinal biopsies in Study 004 affirmed the pharmacodynamic effect of teduglutide, as both teduglutide doses induced expansion of the absorptive epithelium by increasing villus height in the small intestine (40  37 %, 0.05 mg/kg/day, p = 0.0065, and 47  42 %, 0.10 mg/kg/day, p = 0.0024), while villus height decreased (24  28 %) in the placebo group. Plasma citrulline, an amino acid produced by enterocytes serving as a biomarker of a reduced enterocyte mass, increased significantly by 67  67 % and 113  84 % (both p < 0.0001), in relation to treatment with teduglutide at the 0.05 mg/kg/day and 0.10 mg/kg/day doses, respectively. During the 24-week study, two patients in the 0.05 mg/kg/day group achieved complete independence from PS versus none in the placebo group. Twenty-five of the patients who received 0.05 mg/kg/day teduglutide in the 24-week placebocontrolled study opted to continue into the 28-week open-label extension 005 study for a combined treatment period of 52 weeks (Fig. 2). Among these 25 patients, 68 % achieved 20 % reduction of PS volume. The mean parenteral fluid volume reduction was 4.9 L/week (equivalent to a 52 % reduction from baseline levels), and the parenteral energy reduction was 14,690 kJ/week or 2,100 kJ/day (equivalent to 3,511 kcal/week or 500 kcal/day, respectively). The frequency of delivery of PS was reduced by 1 or more days in 68 % of these patients. Furthermore, by Week 52, three patients were PS independent (O’Keefe et al. 2013). Thus, while the 0.10 mg/kg/day dose in the 004 study did not meet the primary endpoint, there was significant evidence that teduglutide even at the 0.05 mg/kg/day dose achieved a clinically meaningful effect. Therefore, the

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Fig. 4 Absolute changes in parenteral support volume (PN/IV) in relation to treatment with teduglutide or placebo

0.05 mg/kg/day teduglutide dose was chosen for the confirmatory phase 3 Study 020. The primary endpoint in Study 020 was the number of responders, defined as patients who achieved a 20 % or greater reduction in PS volume at Week 20 and Week 24 compared to baseline (Jeppesen 2012). The responder rate in the 0.05 mg/kg/day treatment group (27/43 patients, 62.8 %) was greater than that observed in the placebo group (13/43 patients, 30.2 %, p = 0.002). The absolute change in parenteral fluid volume requirements up to Week 24 in Study 020 is shown in Fig. 4. Significant differences from placebo emerged by Week 4 and persisted with longer duration of treatment. All secondary endpoints statistically favored teduglutide, including the ordered categorical response variable used as the primary endpoint in Study 004 ( p = 0.004). Teduglutide-treated SBS-IF patients achieved an average weekly PS volume reduction of 4.37  3.8 L/week ( 32 % from baseline) while maintaining oral fluid intake constant throughout the study (Fig. 5). Placebo-treated patients had average PS fluid reductions of 2.29  2.7 L/week ( 21 %) but significantly increased their

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Fig. 5 Absolute changes at Week 24 from baseline in parenteral support (PS) volume, oral fluid volume, and urine output volume in relation to treatment with teduglutide or placebo

oral fluid intake by 1.58  3.6 L/week ( p < 0.009) in order to maintain stable target urine output of 1.0–2.0 L/day (Fig. 5). In patients treated with teduglutide, urine output continued to increase, indicating increased in intestinal net fluid absorption. Even at the end of the trial, further weaning appeared possible in patients treated with teduglutide. The significant PS volume reduction with teduglutide translated into additional clinical benefit: at the end of the treatment period (at Week 24), the need for PS infusion was reduced by 1 or more days in more than half of the patients in the teduglutide group (53.8 %, 21/39) compared with less than one quarter of those in the placebo group (23.1 %, 9/39; p = 0.005) (Jeppesen 2012). The positive findings on functional adaptation in relation to teduglutide were supported by findings on the structural adaptation. Teduglutide resulted in a significant increase in plasma citrulline concentration from baseline levels. At baseline, mean  SD plasma citrulline concentration values were 18.4  9.5 0 μmol/L and 17.5  9.0 μmol/L in the teduglutide and placebo groups, respectively. At 24 weeks, the mean  SD increase over baseline in plasma citrulline concentration was 20.6  17.5 μmol/L in the teduglutide group versus 0.7  6.3 μmol/L in the placebo group ( p < 0.0001). In the open-label 021 extension study (Fig. 2), 88 patients were scheduled to receive 0.05 mg/kg/ day of teduglutide for an additional 2 years. In an interim analysis, 68 % of 74 patients who received 12 months of 0.05 mg/kg/day teduglutide had a >20 % reduction of PS volume. A reduced frequency of PS by 1 or more days was achieved by

51 % of these patients. Overall, 14 % of the 88 patients enrolled in the study had become PS independent after treatment durations that ranged from 28 weeks to 114 weeks (Fujioka et al. 2013). Thus, more than 90 % of SBS patients who completed their participation in either of the placebo-controlled teduglutide trials (004 or 020) elected to continue treatment in the longterm extension studies demonstrating a high patient acceptance of the continued treatment. As of October 2012, 15 of 134 patients treated with teduglutide 0.05 mg/kg/day dose in either of the two placebo-controlled studies or their extensions had achieved complete independence from PS. The patients achieved independence as early as 3 months and as late as 28 months after initiation of teduglutide treatment (Iyer et al. 2013).

Adverse Reactions to Teduglutide Treatment The total trial experience of teduglutide encompasses 566 individuals who were exposed to at least one dose of teduglutide (190 patient-years of exposure; mean duration of exposure was 17 weeks) during the clinical development program. Of the 566, 173 patients were treated in the two SBS double-blind, placebo-controlled studies (Studies 004 and 020): 134/173 (77 %) at the dose of 0.05 mg/kg/day and 39/173 (23 %) at the dose of 0.10 mg/kg/day (Jeppesen et al. 2011; Jeppesen 2012). In general, teduglutide was well tolerated with the distribution of discontinuation of treatment due to adverse events being similar between

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Table 2 Adverse reactions in 5 % of teduglutide-treated SBS subjects and more frequent than placebo in Studies 004 and 020

Adverse reaction Abdominal pain Upper respiratory tract infection Nausea Abdominal distension Vomiting Fluid overload Flatulence Hypersensitivity Appetite disorders Sleep disturbances Cough Skin hemorrhage Subjects with stoma Gastrointestinal stoma complicationa

Placebo (n = 59) n (%) 16 (27) 8 (14)

Teduglutide (n = 77) 0.05 mg/kg/day n (%) 29 (38) 20 (26)

12 (20) 1 (2) 6 (10) 4 (7) 4 (7) 3 (5) 2 (3) 0 (0) 0 (0) 1 (2)

19 (25) 15 (20) 9 (12) 9 (12) 7 (9) 6 (8) 5 (7) 4 (5) 4 (5) 4 (5)

3 (14)a

13 (42)a

a Percentage based on 53 subjects with a stoma (n = 22 placebo and n = 31 teduglutide 0.05 mg/kg/day) (NPS Pharmaceuticals 2012)

patients given teduglutide and placebo (Jeppesen et al. 2011; Jeppesen 2012). The adverse event (AE) profile was generally consistent with the underlying disease condition and the known mechanism of action of teduglutide: the most frequently reported AEs were GI related (Table 2). The most commonly reported (10 %) adverse reactions in patients treated with teduglutide across all clinical studies (n = 566) were abdominal pain (30.0 %), injection site reactions (22.4 %), nausea (18.2 %), headaches (15.9 %), abdominal distension (13.8 %), and upper respiratory tract infection (11.8 %). The rates of adverse reactions that were reported in 5 % of teduglutide-treated SBS patients and more frequent than placebo in the randomized, placebocontrolled, 24-week, double-blind clinical studies (Study 004 and Study 020) are summarized in Table 2. The majority of these reactions were mild or moderate. Of patients receiving teduglutide at the recommended dose of 0.05 mg/kg/day, 88.3 % (N = 68/77) experienced an

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adverse reaction, as compared to 83.1 % (49/59) for placebo. Many of these adverse reactions were reported in association with the underlying disease and/or PS (NPS Pharmaceuticals 2012). Of note, diarrhea, which was a main complaint of SBS patients, was more commonly reported in the placebo group (11.9 % vs. 6.4 % with teduglutide). Based on the pharmacologic activity and findings in animals, teduglutide has the potential to cause hyperplastic changes including neoplasia (Thulesen et al. 2004). In patients at increased risk for malignancy, the clinical decision to use teduglutide should be considered only if the perceived benefits outweigh the risks. In patients with active gastrointestinal malignancy (GI tract, hepatobiliary, or pancreatic), teduglutide therapy should be discontinued. In patients with active non-gastrointestinal malignancy, the clinical decision to continue teduglutide should be made based on risk-benefit considerations (NPS Pharmaceuticals 2012). Intestinal obstruction has been reported in clinical trials. In patients who develop intestinal or stomal obstruction, teduglutide should be temporarily discontinued while the patient is clinically managed. Teduglutide may be restarted when the obstructive presentation resolves, if clinically indicated (NPS Pharmaceuticals 2012). Cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies. For identification of the onset or worsening of gallbladder/ biliary disease, patients should undergo laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting teduglutide and at least every 6 months while on teduglutide or more frequently if needed. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or biliary tract is recommended; and the need for continued teduglutide treatment should be reassessed (NPS Pharmaceuticals 2012). Pancreatitis has been reported in clinical studies. For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of lipase and amylase within 6 months prior to starting teduglutide and at least every 6 months while on teduglutide or more

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frequently if needed. If clinically meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended; and the need for continued teduglutide treatment should be reassessed (NPS Pharmaceuticals 2012). Fluid overload and congestive heart failure have been observed in clinical trials, which were felt to be related to enhanced fluid absorption associated with teduglutide. If fluid overload occurs, parenteral support should be adjusted and teduglutide treatment should be assessed, especially in patients with underlying cardiovascular disease or if cardiac deterioration develops while on teduglutide (NPS Pharmaceuticals 2012). Altered mental status in association with teduglutide treatment has been observed in patients on benzodiazepines in clinical trials. Patients on concomitant oral drugs (e.g., benzodiazepines, phenothiazines) requiring titration or with a narrow therapeutic index may require dose adjustment while on teduglutide (NPS Pharmaceuticals 2012).

Quality of Life in Relation to Teduglutide Treatment Effects on quality life were examined in the two phase 3 studies. In the 004 study, the overall results from three quality-of-life assessments (SF-36, EuroQol EQ-5D, and IBDQ) were unable to detect significant effects of teduglutide on quality-of-life parameters compared to placebo. The validated Short Bowel Syndrome-Quality of Life (SBS-QoL™) scale (Berghofer et al. 2013) was developed for the 020 study to explore changes in this in relation to PS reduction and in relation to placebo and teduglutide treatments. PS reductions were associated with QoL improvements (ANCOVA, p = 0.0194, SBS-QoL per protocol). Compared to baseline, teduglutide significantly improved the SBS-QoL™ total score and the score of 9 of 17 items at Week 24. These changes were, however, not significant compared to placebo. The short observation period, imbalances in oral fluid intake in patients receiving placebo in relation to PS reductions, large patient

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and effect heterogeneity, and the occurrence of gastrointestinal adverse effects in a subgroup of teduglutide-treated patients may have accounted for the inability to show statistically significant effects of teduglutide on SBS-QoL™ scores compared to placebo (Jeppesen et al. 2013).

Cost of Teduglutide According to NPS Pharmaceutical, the costs of the development program of teduglutide/Gattex ® have been around US$250 million. On January 2, 2013, NPS Pharmaceutical announced that it was pricing teduglutide/Gattex ® at US$295,000 per patient per year. The company estimated that as few as 3000 SBS-IF patients would be available for treatment in the United States. According to NPS Pharmaceuticals, approximately half of the US-based patients would be on commercial insurance. Another third would be on Medicare and the rest would get Gattex ® for free. http://www. forbes.com/sites/matthewherper/2013/01/03/insidethe-pricing-of-a-300000-a-year-drug/. In Europe, teduglutide/Revestive ® has been approved for marketing, but it has not yet been launched. No information on the anticipated European pricing exists.

Summary Recently, the US Food and Drug Administration and European Medicines Agency have given the regulatory approval of teduglutide based on their evaluations of the clinical relevance and positive benefit/risk ratio in the treatment of SBS-IF patients. Teduglutide represents the first evidence-based, effective, long-term treatment modality introduced to this orphan patient population, where pharmacological treatments up til now mainly have relied on experience-based antidiarrheal and antisecretory agents. Teduglutide seems to provide a clinically meaningful increase in intestinal absorption in most SBS-IF patients, as evidenced by decreases in diarrhea and fecal losses of fluids, electrolytes, and macronutrients in the phase 2, metabolic

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Fig. 6 Consequences of improved intestinal absorption in relation to teduglutide treatment. PS parenteral support

balance study. Accordingly, in phase 3 studies, by increasing intestinal absorption, teduglutidetreated SBS-IF patients could be weaned from parenteral support based on their increases in urine production. After treatments with teduglutide at a dose of 0.05 mg/kg/day for 3–28 months, more than 10 % of the SBS-IF patients could be entirely weaned off PS. Considering the combined data across all clinical studies, the targeted effects of teduglutide in the intestine translated into a 30–40 % reduction in PS volume from baseline at 6 months, which allowed approximately half of the teduglutide-treated SBS-IF patients to achieve at least one additional day off PS each week. Even in the most severe SBS-IF patients, where days off PS cannot be provided, reductions in infusion times from 16 to 10 h per day may alleviate the distress of the condition (Fig. 6). The adverse events profile and safety issues in relation to teduglutide treatment seem predictable from the physiological actions of the drug. A postmarketing registry evaluating possible teduglutide complications in relation to long-term treatment is scheduled. It is the hope that teduglutide – in patients with adverse events individually doseadjusted according to tolerability – will optimize intestinal absorption, decrease malabsorption and accompanying symptoms, and reduce the fear, burdens, or complications related to PS, thereby ultimately improving the health-related quality of life in these severely disabled SBS-IF patients. The development program of teduglutide has set high scientific standards for future clinical

trials within the field of short bowel syndrome. It has, however, also displayed the high cost of drug development for this orphan condition. This is now reflected in the high price of teduglutide on the American market (US$300,000 per patient per treatment year). It may be a poor consolation to those unfortunate patients, who cannot afford the drug, but it is possible that the marketing of teduglutide will increase the general awareness of the short bowel syndrome. The low incidence and prevalence of SBS-IF patients reported in some countries and regions may be due to underreporting, but could also suggest that many patients faced with SBS and acute intestinal failure are not even considered for this lifesaving therapy. Healthcare professionals may lack the knowledge that a long-term survival without a bowel is indeed possible, if PS is provided. PS may also be declined or rationed due to inability to manage the care of these patients in the acute postoperative setting. Financial or logistical barriers may also exist. In situations where lack of knowledge, skills, and resources are not to blame, it seems unethical that patients with acute SBS and intestinal failure are left to die, if they, in the same setting, would have been provided with, e. g., dialysis when faced with renal failure. The bringing of awareness to the condition is important, since SBS-IF patients constitute less than 10 % of the number of patients requiring dialysis for chronic renal failure. Therefore, national and regional strategies should facilitate the referral and centralization of these rare patients to dedicated “centers of excellence.” The provision of a

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sufficient patient volume will be needed to allow the multidisciplinary “centers of excellence” to adapt the organization and requirements needed to provide proper quality of care and the best possible mental and physical rehabilitation of these unfortunate patients.

entirely eliminate the need for, provide days off, or reduce the time spent on parenteral support. • A reduction in parenteral support is associated with improvements in the quality of life in SBS-IF patients.

Applications to Critical or Intensive Care and other Conditions

References

GLP-2 or analogs could theoretically benefit any condition, where the integrity of the intestinal mucosa is disrupted. This could include inflammatory conditions, such as Crohn’s disease and Ulcerative Colitis, and chemotherapy-induced mucositis. GLP-2 and analogs could also maintain intestinal barrier function in critically ill subjects, thus preventing bacterial translocation. The potential applications of GLP-2 and teduglutide outside the short bowel syndrome indication are still speculative. However, finding from the SBS development program and the commercial availability of teduglutide may inspire further preclinical and clinical studies with this pluripotent peptide.

Summary Points • Glucagon-like peptide 2 and the analog teduglutide ameliorates some of the pathophysiological features of the short bowel syndrome. GLP-2 or teduglutide tends to restore gastric emptying and intestinal transit, reduce gastric and intestinal hypersecretion, and enhance bowel trophicity. • These structural and functional improvements in the process of intestinal adaptation improve intestinal absorption and reduce fecal excretions. • In SBS patients with intestinal failure, the consequent improvements in intestinal absorption facilitate weaning from parenteral support. • Depending on the degree of intestinal failure and the response of the individual SBS patient to treatment, the reduction in parenteral support in relation to GLP-2 or teduglutide may

Berghofer P, Fragkos KC, Baxter JP, et al. Development and validation of the disease-specific Short Bowel Syndrome-Quality of Life (SBS-QoL) scale. Clin Nutr. 2013;32:789–96. Bjerknes M, Cheng H. Modulation of specific intestinal epithelial progenitors by enteric neurons. Proc Natl Acad Sci U S A. 2001;98:12497–502. Bremholm L, Hornum M, Henriksen BM, et al. Glucagonlike peptide-2 increases mesenteric blood flow in humans. Scand J Gastroenterol. 2009;44:314–9. Bremholm L, Hornum M, Andersen UB, et al. The effect of Glucagon-Like Peptide-2 on mesenteric blood flow and cardiac parameters in end-jejunostomy short bowel patients. Regul Pept. 2011;168:32–8. Brubaker PL, Izzo A, Hill M, et al. Intestinal function in mice with small bowel growth induced by glucagonlike peptide-2. Am J Physiol. 1997;272(6 Pt 1): E1050–8. Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58: 1091–103. Drucker DJ, Erlich P, Asa SL, et al. Induction of intestinal epithelial proliferation by glucagon- like peptide 2. Proc Natl Acad Sci U S A. 1996;93:7911–6. Dudrick SJ, Wilmore DW, Vars HM, et al. Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Ann Surg. 1969;169: 974–84. Estall JL, Drucker DJ. Glucagon-like peptide-2. Annu Rev Nutr. 2006;26:391–411. Fujioka K, Seidner DL, Delmaestro E, et al. Teduglutide in patients with intestinal failure associated with short bowel syndrome: combined data from phase III trials. J Parenter Enteral Nutr. 2013;37:138–49. Henriksen DB, Alexandersen P, Hartmann B, et al. Fourmonth treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone. 2009;45:833–42. Hoyerup P, Hellstrom PM, Schmidt PT, et al. Glucagonlike peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients. Regul Pept. 2013;180:12–6.

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Ivory CP, Wallace LE, McCafferty DM, et al. Interleukin10-independent anti-inflammatory actions of glucagonlike peptide 2. Am J Physiol Gastrointest Liver Physiol. 2008;295:G1202–10. Iyer K, Joelsson B, Heinze H,, Jeppesen PB. Complete enteral autonomy and Independence from Parenteral Nutrition/Intravenous Support in short bowel syndrome with intestinal failure – accruing experience with teduglutide. Gastroenterology. 2013. Oral presentation at Digestive Disease Week, Orlando, 18–21 May 2013. Jeppesen PB. Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome. Ther Adv Gastroenterol. 2012;5:159–71. Jeppesen PB. Short bowel syndrome – characterisation of an orphan condition with many phenotypes. Expert Opin Orphan Drugs. 2013a;1:515–25. Jeppesen PB. The non-surgical treatment of adult patients with short bowel syndrome. Expert Opin Orphan Drugs. 2013b;1:527–38. Jeppesen PB, Mortensen PB. Intestinal failure defined by measurements of intestinal energy and wet weight absorption. Gut. 2000;46:701–6. Jeppesen PB, Hartmann B, Hansen BS, Thulesen J, Holst JJ, Mortensen PB. Impaired meal stimulated glucagonlike peptide 2 response in ileal resected short bowel patients with intestinal failure. Gut. 1999a;45:559–63. Jeppesen PB, Langholz E, Mortensen PB. Quality of life in patients receiving home parenteral nutrition. Gut. 1999b;44:844–52. Jeppesen PB, Hartmann B, Thulesen J, et al. Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon. Gut. 2000;47:370–6. Jeppesen PB, Hartmann B, Thulesen J, et al. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology. 2001;120:806–15. Jeppesen PB, Sanguinetti EL, Buchman A, et al. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54:1224–31. Jeppesen PB, Lund P, Gottschalck IB, et al. Short bowel patients treated for two years with glucagon-like peptide 2: effects on intestinal morphology and absorption, renal function, bone and body composition, and muscle function. Gastroenterol Res Pract. 2009;2009:616054. Jeppesen PB, Gilroy R, Pertkiewicz M, et al. Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut. 2011;60: 902–14. Jeppesen PB, Pertkiewicz M, Forbes A, et al. Quality of life in patients with short bowel syndrome treated with the

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new glucagon-like peptide-2 analogue teduglutide – analyses from a randomised, placebo-controlled study. Clin Nutr. 2013;32:713–21. Messing B, Pigot F, Rongier M, et al. Intestinal absorption of free oral hyperalimentation in the very short bowel syndrome. Gastroenterology. 1991;100:1502–8. NPS Pharmaceuticals. GATTEX® (teduglutide [rDNA origin]) for injection. Prescribing information. 2012. http://www.npsp.com/file_depot/0-10000000/0-10000/ 262/folder/2023/Gattex_PI-IFU_FINAL_2012-12-21.pdf O’Keefe SJ, Jeppesen PB, Gilroy R, et al. Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel syndrome intestinal failure. Clin Gastroenterol Hepatol. 2013;11:815–23. Orskov C, Hartmann B, Poulsen SS, et al. GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul Pept. 2005;124:105–12. Seidner DL, Schwartz LK, Winkler MF, et al. Increased intestinal absorption in the era of teduglutide and its impact on management strategies in patients with short bowel syndrome-associated intestinal failure. J Parenter Enteral Nutr. 2013;37:201–11. Shils ME, Wright WL, Turnbull A, et al. Long-term parenteral nutrition through an external arteriovenous shunt. N Engl J Med. 1970;283:341–4. Sigalet DL, Wallace LE, Holst JJ, et al. Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2. Am J Physiol Gastrointest Liver Physiol. 2007;293:G211–21. Spiller RC. Feedforward and feedback control mechanisms in the gut. With special emphasis on inhibitory feedback by nutrients in the distal small bowel and colon. Dig Dis. 1990;8:189–205. Spiller RC, Trotman IF, Adrian TE, et al. Further characterisation of the ‘ileal brake’ reflex in man– effect of ileal infusion of partial digests of fat, protein, and starch on jejunal motility and release of neurotensin, enteroglucagon, and peptide YY. Gut. 1988;29: 1042–51. Thulesen J, Hartmann B, Hare KJ, et al. Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice. Gut. 2004;53:1145–50. Wojdemann M, Wettergren A, Hartmann B, et al. Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs. Scand J Gastroenterol. 1998;33: 828–32. Wojdemann M, Wettergren A, Hartmann B, et al. Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2. J Clin Endocrinol Metab. 1999;84:2513–7. Yusta B, Huang L, Munroe D, et al. Enteroendocrine localization of GLP-2 receptor expression in humans and rodents. Gastroenterology. 2000;119:744–55.

Intestinal Failure and Parenteral Omega-3 Fatty Acid Lipid Emulsions

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Contents

Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1939

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1930

Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1939

Intestinal Failure-Associated Liver Disease (IFALD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1931

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1939

Risk Factors and Pathogenesis for IFALD . . . . . . 1931 The Role of Parenteral Lipid Emulsions in IFALD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1933 Understanding the Role of Lipid Emulsions in IFALD: Basic Science . . . . . . . . . . . . . . . . . . . . . . . . . . 1933 The Role of Omega-3-Containing Lipid Emulsions in IFALD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1935 Applications to Critical or Intensive Care . . . . . . 1936 Applications to Critical or Intensive Care: IFALD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1936 Applications to Critical or Intensive Care: Inflammation and Oxidative Stress . . . . . . . 1937 Applications to Critical or Intensive Care: Omega-3 Lipid Emulsions Benefit . . . . . . . . 1937 Applications to Critical or Intensive Care: Using Omega-3 Emulsions Caution . . . . . . 1938

J.M. Turner (*) Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada e-mail: [email protected] P.W. Wales Group for Improvement of Intestinal Function and Treatment (GIFT), Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, ON, Canada e-mail: [email protected] # Her Majesty the Queen in Right of Canada 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_61

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Abstract

Intestinal failure will occur in intensive care patients, necessitating the use of parenteral nutrition. It is not known how commonly such patients will develop intestinal failureassociated liver disease (IFALD). Furthermore, liver disease is observed in intensive care patients, independent of parenteral nutrition. Therefore, it is not clear if omega-3 lipid emulsions will benefit intensive care patients, to improve liver disease, as now reported in IFALD. However, omega-3 lipid emulsions may have other benefits in critically ill patients, including immune modulation and reduction in oxidative stress. At this time it is not clear if the benefits for IFALD, or indeed for immune function, are specifically related to the addition of omega-3 lipid or to concomitant reduction in omega-6 lipid.

List of Abbreviations

AA BSEP CCK DHA EFAD EN EPA FXR ICU IFALD

Arachidonic acid Bile salt export pump Cholecystokinin Docosahexaenoic acid Essential fatty acid deficiency Enteral nutrition Eicosapentaenoic acid Farnesoid-X-receptor Intensive care/intensive care unit Intestinal failure-associated liver disease IVLE Intravenous lipid emulsion LA Linolenic acid LCPUFA Long-chain polyunsaturated fatty acid LPS Lipopolysaccharide MCT Medium-chain triglyceride PICU Pediatric intensive care or intensive care unit PN Parenteral nutrition PNALD Parenteral nutrition-associated liver disease TXA2 Thromboxane A2

J.M. Turner and P.W. Wales

Introduction Intestinal failure is arguably best defined by a given temporal requirement for parenteral nutrition support in order to maintain health and in childhood to grow. The minimum time for either full or partial parenteral nutrition (PN) support to meet this definition has been variable, such that no consensus diagnosis truly exists. Common definitions include 42 days of parenteral nutrition support (Wales et al. 2004), 3 weeks of PN providing 75 % of total calories, 3 months providing 50 % (Guarino et al. 2003), or, alternatively, 28 days of any PN support (Barclay et al. 2011). Neonates are at greatest risk of PN complications occurring over a short period of time. In children, intestinal failure is most commonly encountered among premature infants with short bowel syndrome. This may be due to either congenital shortening, as with ileal or jejunal atresia, or following surgical resection, usually due to necrotizing enterocolitis. Motility disorders, such as gastroschisis or Hirschsprung disease, and congenital mucosal disorders, such as tufting enteropathy or microvillus inclusion disease, would also be more common among pediatric causes. In adults, the most common cause of intestinal failure would again be short bowel syndrome, secondary to surgical resection from inflammatory bowel diseases, trauma, ischemic injury, or malignancy. While these traditional causes of intestinal failure necessitate many months or years of PN support, the term has also been applied over periods as short as 14 days, coined Type I or acute intestinal failure (Gardiner 2011). Hence, given the high rates of gastrointestinal dysfunction and feeding intolerance among intensive care patients, the condition must be observed in the critical care setting. In reality the incidence of intestinal failure, and its complications, in critical care patients is unknown. Probably because it is most often seen in conjunction with and overshadowed by multiorgan failure. Furthermore, there is no intensive care-specific definition of intestinal failure,

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and the timing and duration of PN support necessary to increase the risks of this complication in critical care patients is not well understood. Nevertheless, intestinal failure is a contributor to morbidity in intensive care, particularly by increasing the risk of sepsis and hence overall mortality. In intensive care intestinal failure may be classified as acute, often reversible, or chronic and potentially, but not necessarily, irreversible. Acute intestinal failure will most often be due to ileus, in the setting of surgery or sepsis, abdominal or systemic, or secondary to medications, such as opiates and benzodiazepines. Abdominal surgery complicated by multiple adhesions or enterotomies, ischemic bowel injury in the setting of cardiac surgery or shock, and patients admitted to intensive care with traditional causes of intestinal failure will account for most chronic causes. Unlike stable patients with chronic intestinal failure for whom transplantation is an important therapeutic option, many patients in an intensive care unit, with multiorgan failure, will not be candidates for transplantation. Therefore, prevention of complications will be a priority in this setting.

Intestinal Failure-Associated Liver Disease (IFALD) Traditionally, chronic intestinal failure has been associated with a high mortality, without intestinal transplantation. This has been reported as 38 % in infants with intestinal failure secondary to short bowel syndrome (Wales et al. 2004) and 22 % in infants hospitalized with all causes for intestinal failure (Pichler et al. 2012). Mortality is most often due to PN-related complications of sepsis and liver disease. These same complications are also observed in adult home PN patients, although much less frequently. In adults, 1 year all-cause mortality is lower, at only 14 % (Lloyd et al. 2006). The term intestinal failure-associated liver disease (IFALD) recognizes etiological factors for this condition related to both the use of PN and to factors unique to intestinal failure, including

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patient factors and its causation. However, this diagnosis is not considered in the absence of PN. Therefore, how this diagnosis applies to intensive care patients, who require PN and coincidentally develop liver disease, is unclear. In intensive care PN there are many causes of liver disease (Table 1). Therefore, how well prevention and treatment strategies developed for more traditional IFALD will translate to an intensive care population requires further investigation. Given the paucity of IFALD research specific to this population, the discussion will focus on traditional IFALD. This includes hepatic steatosis, steatohepatitis, intrahepatic and extrahepatic cholestasis (including biliary sludge and cholelithiasis), and cirrhosis. In neonatal onset IFALD, cholestasis dominates, with early onset and rapid progression.

Risk Factors and Pathogenesis for IFALD In 1968 a new era in the management of intestinal failure patients began, when the first patient with short bowel syndrome was discharged home on PN (Dudrick et al. 1968). Recognition of IFALD quickly followed (Peden et al. 1971). At the time PN consisted of glucose, protein hydrolysates, electrolytes, and vitamins. Therefore, this first report also highlights that parenteral lipid is only one potential risk factor. The etiological factors for IFALD should be viewed as host specific and PN specific. Decreased or absent enteral intake is a key risk factor in all cases, probably due to decreased nutrient-stimulated release of gastrointestinal hormones, such as cholecystokinin (CCK). Reduced enteral intake contributes to intestinal dysmotility and dysbiosis. Experimental animal models suggest that bacterial overgrowth and translocation have a role in hepatic inflammation (Lichtman et al. 1990). Prematurity is the major host factor; therefore, liver maturation is likely important in the pathogenesis. The premature infant has reduced hepatic bile salt synthesis, a smaller bile salt pool, and

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Table 1 Common liver injuries observed in intensive care patients Hypoxicischemic liver injury

Predominant biochemical findings Rapid rise in hepatic transaminases, later cholestasis, often with early-onset synthetic dysfunction and other organ dysfunction

Inflammatory injury

More gradual onset of mixed hepatitis and cholestasis, with or without synthetic dysfunction

Biliary sludge

Mainly cholestasis

Drug-induced liver injury

Can be predominant hepatitis, cholestasis, or mixed picture, with our without synthetic dysfunction

Post liver transplantation

Usually mixed hepatitis and cholestasis with hepatic dysfunction

hence reduced enterohepatic circulation (Watkins et al. 1975). Immature amino acid metabolism may also increase both the risk of excess and deficient amino acid delivery. This may particularly be the case related to cysteine, methionine, and glutathione metabolism (Vina et al. 1995). Surgical short bowel syndrome also increases the risk of IFALD, with greater risk associated with inflammatory causes, such as necrotizing enterocolitis, cancer, and inflammatory bowel diseases. These conditions are associated with surgical resection of the terminal ileum, again reducing bile salt reuptake and enterohepatic circulation. Sepsis, independent of intestinal failure, can cause cholestasis, particularly in developing humans, who are vulnerable to recurrent sepsis. In IFALD, sepsis has repeatedly been shown to either precede or exacerbate the cholestasis. Sources for sepsis include the need for long-term indwelling central venous catheters as well as dysbiosis and bacterial translocation as discussed. Pro-inflammatory cytokines elaborated following endotoxin exposure have been shown to downregulate molecular mechanisms underlying bile acid transport (Ghose et al. 2004). PN-related risk factors in IFALD include feeding excess calories and specific amino acid and trace element excess or deficiency. That excess

Specific risk factors Shock Cardiac failure Pulmonary failure Trauma Postoperative vascular thrombosis SIRS with multiorgan failure Sepsis Postoperative Neurosurgery ECMO Many drugs implicated, e.g., corticosteroids, propofol, antibiotics, antiepileptics, amiodarone, etc. Primary graft nonfunction Vascular injury, including hepatic or portal vein thrombosis Hyperacute rejection

calories have been implicated is relevant to the intensive care setting, where a mismatch of energy delivery to actual metabolic demands is common. Excess glucose administration is a well-known risk factor for hepatic steatosis, including with PN (Kaminski et al. 1980). Increased protein delivery has been associated with cholestasis (Vileisis et al. 1980). Taurine is required for bile synthesis, and taurine supplementation increases bile flow in animal models, although the advent of taurine containing amino acid solutions has not improved IFALD (Hata et al. 2002). Cysteine is often deficient, even in current amino acid solutions, and N-acetylcysteine improved IFALD in a single-center report (Mager et al. 2008). Methionine is likely in excess in current amino acid solutions and has been implicated in animal models of IFALD (Moss et al. 1999). Deficiency of choline has been associated with hepatic steatosis that can be reversed with supplementation (Buchman et al. 2001). Carnitine supplementation in contrast does not appear to improve IFALD (Bowyer et al. 1988). Manganese has been implicated in the development of IFALD. Children on long-term PN have excess blood manganese levels that correlate with the degree of cholestasis (Fell et al. 1996). Since manganese is excreted in bile, accumulation

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Table 2 Composition of lipid emulsions Brand name Intralipid (manufacturer) (Fresenius Kabi) Oil (g/L) Soybean 200 Olive MCT Fish Fatty acid composition (%wt total): Linoleic (18:2ω-6) 53 Arachidonic acid 0.1 (20:4ω-6) α-Linolenic 8 (18:3ω-3) Docosahexaenoic 0 acid (22:6ω-3) Oleic acid (18:1ω-9) 24 Phytosterolsa ++ α-Tocopherol 87 (μmol/L)

ClinOleic (Baxter)

Lipofundin (Braun)

SMOFLipid (Fresenius Kabi)

Omegaven (Fresenius Kabi)

40 160

100

60 50 60 30

100

100

18.7 0.5

29.1 0.2

37.2 1

4.4 2.1

2.3

4.5

4.7

1.8

0.5

0

4.4

12.1

62.3 ++ 75

11 + 502

55.3 + 500

15.1 505

Table adapted from Wanten and Calder, Am J Clin Nutr (2007;85(5):1171–84), American Society for Nutrition Indicated to be present in increasing concentration according to plus sign (plant contaminant present in plant-based oil)

a

is likely given in any cholestatic liver disease. Similarly, copper is also potentially hepatotoxic, has biliary excretion, and can accumulate in cholestatic liver diseases; however, its role in IFALD appears limited (Frem et al. 2010).

The Role of Parenteral Lipid Emulsions in IFALD Parenteral lipid emulsions have been implicated in IFALD pathogenesis in children and adults, specifically plant-based lipid emulsions, the firstgeneration lipid emulsions and the most widely used. Using multiple-variable analysis in a large cohort of intestinal failure patients, the odds of developing severe cholestasis (defined as a serumconjugated bilirubin >100 umol/l or >5.8 mg/dL) increased 4 % for every single day that parenteral lipid doses exceeded 2.5 g/kg/day (Diamond et al. 2011). This would translate to a child having severe cholestasis within as little as 60 days of PN therapy, with lipids provided at or above this threshold. In adults, a lipid dose in excess of

1 g/kg/day is related to the development of IFALD (Cavicchi et al. 2000). The composition of commonly used parenteral lipid emulsions is shown in Table 2. Plant-based emulsions may contribute to IFALD in a number of key ways particularly related to their long-chain polyunsaturated fatty acid content (LCPUFA). IFALD may relate to accumulation of plantbased phytosterols (Llop et al. 2008) or to inflammation and/or oxidative stress promoted by the high omega-6 LCPUFA content (Basu et al. 1999; Broughton and Wade 2002; Grimm et al. 1994). In addition, the active form of vitamin E contained in the lipids (α-tocopherol) varies considerably and may be inadequate to prevent complications from oxidative stress.

Understanding the Role of Lipid Emulsions in IFALD: Basic Science Long-chain polyunsaturated fatty acids (LCPUFA) are incorporated in a dose-dependent manner into cell phospholipid membranes and

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Fig. 1 Molecular mechanism of bile transport. Bile salt transport into hepatocytes is mainly via sodium-taurocholate cotransporting polypeptide (NTCP), and less so via organic anion-transporting protein (OATP). Bile transport into the canaliculus (the rate-limiting step for extrahepatic bile flow) involves multiple carrier proteins for bile salts and other bile constituents, including cholesterol, phosphatidylcholine, and drugs (not all shown). Multidrug resistance-associated protein 2 (MRP2) has high affinity for divalent bile salts. Bile salt export pump (BSEP), the main transporter, has high affinity for primary monovalent bile salts. Multidrug-resistant transporter (MDR3) has high affinity for phosphatidylcholine. The organic soluble transporter (OSTα) functions as an efflux pump, upregulated in the presence of nonphysiologic levels of intrahepatic bile salts (i.e., cholestasis). Also shown is the major regulator of bile transport, farnesoid-X-receptor (FXR), and its actions within the hepatocytes (indicated by arrows, +/ ). Factors that regulate FXR expression are shown on the right

other tissues. Hence, they are involved in cell signaling, gene transcription, and cell membrane structure and fluidity, all of which may directly impact bile transport. These may well be the most important, but least studied, mechanism by which lipid emulsions alter bile flow. It is more often supposed that the production of eicosanoids involved in immune function leads to cytokine imbalances that may cause direct hepatocellular and/or bile canalicular damage. Animal models that induce cholestasis, such as by bile duct ligation, demonstrate that omega-3 fatty acids reduce hepatic inflammation and early fibrosis, presumably the result of bile acid toxicity (Chen et al. 2012). LCPUFAs are the major substrates producing eicosanoids for immune signaling. Eicosanoids arising from omega-6 fatty acids (thromboxane A2, leukotrienes B4, C4, D4, prostaglandins D2, E2, and F2, and prostacyclin I2) are considered to have a primarily pro-inflammatory function (Broughton and Wade 2002). Those arising from omega-3 fatty acids (leukotrienes B5, C5, D5, prostaglandins D3, E3, and F3) are considered to be anti-inflammatory. Both series contribute to inflammation resolving omega-6-derived lipoxins and omega-3-derived resolvins and protectins

(Anderson and Delgado 2008). Hence, excess or deficiency of either will likely have deleterious effects on immune function and promote oxidative stress (Grimm et al. 1994). In addition to a role in immune modulation, omega-6 eicosanoids can directly reduce bile flow, presumably a signaling role independent of immunological function (Beckh et al. 1994). In Fig. 1 the molecular signaling important for intrahepatic bile flow is demonstrated. Reuptake and intrahepatic secretion of bile salts are major determinants of extrahepatic bile flow. This process is regulated by the terminal ileum, principally by the nuclear farnesoid-X-receptor (FXR) (Davis and Attie 2008). In the ileum, activation of FXR increases transcription of fibroblast growth factor 19, then it is transported in portal blood to the liver where it downregulates bile synthesis in hepatocytes, again via FXR (Modica et al. 2012). Therefore, it is understandable why patients with intestinal failure who lack ileum are at risk for IFALD, given reduced enterohepatic circulation and potentially increased bile acid synthesis. However, this is not likely to be relevant in intensive care, given most patients will have ileum. In the liver, FXR upregulates expression of the major canalicular transporter, the bile salt export

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pump (BSEP). Most bile salts are agonists of FXR and will increase expression of BSEP. Phytosterol contaminants present in plant-based lipid emulsions are antagonists (Carter et al. 2007). In neonatal piglets intravenous administration of phytosterols will reduce bile flow, which appears related to inhibition of bile transport function out of hepatocytes in vitro (Iyer et al. 1998). There are emerging roles for FXR in regulation of inflammation in the liver, likely to be relevant for IFALD in intensive care. FXR activation appears to be protective in rodent models of inflammation and fibrosis (Wang et al. 2008a). Furthermore, FXR knockout mice have increased levels of markers of hepatic oxidative stress (Nomoto et al. 2009). Lipid emulsions containing plant-based phytosterols may theoretically act as antagonists of FXR and increase susceptibility to hepatic injury, when given to critically ill patients with inflammation. The molecular mechanisms that have been studied in critically ill patients with cholestasis do suggest that FXR expression may be reduced associated with a downregulation of BSEP and increase in de novo bile acid synthesis (Vanwijngaerden et al. 2011). It is not stated if the patients were on PN including plant-based lipid emulsions.

The Role of Omega-3-Containing Lipid Emulsions in IFALD The justification of considering fish oil lipid emulsions as an alternate to plant oil-based emulsions will be clear following the previous discussion. Studies in neonatal piglets given total parenteral nutrition first showed improved bile flow with omega-3-rich fish oil-based lipid compared to plant-based omega-6-rich lipid (Van Aerde et al. 1999). Subsequently case reports emerged of patients with IFALD improving when switched from Intralipid ® to Omegaven ® (Gura et al. 2006). Many reports of improving biochemical evidence for pediatric IFALD by use of fish oil emulsions, in various dose regimens, either with or without additional soy lipid, have followed (Diamond et al. 2009; Muhammed et al. 2012; Puder et al. 2009).

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Table 3 Theoretical advantages of omega-3 lipid emulsions, including in the ICU Putative mechanisms to improve cholestasis in IFALD Direct improvement of bile flow via eicosanoid-mediated actions Reduction of phytosterols that directly reduce bile flow Indirect improvement in inflammation May reduce LCPUFA content and hence lipid peroxidation Have higher α-tocopherol content and greater antioxidant potential

Based on the prior discussion, the potential mechanisms for fish oil-based emulsions to improve IFALD are summarized in Table 3. However, it is possible that the major advantage of fish oil lipid emulsions has simply been reduction in omega-6 LCPUFA dose delivery. This is supported by a successful treatment of IFALD by lipid minimization, without omega-3 LCPUFA supplementation (Cober et al. 2012). At this time no controlled clinical trials comparing equivalent doses of omega-6- or omega-3-containing emulsions in the treatment or prevention of IFALD have been published. In addition to the concern over lack of contemporary controlled data, other controversies exist regarding use of omega-3 lipid emulsions. Excess doses of omega-6 or omega-3 fatty acids that result in extreme ratios of one to the other may not support optimal immune function (Grimm et al. 1994). In infants there also exists a concern over the risk of essential fatty acid deficiency (EFAD). This has been dismissed on the basis of normal triene/tetraene ratios in existing cohort studies (de Meijer et al. 2010). An increased ratio will be observed when insufficient LA is supplied or when there is competitive inhibition, principally by omega-3 fatty acids, of LA to AA. While an increase in triene to tetraene ratio has been reported in patients on Omegaven ®, this has only been observed without clinical symptoms of EFAD (Puder et al. 2009). However, EFAD is probably being underreported given reliance on a ratio when suboptimal supply of both triene and tetraene precursors is likely. In intensive care, perhaps more than the concern over EFAD limiting growth, there is the

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potential for AA deficiency to promote bleeding. This has not yet been reported in the IFALD population given omega-3 lipid emulsions. Theoretically, bleeding time can be increased by high doses of omega-3 fatty acids competitively inhibiting AA production, hence decreasing thromboxane A2 production (TxA2) (Kim et al. 1995). However, oral fish oil supplements do not seem to exert a greater antiplatelet effect than aspirin (Svaneborg et al. 2002). Furthermore, parenteral fish oil supplementation does not appear to increase the risk of bleeding following major abdominal surgery (Heller et al. 2002).

Applications to Critical or Intensive Care Malnutrition is a significant problem in intensive care (ICU) patients, particularly for the very young and the elderly, or any patient who enters ICU with depleted protein-energy stores. However, ICU patients are also at risk of overfeeding, as energy requirements are difficult to predict without direct measurement and are not readily related to clinical status (Mehta et al. 2011). For those patients in the ICU who require parenteral nutrition, lipid emulsions are an important source of energy. Excess glucose delivery promotes lipogenesis and excess CO2 production while at the same time reducing fat oxidation (Coss-Bu et al. 2001). Hyperglycemia compromises lung and liver function and increases the risk of sepsis. In contrast, acute negative health consequences from hypertriglyceridemia are less evident. The risks of lipid infusions in ICU, concern over sepsis, oxidative stress, and inflammation, are more theoretical than clearly elucidated.

Applications to Critical or Intensive Care: IFALD However defined, the majority of patients requiring PN in the ICU will do so because of intestinal failure. Given adequate intestinal function, enteral nutrition (EN) is preferred. EN is not without

J.M. Turner and P.W. Wales

risks, the most serious being gut ischemia, with risk of perforation, necrosis, and resection, another cause for intestinal failure in ICU. Increasing rates of necrotizing enterocolitis, in term infants following complex congenital heart surgery, are an emerging ICU intestinal failure population. While gastrointestinal dysfunction is frequent in ICU patients, the majority of patients can continue receiving EN, including by the transpyloric route (Sanchez et al. 2007). Concerns over the risk of gut ischemia or the adequacy of nutrition support, given frequent interruptions to enteral delivery, are common reasons to use PN. The latter is so common that combination of PN and EN in the ICU has become commonplace, despite limited evidence for benefit (Dhaliwal et al. 2004). The most likely patient group to benefit from such approach will be pediatric patients, especially neonates, also at greatest risk of IFALD. Liver dysfunction, based on biochemistry, occurs as frequently as in 61 % of adult ICU patients not receiving PN (Thomson et al. 2009). Sepsis is the major identified risk factor for cholestasis in the ICU (Field et al. 2008). Early-onset liver dysfunction is a predictor of poorer outcome in adult ICU patients; however, PN is not clearly implicated (Kramer et al. 2007). Very little research has focused on the role of PN in ICU liver dysfunction, although it does appear to increase the risk, it’s an uncommon cause (Grau et al. 2007). Given greater use of PN in PICU to meet increased energy needs, the increased risk of IFALD in neonates is probably more common. In PICU, de Lucas et al. found PN use associated with cholestasis more often than transpyloric EN (de Lucas et al. 2000). Specific risk factors for cholestasis may be more common in contemporary PICU practice, including complex cardiac surgery and ECMO (Vazquez et al. 2001; Walsh-Sukys et al. 1992). In a randomized controlled trial of an omega-3supplemented lipid emulsion compared to standard plant-based emulsion, Heller et al. showed improved liver function in cancer patients undergoing major abdominal surgery (Heller et al. 2004). A randomized trial of ICU patients

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with sepsis found less hepatic steatosis with fish oil lipid compared to a mixed LCT/MCT lipid emulsion (Sungurtekin et al. 2011). However, the very small sample size and the poor sensitivity of ultrasound limit the validity of these findings.

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severe inflammation and counter-regulatory immunosuppression. These patients have pronounced oxidant stress and waning antioxidant defenses, exacerbated by the use of PN.

Applications to Critical or Intensive Care: Omega-3 Lipid Emulsions Benefit Applications to Critical or Intensive Care: Inflammation and Oxidative Stress Beyond reduction in cholestasis, the potential benefits of omega-3 lipid emulsions in the ICU would include reduction of sepsis, inflammation, and oxidative stress. Therefore, the first question must be, what is the evidence that these are exacerbated with the use of plant-based lipid emulsions in this setting? In pediatric patients in critical care, particularly given longer length of stay, PN may be a risk factor for sepsis (Rey et al. 2011; Wylie et al. 2010). This evidence is limited by being observational. In a randomized trial in adult ICU patients, to PN with or without lipids, sepsis and length of ventilation increased when given plant-based lipids (Battistella et al. 1997). Unfortunately, the study is confounded by lower total calorie delivery in the group not given lipid. A more contemporary trial using PN only when EN was impossible did not find a negative impact of PN on sepsis rates (Doig et al. 2013). While risk of infection is an important core clinical outcome in the ICU, unfortunately, most studies have used only surrogate outcomes of inflammation and oxidative stress and have not linked those to important clinical outcomes. The in vitro and in vivo studies are often confounded by high doses of lipid. Overall a negative impact of plant-based lipids on immune function is not supported (Wirtitsch et al. 2007). Using a rigorous crossover study design, in the absence of inflammation, parenteral fish oil does not alter immune function relative to soy in the short term (Versleijen et al. 2012). This is not to say that the potential risks of plant-based lipids are not relevant in the ICU. Many ICU patients, particularly given prolonged admission, experience both

Retrospective data in adult patients suggests perioperative use of PN containing fish oil improves overall mortality, length of ventilation, and hospital stay after gastrointestinal surgery (Tsekos et al. 2004). In critically ill patients with pancreatitis, surrogate markers of inflammation, pulmonary and renal function all improved when fish oil was combined with standard PN therapy over 5 days (Wang et al. 2008). Small randomized trials of adult ICU patients have shown improved measures of oxidant stress and antioxidant status with omega-3 lipid emulsions (Antebi et al. 2004; Linseisen et al. 2000). Unfortunately, prospective studies have not confirmed clinical benefits (Barbosa et al. 2010; Khor et al. 2011). The benefit seems to be diagnosis dependent, with more utility in surgical than medical ICU patients (Heller et al. 2006). Meta-analyses confirmed surgical patients can have improved clinical and laboratory parameters when given omega-3 lipid emulsions perioperatively (Chen et al. 2010; Wei et al. 2010). In contrast no benefit is found in more mixed ICU (Palmer et al. 2013; van der Meij et al. 2011). A caveat to older studies included in such reviews is recognition of the tendency to hypercaloric feeding historically in the ICU. A randomized trial in burn patients found dose restriction of omega-6 lipid improved outcomes to an equivalent degree as the addition of omega-3 lipids (Garrel et al. 1995). Hence, a similar controversy exists regarding the benefit of omega-3 lipids being more related to dose restriction of omega-6 lipids, as in the IFALD literature. The pediatric data is much more limited, and while systematic review does not yet support the use of omega-3 lipid emulsions in PICU, this is primarily due to lack of randomized controlled data (Seida et al. 2013).

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Applications to Critical or Intensive Care: Using Omega-3 Emulsions Caution Potential for adverse events when using omega-3 lipid emulsions in the ICU must not be forgotten. Risk of bleeding has been discussed. In addition, the immune function of patients in the ICU fluctuates widely over time from immune activation

to suppression, and this process is poorly understood. The use of parenteral lipids to modulate immune status has potential both to reduce immune activation and to enhance immune suppression. Theoretically, this could lead to increased risk of sepsis and decrease survival. Additional randomized trials in ICU patients, given appropriate and equivalent total calories from PN, varying only in lipid emulsion, will help clarify risks and benefits.

Table 4 Summary guidelines for the use of omega-3 lipid emulsions in the ICU Title Guidelines for specialized nutritional and metabolic support in the critically-ill patient (Montejo Gonzalez et al. 2011; Ortiz Leyba et al. 2011)

Year 2011

Author SEMICYUCSENPE

Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient (McClave et al. 2009)

2009

SSCM ASPEN

ASPEN Clinical Guidelines: Nutrition support of the critically ill child (Mehta et al. 2009)

2009

ASPEN

ESPEN Guidelines on parenteral nutrition: intensive care (Singer et al. 2009)

2009

ESPEN

ESPEN Guidelines on parenteral nutrition: hepatology (Plauth et al. 2009)

2009

ESPEN

Canadian Clinical Practice Guidelines for nutrition support in mechanically ventilated, critically ill adult patients (Heyland et al. 2003)

2003

CCC-CPGC

Recommendation for omega-3 lipid emulsions Liver failure and liver transplantation: It is recommended to use lipid emulsions containing ω-3 fatty acids in patients with liver disorders during parenteral nutrition Septic patient: If parenteral nutrition is used, it is recommended to use lipid emulsions with low contents in ω-6 emulsions containing ω-3 may be used in these patients No specific comment In the first week of hospitalization in the ICU when PN is required and EN is not feasible, patients should be given a parenteral formulation without soy-based lipids No specific comment Based on the available pediatric data, routine use of immunonutrition in critically ill children is not recommended Addition of EPA and DHA to lipid emulsions has demonstrable effects on cell membranes and inflammatory processes Fish oil lipid emulsions probably decrease length of stay in critically ill patients In alcoholic steatohepatitis and cirrhosis: Lipid should be provided using emulsions with a content of n-6 unsaturated fatty acids lower than in traditional pure soybean emulsions There are insufficient data to make a recommendation on the type of lipids to be used in critically ill patients receiving PN

Evidence Grade B

Grade B Grade C

Grade D

Grade D

Grade B

Grade B Grade C

N/A

SEMICYUC Spanish Society of Intensive Care Medicine and Coronary Units, SENPE Spanish Society of Parenteral and Enteral Nutrition, SSCM Society for Critical Care Medicine, ASPEN American Society for Parenteral and Enteral Nutrition, ESPEN European Society for Parenteral and Enteral Nutrition, CCC-CPGC Canadian Critical Care Clinical Practice Guidelines Committee

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Guidelines and Protocols • No guidelines or protocols address IFALD, or omega-3 lipid emulsions for treatment of IFALD, in ICU. At this time guidelines for using omega-3 lipid emulsions in intestinal failure populations have not been developed. A summary of guidelines for the ICU that are relevant, as they relate to the use of PN or nutrition management in liver diseases, are shown in Table 4. Recommendations on use of omega-3 lipid emulsions in European guidelines reflect greater access to the alternative intravenous lipid emulsions (IVLEs) compared to North America. In 2012, ASPEN published a position paper on the role of alternative IVLEs (Vanek et al. 2012). It concluded that evidence for use of alternative IVLEs is not clear. Research priorities identified included identifying patients who would benefit from EPA and DHA, identifying the ideal admixture available, identifying priority clinical uses, more research on use of fish oil in IFALD, and clarifying the dose of fish oil for optimal benefit and minimal risk. Finally, it must be remembered that the major issue for ICU patients is poor outcome from overfeeding macronutrients, particularly during the acute injury phase, as well as worsening malnutrition, particularly given prolonged admission. Furthermore there is good evidence that adherence to feeding protocols will optimize the use of EN in the ICU (Mackenzie et al. 2005). EN has never been directly compared to the use of PN including alternate lipid emulsions and may be more advantageous and cost-effective, whenever possible.

Summary Points • Lipids are a necessary part of nutrition support, including in ICU. • EN is preferred whenever possible, and use of EN can be optimized in ICU. • Omega-3 parenteral lipids may have a role in ICU, when exclusive EN is not possible, to

• • •

•

•

•

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prevent cholestasis and to decrease inflammation and oxidative stress. Most experience with omega-3 lipid emulsions for treatment of cholestatic liver disease arises outside the intensive care setting. Intestinal failure in the ICU is common, often acute and potentially reversible. IFALD is multifactorial, secondary to patient factors and PN composition. Plant-based lipid emulsions may promote cholestasis due to high omega-6 LCPUFA content, phytosterol content, and low antioxidant content. Omega-3 lipid emulsions may prevent cholestasis by improving bile flow through production of less inflammatory eicosanoids and by reduction in total omega-6 LCPUFA content. Although omega-3 lipid emulsions show promise, the overall quality of evidence in the literature is poor, and more controlled trials are necessary. In addition, potential risks need to be explored specifically in the ICU, including the potential to worsen immunosuppression in some patients.

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1942 Muhammed R, Bremner R, Protheroe S, Johnson T, Holden C, Murphy MS. Resolution of parenteral nutrition-associated jaundice on changing from a soybean oil emulsion to a complex mixed-lipid emulsion. J Pediatr Gastroenterol Nutr. 2012;54(6):797–802. Nomoto M, Miyata M, Yin S, Kurata Y, Shimada M, Yoshinari K, et al. Bile acid-induced elevated oxidative stress in the absence of farnesoid X receptor. Biol Pharm Bull. 2009;32(2):172–8. Ortiz Leyba C, Montejo Gonzalez JC, Vaquerizo Alonso C, Metabolism, Nutrition Working Group of the Spanish Society of Intensive Care M, Coronary U. Guidelines for specialized nutritional and metabolic support in the critically-ill patient: update. Consensus SEMICYUC-SENPE: septic patient. Nutr Hosp. 2011; 2:67–71. Palmer AJ, Ho CK, Ajibola O, Avenell A. The role of ω 3 fatty acid supplemented parenteral nutrition in critical illness in adults: a systematic review and meta-analysis. Crit Care Med. 2013;41(1):307–16. Peden VH, Witzleben CL, Skelton MA. Total parenteral nutrition. J Pediatr. 1971;78(1):180–1. Pichler J, Horn V, Macdonald S, Hill S. Intestinal failureassociated liver disease in hospitalised children. Arch Dis Child. 2012;97(3):211–4. Plauth M, Cabre E, Campillo B, Kondrup J, Marchesini G, Schutz T, et al. ESPEN guidelines on parenteral nutrition: hepatology. Clin Nutr. 2009;28(4):436–44. Puder M, Valim C, Meisel JA, Le HD, de Meijer VE, Robinson EM, et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg. 2009;250(3):395–402. Rey C, Alvarez F, De-La-Rua V, Concha A, Medina A, Diaz JJ, et al. Intervention to reduce catheter-related bloodstream infections in a pediatric intensive care unit. Intensive Care Med. 2011;37(4):678–85. Sanchez C, Lopez-Herce J, Carrillo A, Mencia S, Vigil D. Early transpyloric enteral nutrition in critically ill children. Nutrition. 2007;23(1):16–22. Seida JC, Mager DR, Hartling L, Vandermeer B, Turner JM. Parenteral omega-3 fatty acid lipid emulsions for children with intestinal failure and other conditions: a systematic review. JPEN J Parenter Enteral Nutr. 2013;37(1):44–55. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr. 2009;28(4): 387–400. Sungurtekin H, Degirmenci S, Sungurtekin U, Oguz BE, Sabir N, Kaptanoglu B. Comparison of the effects of different intravenous fat emulsions in patients with systemic inflammatory response syndrome and sepsis. Nutr Clin Pract. 2011;26(6):665–71. Svaneborg N, Kristensen SD, Hansen LM, Bullow I, Husted SE, Schmidt EB. The acute and short-time effect of supplementation with the combination of n-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids. Thromb Res. 2002;105(4):311–6.

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148

€rkay, Aslıhan Tug, Sıtkı Nadir Sinikoglu, Meltem Tu Yakup Tomak, Mehmet Salih Sevdi, Serdar Demirgan, and Aysin Alagol

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1946 Applications to Intensive Care . . . . . . . . . . . . . . . . . . . Ventilator-Associated Pneumonia . . . . . . . . . . . . . . . . . . Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glutamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1946 1946 1949 1949 1951

Applications to Other Conditions . . . . . . . . . . . . . . . . 1953 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1953 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1954 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1954

M. T€urkay (*) • S.N. Sinikoglu • M.S. Sevdi • S. Demirgan • A. Alagol Department of Anesthesiology and Reanimation, Bagcılar Training and Research Hospital, Istanbul, Turkey e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] A. Tug Department of Anesthesiology and Reanimation, Istanbul Training and Research Hospital, Istanbul, Turkey e-mail: [email protected] Y. Tomak Department of Anesthesiology and Reanimation, Faculty of Medicine, Sakarya University, Sakarya, Turkey e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_76

Nosocomial infections are an important factor in the morbidity and mortality of patients in the intensive care unit, and ventilator-associated pneumonia is the most common nosocomial infection observed in patients receiving mechanical ventilation for more than 48 h. In intensive care patients, mucosal atrophy develops in the gastrointestinal tract, and bacterial translocation increases during the administration of parenteral nutrition. For this reason, precautions must be taken in order to preserve the intestinal integrity of patients undergoing parenteral nutrition, with glutamine supplementation being one of these precautions. The gastrointestinal tract is the biggest user of glutamine in the body, and glutamine, which has a trophic effect on enterocytes, assists in preserving the integrity of the intestinal wall and preventing bacterial translocation, which may lead to septicemia and organ failure. With glutamine-supplemented parenteral nutrition, the weight of the jejunal mucosa and the nitrogen increases, while villous atrophy decreases. Glutamine is also an important substrate for the critical cells of the immune system, such as lymphocytes and macrophages, and actively affects the immune system from various aspects. As a result of glutamine supplementation, the incidence of infectious complications and pneumonia decreased in the administration of parenteral nutrition. 1945

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M. T€ urkay et al.

List of Abbreviations

HLA-DR IFN γ IgA TH TNF α

Human leukocyte antigen-DR Interferon γ Immunoglobulin A Helper T cell Tumor necrosis factor α

Table 1 Types of effective pathogens in VAP Early VAP Haemophilus influenza Methicillin-sensitive Staphylococcus aureus Streptococcus pneumoniae Moraxella catarrhalis

Late VAP Methicillin-resistant Staphylococcus aureus Pseudomonas aeruginosa Acinetobacter spp. Enterobacter spp.

Introduction Nosocomial infections are one of the largest sources of morbidity and mortality in the intensive care unit (ICU) (Zilberberg and Shorr 2011; Díaz et al. 2010), and ventilator-associated pneumonia (VAP) is the most common nosocomial infection observed (Zilberberg and Shorr 2011). It is estimated that the mortality rate attributable to VAP is 25–50 % (Díaz et al. 2010); therefore, avoiding VAP should be the primary goal of intensive care doctors (Efrati et al. 2010). Preventing VAP decreases mortality, morbidity, and healthcare costs and increases patient safety (Díaz et al. 2010; Efrati et al. 2010; Vincent and Jakops 2006). Nutritional support is part of the standard care of critical adult patients (Gramlich et al. 2004), and parenteral nutrition (PN) is one technique for achieving nutritional support. Parenteral nutrition consists of the intravenous administration of glucose, amino acids, triglycerides, vitamins, trace elements, water, and electrolytes (Thibault and Pichard 2013). However, during PN administration, the incidence of infection has been increasing, with harmful effects on the gastrointestinal tract (Thibault and Pichard 2013; Hartl et al. 2009). In this section, the authors aimed to discuss the development of pneumonia in patients who were administered with glutaminesupplemented PN in the ICU.

ICU and hospital, increasing costs, mortality, and morbidity (Efrati et al. 2010; Murray and Goodyear-Bruch 2007). Its incidence varies between 9 % and 67 % in patients undergoing mechanical ventilation, and the additional cost for each VAP episode varies between 9,000 and 31,000 Euros (Díaz et al. 2010). Ventilator-associated pneumonia developing within the first 4 days of mechanical ventilation is considered to be early VAP, and VAP developing after 5 days or more is considered to be late VAP. The most important differences between early and late VAP are the types of effective pathogens, clinical course, and prognosis. Active pathogens in early VAP include Haemophilus influenza, methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae, and Moraxella catarrhalis. On the other hand, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter spp., and Enterobacter spp. are the most frequently observed pathogens in late VAP (American Thoracic Society 1996; Chastre and Fagon 2002) (Table 1).

Ventilator-Associated Pneumonia

Pathogenesis Two phases of pathogenesis come into play for VAP development in intensive care patients: colonization of the respiratory and digestive tracts and micro-aspiration of the secretions of the upper and lower parts of the airway (Augustyn 2007). Pathogens leading to VAP reach the lower respiratory tract in one of three ways (Quenzer and Allen 1994):

Ventilator-associated pneumonia is an important and dangerous clinical complication, often extending the length of a patient’s stay in the

1. Aspiration of oropharyngeal microorganisms 2. Inhalation 3. Hematogenous spread

Applications to Intensive Care

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1947

The most important etiological mechanism for VAP is the gross or micro-aspiration of oropharyngeal organisms into the distal bronchi from the surroundings of the endotracheal tube (Efrati et al. 2010). The sources of pathogenic bacteria causing VAP are the oropharynx, subglottic area, dental plaques, and paranasal sinuses. The endotracheal intubation of patients distorts the natural barrier between the oropharynx and the trachea, enabling the contaminated secretions around the cuff to pass into the lungs. This occurs primarily in intubated patients being kept in a supine position (Augustyn 2007). Endotracheal tubes do not prevent aspiration from the upper respiratory tract or stomach, and according to some authors, the high-intensive gastric colonization of microorganisms in patients undergoing mechanical ventilation is an important risk factor in the development of nosocomial pneumonia (Zimmerli 1991).

Table 2 Potential risk factors of VAP

Risk Factors There are multiple risk factors for VAP (Díaz et al. 2010). The application time of mechanical ventilation is an independent risk factor (Efrati et al. 2010), and prolonged endotracheal intubation and mechanical ventilation (more than 48 h) increase the possibility of VAP (Chastre et al. 2013). Re-intubation is a risk factor for nosocomial pneumonia (Torres et al. 1995), which is developing more frequently in elderly patients older than 60 years of age (Charles et al. 2013). Acute Physiology and Chronic Health Evaluation II scores above 16 reflect a risk factor for developing pneumonia (Gursel and Demirtaş 2006). Surgical procedures, low albumin levels, low physiological status using the American Society of Anesthesiologists (ASA) scoring system, prophylactic antibiotic therapy, coma, stress ulcer prophylaxis, tracheotomy, sinusitis, and transportation of the patients within the hospital are also considered to be risk factors (Chastre and Fagon 2002; Gadani et al. 2010; Iribarren et al. 2009). In patients fed through nasogastric tubes in a supine position, reflux and tracheal aspiration were observed at a very high rate (American Gastroenterological Association 1995). Underlying chronic diseases, such as chronic obstructive pulmonary disease, congestive heart

failure, kidney failure, and cancer, affect outcomes in patients with VAP, due to comorbid factors which decrease the host’s response to infection (Napolitano 2010) (Table 2).

Mechanical ventilation for more than 48 h Re-intubation Advanced age Feeding through nasogastric tube in supine position High Acute Physiology and Chronic Health Evaluation II score Low albumin levels Low ASA score Prophylactic antibiotic therapy Coma Stress ulcer prophylaxis Tracheotomy Sinusitis Transportation of patients inside the hospital Comorbidity (chronic obstructive pulmonary disease, congestive heart failure, kidney failure, or cancer VS) ASA American Society of Anesthesiologists

Prevention Strategies With the management and standardization of care conditions in patients, incidences of VAP can be decreased (Murray and Goodyear-Bruch 2007). Meticulous nursing, a well-controlled cuff pressure, and maintaining the patient’s head at a 30–45 angle are highly effective in decreasing the incidence of VAP in patients undergoing mechanical ventilation (Elorza Mateos et al. 2011). Bathing, tracheal aspiration, enteral nutrition, and tube manipulations are significant in the transmission of pathogens (Augustyn 2007). Pathogens can also be moved to the patient through the healthcare provider’s hands during patient care or as a result of the contamination of instruments used during care. Mechanical ventilator circuits, humidifiers, and aspiration catheters can be contaminated by the surroundings or hands of the personnel conducting the procedures, and the accumulation of water in ventilator circuits is a very suitable environment for bacterial growth. Ventilator circuits must be changed (at least) every 3 days, especially within the first 10 days

1948 Table 3 Strategies to prevent VAP Meticulous and relevant nursery Well-controlled cuff pressure 30 and 45 head up position Infrequently changed ventilator circuits Daily use of sedation vacation Decontamination of oropharynx Oral care of patients Management of the medicines used Nutrition Continuous aspiration of oropharyngeal secretions Glycemic control Hand hygiene

of use (Demir et al. 2002). The daily use of sedation vacation and decontamination of the oropharynx are effective methods in preventing the development of VAP (Efrati et al. 2010). It has also been demonstrated that the use of probiotics decreases the incidence of nosocomial infections and VAP and shortens the length of the stay in the ICU; however, it does not affect the mortality rate (Gu et al. 2013). The management of the medications used and management of nutrition level of the patient are some of the processes that are also considered to decrease VAP (Murray and Goodyear-Bruch 2007). Even oral care alone has been demonstrated to decrease the incidence of VAP by decreasing the number of potential pathogenic bacteria in the oral cavity (Mori et al. 2006). The continuous aspiration of oropharyngeal secretions, glycemic control, and hand hygiene also lower VAP rates in a meaningful manner, and planning treatment to prevent VAP is one of the most important determinants affecting the results of these patients (Chastre and Fagon 2002) (Table 3). Additionally, the inadequate or delayed commencement of antibiotic treatment is closely associated with the increase in mortality and extension of the length of the patient’s hospital stay (Suka et al. 2007).

Diagnosis The diagnosis of VAP is difficult and may create problems for intensive care doctors who are planning treatment (Vincent and Jakops 2006). The presence of VAP should be suspected in the cases of clinical findings such as a new fever, high

M. T€ urkay et al. Table 4 Clinical findings of VAP Fever Leukocytosis High amount of purulent secretions Increase in ventilations per minute and/or disruption in arterial oxygenation The development of new and progressive infiltrations upon radiography

amount of purulent secretions, leukocytosis, increase in ventilations per minute and/or disruption in arterial oxygenation, and the development of new and progressive infiltrations upon radiography (Chastre et al. 2013) (Table 4). For the diagnosis of VAP, two of the following criteria must be present: fever over 38  C, leukocytosis/ leukopenia, and an increase in purulent respiratory secretions (Chastre and Fagon 2002).

Etiological Agents Gram-negative microorganisms are the dominant etiological agents in nosocomial pneumonia in most ICUs (Zimmerli 1991), and Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacter spp., and Acinetobacter spp. are the pathogens most frequently leading to VAP. Mortality attributable to VAP depends on the host’s immunity, response to pathogens, and treatment method applied (Faisy et al. 2011). Treatment Early treatment is important in maximizing positive results; however, inappropriate antibacterial treatment has its own risks. The negative effects (resistant pathogens, costs, and adverse reactions) and therapeutic benefits of antibiotics should be taken into consideration while planning treatment. Because of the high rate of mortality and morbidity, the best overall treatment is to prevent VAP from occurring (Vincent and Jakops 2006). Antimicrobial treatment of VAP consists of two phases. The first phase is to begin broadspectrum antibiotics in order to avoid the insufficient treatment of bacterial pneumonia. Empiric antibiotic treatments must be started immediately and meticulously after the detection of pneumonia and must be planned according to the etiology of the pathogen and by taking into consideration the

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local active pathogens. The second phase is to individualize the treatment without causing the excessive use and abuse of antibiotics. This phase must include ending the antibiotherapy in patients with a low risk of VAP and beginning antibiotherapy for the etiologic agent discovered, ceasing monotherapy after 3 days, keeping treatments shorter than 7–8 days, and making decisions according to the clinical responses and results of the patient (Chastre et al. 2013).

Nutrition Nutritional support is generally considered to be an essential component in the management of intensive care patients (Schetz et al. 2013). Adding specific nutrients may provide benefits such as securing intestinal integrity, minimizing liver injury, assisting the blood flow of the liver and intestines, accelerating wound healing, improving immune functions, and decreasing infection rates (Robert and Zaloga 2000). Protein–energy malnutrition (PEM) is a frequently seen component of many diseases and develops through insufficient oral intake and the loss of nutrients through the tissues. Of the patients admitted to the hospital, 50 % present with malnutrition. Inflammatory intestinal disease, rheumatic disease, congestive heart failure, and pre-occurring functional organ disorders such as cirrhosis and malignancy are the most important risk factors for malnutrition, which is the most frequent reason for secondary immunodeficiencies (Sternberg and Robovsky 2000). Protein–energy malnutrition frequently results in a disrupted immune response, affecting the clinical course of certain infections such as pneumonia. Energy deficiency develops within the first week after admittance to the ICU, and as an independent factor, this deficiency can contribute to the development of complications such as infection. Energy deficiency developing in intensive care patients is associated with the coexistence of hypermetabolism and low intake. Oftentimes the reason for low intake is frequent ceases in nutrition for diagnostic and therapeutic reasons or gastrointestinal intolerance (Faisy et al. 2011).

1949

The relationship between the nutritional condition and infection, especially in elderly patients with PEM, and micronutrient deficiencies has been clearly demonstrated. In cases of chronic PEM, T-lymphocyte deficiencies, disruption in immune regulation, oxidative stress deterioration and barrier defects in the mucosal membrane, changes in microbial flora, and decreases in the resistance to bacterial and viral infections can be observed. With chronic PEM in intensive care patients, the tracheobronchial colonization of gram-negative bacilli rather than gram-positive pathogens can be observed (Faisy et al. 2011). Nutrition can be enterally or parenterally achieved, and nutritional support specialists suggest using the gastrointestinal tract in critical patients with functional intestinal continuity. The enteral tract is the most preferred way for administering nutrition, and available data suggests that enteral nutrition (EN) must be started in early periods, provided that the intestines are functional and the condition of the patient is stable (Moral and Uyar 2003). The presence of EN is a potent tropical stimulus of the gastrointestinal tract, and nutrients directly stimulate intestinal growth. It has been demonstrated that intestinal barrier atrophy develops in the absence of luminal nutrients, and as a result, an increase is observed in bacterial translocation (Robert and Zaloga 2000). Mesenteric hypoperfusion is an important factor leading to bacterial translocation, as well as the long-term nonuse of the intestine. The risk of sepsis derived from the gastrointestinal system may be decreased because EN can abolish these factors. Enteral nutritional products have favorable effects on intestinal cell viability and the function of the mucosal barrier (Cinel et al. 2002). However, although the early administration of EN is usually beneficial, it has disadvantages such as gastric colonization, gastroesophageal reflux, aspiration, and an increase in the rate of pneumonia (Torres et al. 1996).

Parenteral Nutrition Parenteral nutrition (PN) is indicated if the gastrointestinal tract cannot be used or if absorption is

1950 Table 5 Technical complications associated with catheter (Morgan et al. 2002) Pneumothorax Hemothorax Chylothorax, hydrothorax Air embolization Cardiac tamponade Thrombosis Hematoma Septic complications

insufficient (Morgan et al. 2002). It was developed in the 1960s when it began to be used frequently in ICUs (Thibault and Pichard 2010). It can be applied through central venous access, most often in the subclavian or internal jugular vein. The subclavian vein is the preferred site of central access (Sternberg and Robovsky 2000). Parenteral nutrition is lifesaving in a variety of clinical conditions but may also result in numerous, potentially serious, side effects. The risk of such complications can be decreased by attentively monitoring patients and the use of nutrition support teams (Hartl et al. 2009). Parenteral nutritional complications can be examined in two groups: as catheter-related complications (Table 5) (Morgan et al. 2002) and metabolic complications (Table 6) (Hartl 2009; Morgan et al. 2002). Especially during the first years of the 1980s and 1990s, studies regarding an increase in mortality and infectious morbidity due to PN were published. The harmful effects of PN are most often associated with overfeeding and hyperglycemia, as well as bacterial translocation and intestinal permeability (Thibault and Pichard 2010, 2013). Furthermore, rapid changes can be seen in the secretory IgA levels, B cells, and gut-associated lymphoid tissue T cells in the gastrointestinal and respiratory tracts. IgA-related mucosal immunity and neutrophil functions can be deteriorated, and mucosal atrophy can occur in the gastrointestinal tract (Li et al. 1995). Therefore, instead of PN, EN was accepted as the gold standard in the 1980s due to its beneficial effects on the gastrointestinal system. However, it was determined that EN by itself can lead to a

M. T€ urkay et al. Table 6 Metabolic complications (Morgan et al. 2002) Azotemia Liver dysfunction Cholestasis Hyperglycemia: hyperosmolar coma, diabetic ketoacidosis Excessive CO2 production Hypoglycemia Metabolic acidosis or alkalosis Hypernatremia Hyperkalemia Hypokalemia Hypocalcemia Hypophosphatemia Hyperlipidemia Pancreatitis Fat embolism syndrome Anemia Vitamin D deficiency Vitamin K deficiency Bone demineralization and osteoporosis Essential fatty acid deficiency Hypervitaminosis A Hypervitaminosis D Intestinal side effects (mucosal atrophy, increased translocation of microorganisms)

deficiency in meeting energy needs, and the protein–energy deficiency that may occur afterwards can cause more severe clinical conditions (Thibault and Pichard 2010). Enteral nutrition and PN have their own peculiar risks and benefits, and when choosing between EN and PN, various factors are taken into consideration. The first choice for nutritional support in critical patients must be EN because it can decrease infectious complications and can be more appropriate in terms of costs when compared to PN (Gramlich et al. 2004). It has also been reported that appropriate EN is an important factor in preventing the development of VAP (Chen 2009). Recent evidence demonstrates that PN does not have a significantly negative effect on mortality and infectious morbidity in intensive care patients, even if hyperimplementation is avoided, and it is used on its own with good glycemic control. Therefore, the use of PN in the ICU has come into question once again; however, in cases

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where energy needs cannot be met adequately, nutritional deficiencies can be prevented by administering PN. Clinical studies demonstrate that the combined application of PN and EN in intensive care patients can improve the clinical results (Thibault and Pichard 2010, 2013), and for this reason, PN must be integrated into the management of intensive care patients to prevent deterioration including energy deficiencies, loss of lean body mass, and complications associated with malnutrition (Thibault and Pichard 2013).

Glutamine The purpose of determining the types and amounts of nutritional supplementation to be applied in the ICU is to support the immune system and increase the response of the host to stress (Jayarajan and Daly 2011). In recent years, glutamine, which is a nonessential amino acid, has become a focus of attention in scientific terms since it has important physiological roles in both human and animal tissues and cell cultures. Glutamine is the most common amino acid found in the body, and it plays an important role in many metabolic functions (Lacey and Wilmore 1990). Since it can be synthesized by the cell via glutamine synthetase, it is considered to be a nonessential amino acid; however, it becomes essential since glutamine production cannot meet the needs of the body in critical patients under stress (Moral and Uyar 2003; Lacey and Wilmore 1990). Glutamine is used for maintaining the acid–base balance of the kidneys; it functions as a preferred respiratory fuel for rapidly proliferating cells, such as enterocytes and lymphocytes, and is an important precursor of proteins, amino saccharides, nucleotides, and nucleic acids, in addition to conveying nitrogen between the tissues (Lacey and Wilmore 1990). Glutamine has an unstable structure on its own and denatures rapidly in water; however, the dipeptide structure created by the combination of alanine and glutamine can remain stable in a water solution (van der Hulst et al. 1993). Since commercial amino acid solutions possess unstable structures, they do not contain glutamine.

1951

Therefore, in the case of nutrition through standard PN, a stress-related decrease in glutamine levels is inevitable (Cetinbas et al. 2010). Glutamines are important substrates for the critical cells of the immune system, such as lymphocytes and macrophages, as well as epithelial cells and rapidly reproducing cells such as enterocytes and fibroblasts (Cetinbas et al. 2010; Wilmore 2001; Mondello et al. 2010; Lin et al. 2002). Some amino acids absorbed from the gastrointestinal system travel to the liver, while some are used in the synthesis of proteins and nitrogencontaining substances by accumulating in cell amino acid pools. Additionally, glutamine is metabolized in enterocytes and provides most of the energy required for these cells. It regulates protein synthesis and is the most important leading substance in the nucleic acid synthesis of all cells (Dudrick and Souba 1991). Skeletal muscles and lungs are the most important synthesis and storage places for glutamine (Dudrick and Souba 1991; Souba et al. 1985), and the glutamine concentration in the skeletal muscle is equal to 30-fold of that in the blood (Dudrick and Souba 1991). The gastrointestinal tract is the most significant user of glutamine in the body, which has a trophic effect on enterocytes (Dudrick and Souba 1991; Souba et al. 1985). It assists in maintaining the integrity of the intestinal wall and prevents bacterial translocation, which can lead to septicemia and multiple organ deficiencies (van der Hulst et al. 1993; Souba et al. 1985, 1990). Glutaminesupplemented PN increases the weight of the jejunal mucosa, increases the nitrogen content (together with DNA), and decreases villous atrophy (Souba et al. 1985). Since glutamine can also lead to glutathione synthesis, a major antioxidant protecting tissues against free radical damage, it can play a role in the protection of mucosal damage after shock and in postischemic reperfusion (Hong et al. 1992). Glutamine affects the immune system in various ways as an active barrier. It is also essential for neutrophils and macrophages to perform their functions, in addition to lymphocyte proliferation. In cases where the level of plasma glutamine is

1952 Table 7 The effect of glutamine on the immune system Depression of T lymphocytes Disruption of neutrophil bactericidal functions Decrease in phagocytic activities of the macrophages and interleukin production

low, T lymphocytes are pressed (O’Riordain et al. 1994), bactericidal functions of neutrophils are disrupted (Ogle et al. 1994), and the phagocytic activities of the macrophages and interleukin (IL-1) production decrease (Wallace and Keast 1992) (Table 7). Although there is still insufficient evidence for the use of exogenous glutamine in critical patients undergoing EN, glutamine supplementation in critical patients undergoing PN has become an almost standard approach (Wernerman 2008). Studies have demonstrated that parenteral glutamine supplementation has enabled the continuity of the intracellular glutamine pool, corrected the nitrogen balance, improved the immunological condition, and shortened the period of stay in the ICU for critical patients (Mondello et al. 2010; Lin et al. 2002). It has also been reported that glutamine leads to a decrease in the incidence of infection due to its roles in immune function (Boelens et al. 2002; Griffiths et al. 2002). The risk of sepsis in critical patients in the ICU is substantially increased, which is a major reason for mortality, and recent findings have demonstrated that the disruption in the immune system leads to the development of sepsis in critical patients. Monoacids, especially, decrease the HLA-DR antigen expression, which is associated with a disruption in the antigen presentation capacity and decreased phagocytic activity. Lymphocytes show a decreased proliferation response to mitogens, contributing to a disruption of immunity by creating a change in the TH1/TH2 rate of helper T cells (Andrews and Griffiths 2002). Recently, the effects of nutritional support on critical patients in sepsis have attracted a large amount of attention, and in most of the studies, conflicting results were obtained; however, there were many positive publications regarding nutritional support for preventing sepsis (Cohen and Chin 2013).

M. T€ urkay et al.

It was demonstrated in various studies that glutamine-supplemented PN decreases infection in surgical patients (Andrews and Griffiths 2002; Cohen and Chin 2013), and the clinical benefits of glutamine-supplemented PN are clearly observed in the hospitalized surgical patient group. It was reported that glutamine-supplemented PN did not change infection rates after surgery for pancreatic necrosis in surgical intensive care patients but clearly reduced infection after cardiac, vascular, and colonic surgery (Estívariz et al. 2008). In studies conducted to evaluate the activity of glutamine-supplemented PN on the development of nosocomial infections, it was reported that glutamine-supplemented PN was associated with decreased pneumonia and infectious complications and better tolerance and better glycemic control in the ICU (Déchelotte et al. 2006; Grau et al. 2011). In a meta-analysis, it was reported that the perioperative administration of glutamine-supplemented PN in patients undergoing surgery shortened the length of their stay in the hospital, decreased postoperative infectious complications, and regulated their nitrogen balance (Yue et al. 2013). It was proven that especially traumatic patients had immune system changes, increased infectious complications, sepsis, potential organ failure, and tendencies for death; however, the supplementation of glutamine to the PN of these patients led to better clinical results (Al Balushi et al. 2011). In one study, it was demonstrated that the application of PN in a rat model caused a loss in the local inflammatory response, and as a result, an interruption in the epithelial barrier function developed (Feng et al. 2012). Although the underlying mechanisms were not known, the major factor contributing to this condition was decreased signalization based on the loss of growth factors. Another factor contributing to the loss of epithelial barrier function in PN application was an increase in proinflammatory cytokines, such as TNF α and IFN γ, in the mucosal epithelium. A decrease in critical nutrients, such as glutamine and glutamate, can affect epithelial barrier function, with a loss of tight junction proteins. During the administration of PN, taking precautionary measures to protect the small

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intestines is an important clinical requirement. Supplementary glutamine and glutamate are examples of such agents (Feng et al. 2012), and research has been conducted based on the idea that glutamine-supplemented PN can prevent loss and have a protective effect (Nose et al. 2010). Glutamine-supplemented PN clearly decreases the number of leukocytes and natural killer cells, thus suppressing inflammation. Additionally, the number of total lymphocytes, B lymphocytes, T lymphocytes, and their subclasses (helper T lymphocytes, cytotoxic T lymphocytes) increased, and it was reported that these increases can play a role in improving the immune system (Cetinbas et al. 2010). In critical patients, reactive oxygen species are continually produced and this oxidative stress must be neutralized. The glutathione system is the most important part of endogenous antioxidant protection, and it has been demonstrated that glutamine supplementation to increase glutathione provides protection against oxidative damage, leading to a decrease in morbidity and mortality. The use of glutamine in critical patients improves the protection of antioxidants, and in this case, lipid peroxidation and morbidity in the ICU decrease (Abilés et al. 2008). In studies conducted on animals, it has been demonstrated that glutamine supplementation in patients fed through PN over an extended period of time decreases mucosal hypoplasia and that dramatic effects occur in the T cells connected with the lymphoid tissues of the intestine (O’Dwyer et al. 1989). Similar affects were observed in studies conducted on humans as well (Buchman et al. 2003).

Applications to Other Conditions It is known that supplementary glutamine reduces the postsurgical complications (Prabhu et al. 2003). Glutamine has protective effects against the damage on the intestines and the pancreas caused by abdominal irradiation (Erbil et al. 2005). Supplementary glutamine decreases the intestinal injury of chemotherapeutics and improves survival in enterocolitis (Fox et al. 1988).

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Guidelines and Protocols There are a limited number of studies examining the development of nosocomial pneumonia in patients fed through glutamine-supplemented PN in the ICU. It was reported that about 90 % of the nosocomial pneumonia episodes observed in intensive care patients were observed during mechanical ventilation and tracheal intubation, contributing to an increase in the risk of infection (Déchelotte et al. 2006). The authors reported that glutamine-supplemented PN decreased infectious complications, which was associated with a low incidence of nosocomial pneumonia in patients undergoing glutamine-supplemented PN (Déchelotte et al. 2006). In a study performed on a smaller but heterogeneous patient group, it was demonstrated that the development of pneumonia in the glutamine-supplemented PN group was less than in the enteral and standard PN patients; however, the differences between the groups were not statistically significant (Aydogmuş et al. 2012). In another study, it was determined that the supplementation of glutamine to PN prevented harmful effects to IgA through the development of lymphoid tissue, which enabled protection through the IgA-mediated immunity against influenza in the upper respiratory tract (DeWitt et al. 1999). In this study examining glutaminesupplemented PN protecting respiratory immunity in fatal pneumonia, it was reported that immunity weakened and survival decreased due to the use of PN, but that glutamine supplementation enabled the effective protection of immunization. Pseudomonas aeruginosa immunization decreases the mortality attributable to pseudomonal pneumonia; however, this immunization is lost as a result of using PN. It was reported that supplementing glutamine to PN enabled the immunity of the respiratory tract, and the mortality attributable to fatal bacterial pneumonia decreased when compared to standard PN (DeWitt et al. 1999). The results of this study determine that glutamine must be supplemented to prevent the changes in the gastrointestinal tract which occur due to PN administration in intensive care

1954

patients. Since glutamine protects the integrity of the intestinal wall and affects the immune system from various aspects as an active barrier, infectious complications and the incidence of pneumonia can be decreased by applying glutamine-supplemented PN.

Summary Points • Bacterial translocation and intestinal permeability increase during the administration of PN in intensive care patients. • Glutamine, which has a trophic effect on enterocytes, prevents bacterial translocation via preserving the integrity of the intestinal wall. • Glutamine is an important substrate for the critical cells of the immune system, such as lymphocytes and macrophages; besides this it also actively affects the immune system from various aspects. • Parenteral nutrition administration with glutamine supplementation is decreasing the incidence of infectious complications and pneumonia.

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M. T€ urkay et al. Aydogmuş MT, et al. Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit. Balkan Med J. 2012;29:414–8. Boelens PG, et al. Glutamine-enriched enteral nutrition increases HLA-DR expression on monocytes of trauma patients. J Nutr. 2002;132:2580–6. Buchman AL, et al. AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterology. 2003;124:1111–34. Cetinbas F, et al. Role of glutamine administration on cellular immunity after total parenteral nutrition enriched with glutamine in patients with systemic inflammatory response syndrome. J Crit Care. 2010; 25:661.e1–6. Charles MP, et al. Incidence and risk factors of ventilator associated pneumonia in a tertiary care hospital. Australas Med J. 2013;6:178–82. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002;165:867–903. Chastre JE, et al. Pneumonia in the ventilator-dependent patient. In: Tobin MJ, editor. The principles and practice of mechanical ventilation. 3rd ed. China: The McGraw-Hill; 2013. p. 1091–122. Chen YC. Critical analysis of the factors associated with enteral feeding in preventing VAP: a systematic review. J Chin Med Assoc. 2009;72:171–8. Cinel I, et al. Comparison of the effect of enteral formulas on bacterial translocation, cytokines and lipid peroxidation in a rat malnutrition model. Mersin Üniv Tıp Fak Derg. 2002;1:31–9. Cohen J, Chin wD. Nutrition and sepsis. World Rev Nutr Diet. 2013;105:116–25. Déchelotte P, et al. L-alanyl-L-glutamine dipeptidesupplemented total parenteral nutrition reduces infectious complications and glucose intolerance in critically ill patients: the French controlled, randomized, doubleblind, multicenter study. Crit Care Med. 2006;34: 598–604. Demir E, et al. Erişkin ve Çocuklarda Hastane Kökenli Pnömoniler ve Bağışıklığı Baskılanmış Hastalarda Pnömoniler Tanı ve Tedavi Rehberi. Toraks Derg Ek. 2002;3:015–26. DeWitt RC, et al. Glutamine-enriched total parenteral nutrition preserves respiratory immunity and improves survival to a Pseudomonas pneumonia. J Surg Res. 1999;84:13–8. Díaz LA, et al. Non-pharmacological prevention of ventilator-associated pneumonia. Arch Bronconeumol. 2010;46:188–95. Dudrick PS, Souba WW. Amino acids in surgical nutrition. Principles and practice. Surg Clin North Am. 1991;71: 459–76. Efrati S, et al. Ventilator-associated pneumonia: current status and future recommendations. J Clin Monit Comput. 2010;24:161–8. Elorza Mateos J, et al. Nursing care in the prevention of ventilator-associated pneumonia. Enferm Intensiva. 2011;22:22–30.

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1955 severity of diseases in surgical patients. Clin Nutr. 2002;21:213–8. Mondello S, et al. Glutamine-supplemented total parenteral nutrition improves immunological status in anorectic patients. Nutrition. 2010;26:677–81. Moral AR, Uyar M. Yoğun Bakım Hastalarında Beslenme. In: Şahinoğlu H, editor. Yoğun Bakım Sorunları ve Tedavileri. 2nd ed. Ankara: T€ urkiye Klinikleri; 2003. p. 251–81. Morgan GE, et al. Clinical anesthesiology. 3rd ed. New York: McGraw-Hill; 2002. p. 951–94. Mori H, et al. Oral care reduces incidence of ventilatorassociated pneumonia in ICU populations. Intensive Care Med. 2006;32:230–6. Murray T, Goodyear-Bruch C. Ventilator-associated pneumonia improvement program. AACN Adv Crit Care. 2007;18:190–9. Napolitano LM. Use of severity scoring and stratification factors in clinical trials of hospital-acquired and ventilator-associated pneumonia. Clin Infect Dis. 2010;51:67–80. Nose K, et al. Glutamine prevents total parenteral nutritionassociated changes to intraepithelial lymphocyte phenotype and function: a potential mechanism for the preservation of epithelial barrier function. J Interferon Cytokine Res. 2010;30:67–80. O’Dwyer ST, et al. Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. J Parenter Enteral Nutr. 1989;13:579–85. O’Riordain MG, et al. Glutamine-supplemented total parenteral nutrition enhances T-lymphocyte response in surgical patients undergoing colorectal resection. Ann Surg. 1994;220:212–21. Ogle CK, et al. Effect of glutamine on phagocytosis and bacterial killing by normal and pediatric burn patient neutrophils. J Parenter Enteral Nutr. 1994;18:128–33. Prabhu R, et al. Oral glutamine attenuates surgical manipulation-induced alterations in the intestinal brush border membrane. J Surg Res. 2003;115:148–56. Quenzer R, Allen S. Infections in the critically ill. In: Bongard FS, editor. Current critical care diagnosis and treatment. 1st ed. Stamford: Appleton & Lange; 1994. p. 131–55. Robert PR, Zaloga GP. Enteral nutrition. In: Shoemaker WC, editor. Textbook of critical care. 4th ed. Philadelphia: WB. Saunders; 2000. p. 875–97. Schetz M, et al. Does artificial nutrition improve outcome of critical illness? Crit Care. 2013;17:302. Souba WW, et al. Glutamine metabolism by the intestinal tract. J Parenter Enteral Nutr. 1985;9:608–17. Souba WW, et al. Glutamine nutrition: theoretical considerations and therapeutic impact. J Parenter Enteral Nutr. 1990;14:237–43. Sternberg JA, Robovsky SA. Total parenteral nutrition for the critically ill patient. In: Shoemaker WC, editor. Textbook of critical care. 4th ed. Philadelphia: WB. Saunders; 2000. p. 898–907. Suka M, et al. Incidence and outcomes of ventilatorassociated pneumonia in Japanese intensive care

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M. T€ urkay et al. Wallace C, Keast D. Glutamine and macrophage function. Metabolism. 1992;41:1016–20. Wernerman J. Role of glutamine supplementation in critically ill patients. Curr Opin Anaesthesiol. 2008;21: 155–9. Wilmore DW. The effect of glutamine supplementation in patients following elective surgery and accidental injury. J Nutr. 2001;131:2543–9. Yue C, et al. The impact of perioperative glutaminesupplemented parenteral nutrition on outcomes of patients undergoing abdominal surgery: a metaanalysis of randomized clinical trials. Am Surg. 2013;79:506–13. Zilberberg MD, Shorr AF. Ventilator-associated pneumonia as a model for approaching cost-effectiveness and infection prevention in the ICU. Curr Opin Infect Dis. 2011;24:385–9. Zimmerli W. Nosocomial pneumonia in ventilated patients. Schweiz Med Wochenschr. 1991;121: 1658–63.

Parenteral Amino Acid Strategies for Nutritional Optimization in Low Birth Weight Infants

149

Cynthia L. Blanco and Julie C. Hisey

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1958 Amino Acids as Parenteral Nutritional Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein Requirement, Initiation, and Dosage . . . . . . Concerns and Misconceptions . . . . . . . . . . . . . . . . . . . . . . Role of Individual Amino Acids and Aminocidemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1958 1958 1959 1961 1963 1965 1967

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1967

C.L. Blanco (*) Division of Neonatology, Department of Pediatrics, University of Texas Health Science Center San Antonio, San Antonio, TX, USA e-mail: [email protected] J.C. Hisey Laredo Medical Center, Laredo, TX, USA e-mail: [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_120

Parenteral amino acid (AA) supplementation is vital for appropriate nutrition in preterm infants. Amino acids and proteins are essential components of growth, development, and regulation of metabolism. Growth restriction during this vulnerable time has been negatively associated with short-/longterm outcomes. In order to improve postnatal growth to that which parallels a healthy, growing fetus, it is important to mimic AA accretion by the fetus. Early loss of protein stores can be prevented or minimized by provision of as little as 1–1.5 g/kg/day of parenteral AA. The minimum AA requirement necessary to approximate intrauterine rates of protein accretion is 3 g/kg/day, but the placenta serves as a metabolic organ in utero; premature infants may not have mature metabolic pathways and therefore, may not tolerate the same protein load ex-utero. Although BUN may correlate with AA plasma levels, it cannot effectively be utilized to assess protein accretions, but a level >60 mg/dL may suggest immature metabolic pathways in the absence of renal disease. With the current data available, Parenteral AA supplementation should be started shortly after birth at a minimum dose of 1–1.5 g/kg/day to prevent catabolism in all VLBW infants. A maximum of 3.5 g/kg/day is recommended until enteral nutrition is established for VLBW infants. Higher doses of protein 1957

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C.L. Blanco and J.C. Hisey

supplementation have not shown additional benefits and may cause deleterious effects in overall growth and neurodevelopment. Additional glutamine and/or higher L-cysteine or arginine supplementation does not provide additional benefits. Larger randomized controlled trials that examine long-term outcomes are needed to develop a safe and maximally beneficial AA administration strategy.

List of Abbreviations

AA BCAA BUN ELBW LBW VLBW

Amino acids Branched-chained AA Blood urea nitrogen Extremely low birth weight Low birth weight Very low birth weight

Introduction Survival rates continue to improve for preterm infants, even for those born as early as 22 weeks’ gestational age and as small as 400–500 g. The goal of achieving normal intrauterine growth rates for these neonates remains elusive, and postnatal growth failure is common (Ehrenkranz et al. 1999; Clark et al. 2003). Parenteral amino acid (AA) supplementation is a vital part of early nutrition in preterm infants. Amino acids and proteins are essential components of growth, development, and regulation of metabolism. After birth, preterm infants are dependent on exogenous nutrients, as their internal supply of stored energy is minimal. Without externally administered nutrition, protein breakdown continues to increase with increasing metabolic demands, resulting in a detrimental catabolic state. Growth restriction during this vulnerable time has been negatively associated with both short- and long-term outcomes (Clark et al. 2003; Ehrenkranz et al. 2006; Denne 2007).

Amino Acids as Parenteral Nutritional Therapy Mechanism of Action In order to improve postnatal growth to that which parallels a healthy, growing fetus, it is important to understand the fetal model of AA and protein metabolism. In utero, fetuses are supplied with large amounts of AA via active transport. Animal models have shown that elevated AA uptake rates are necessary to supply the uniquely high rates of protein synthesis. In fetal sheep, these rates have been shown to be several-fold higher at gestational ages correlating to 24–28 week preterm infants as compared to term (Fig. 1) (Kennaugh et al. 1987; Meier et al. 1981). This remarkable AA accretion by the fetus exceeds the amount required for net protein synthesis. Excess AA serves as an important energy source via oxidative metabolism, second only to glucose in fetal energy production (Lemons et al. 1976; van Veen et al. 1987). Based on knowledge of the fetal environment, it follows that the preterm neonate would also have a significant AA requirement, but extrauterine life poses unique challenges. Failure to provide the needed substrates can result in pronounced catabolism beginning shortly after birth. It has been estimated that extremely low birth weight (ELBW) infants can lose up to 1.5 g/kg/day of protein stores over the first week of life (Denne 2007; Kalhan and Edmison 2007). Studies have consistently shown that the early postnatal provision of parenteral AA can optimize the metabolic state by improving nitrogen balance and decreasing protein breakdown although the latter, only transiently (Denne 2007). Stable isotope techniques have demonstrated improved nitrogen balance after AA infusion provided shortly after birth in premature neonates (Fig. 2). Enhanced protein synthesis is key to this positive balance; increased rates have been shown using a variety of amino acid dosing schedules (Denne et al. 1996; Poindexter et al. 2003; Van Goudoever et al. 1995;

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Parenteral Amino Acid Strategies for Nutritional Optimization in Low Birth Weight Infants

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(Denne et al. 1996; Parimi et al. 2005; Kadrofske et al. 2006), but this effect is not evident after prolonged AA infusion. This research is commonly interpreted to show that in preterm infants, AA infusion improves protein synthesis but does not impact proteolysis.

Protein Requirement, Initiation, and Dosage

Fig. 1 Data from fetal sheep at gestational ages equivalent to human fetuses of 20 weeks to term showing increasingly high fractional rates of protein synthesis (Ks, upper line) determined with leucine (closed circles) and lysine (open circles) radioactive tracers, compared with fractional growth rates (KG) at similar gestational ages (lower line). When scaled to human fetal growth rates, the fetal sheep data predict fetal amino acid requirements of 3.6–4.8 g/kg/ day that bracket the 4 g/kg/day requirement predicted by Ziegler (1994) using the factorial method for normal human fetal amino acid requirements to meet normal rates of fetal growth (Reproduced with permission from Hay and Thureen (2010))

te Braake et al. 2005; Thureen et al. 2003). The other major player in the nitrogen balance equation is proteolysis. Suppression of protein breakdown is an important component of how nutritional therapy preserves protein in adults. In the sick, premature infant, however, suppression of proteolysis is less clear. Most studies have shown a minimal, if any, reduction in overall proteolysis rates in response to intravenous nutrition (Fig. 3) (Clark et al. 1997; Denne et al. 1996; Poindexter et al. 2001; Thureen et al. 2003). Other data have demonstrated a transient decrease in protein breakdown after an acute AA load

Preterm infants need to be provided with enough AA to prevent catabolism, but the exact dosage, timing, and requirement are yet to be determined and should vary based on severity of illness and gestational age. Multiple sources have demonstrated that the early loss of protein stores can be prevented or minimized by provision of as little as 1–1.5 g/kg/day of parenteral AA (Thureen et al. 2003; Van Goudoever et al. 1995; Rivera et al. 1993). However, this limited amount is not sufficient to achieve growth. Although the minimum AA requirement necessary to approximate intrauterine rates of protein accretion is ~3 g/kg/day (Zlotkin 1984), the placenta serves as a metabolic organ for the feuts in utero, and premature infants may not have mature metabolic pathways. However, even this increased amount will not account for any loss of lean body mass that occurs before an infant regains birth weight (Thureen and Heird 2005). In those most at risk, ELBW infants, it has been estimated that a higher intake of 3.5–4.0 g/kg/day is necessary (Fomon and Heird 1986; Ziegler 1994). While the protein requirement for low birth weight (LBW) infants may vary on an individual basis, it is clear that most preterm infants will benefit from early provision of protein. Based on its ability to reverse negative nitrogen balance early in life, current clinical practice recommends that parenteral AA be provided immediately after birth (Thureen et al. 2003; Van Goudoever et al. 1995; Rivera et al. 1993). The optimal dosage and rate of advancement, however, remain in question. Historically,

1960 2.0

1 g/kg/d amino acid intake 3 g/kg/d amino acid intake

1.5 Protein Balance(g. kg−1-d−1)

Fig. 2 Comparison of protein balance results using two different methods. Solid and shaded bars indicate balance at intake of 1 and 3 g/kg/day amino acid, respectively. Values expressed as mean and SEM (Reproduced with permission from Thureen et al. (2003))

C.L. Blanco and J.C. Hisey

1.0

0.5

p60 mg/dL may suggest immature metabolic pathways in the absence of renal disease. 6. Glutamine supplementation and higher L-cysteine or arginine supplementation do not provide additional benefits.

References Amin HJ, Zamora SA, McMillan DD, et al. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr. 2002;140:425–31. Blanco CL, Falck A, Green BK, Cornell JE, Gong AK. Metabolic responses to early and high protein supplementation in a randomized trial evaluating the prevention of hyperkalemia in extremely low birth weight infants. J Pediatr. 2008;153:535–40. Blanco CL, Gong AK, Green BK, Falck A, Schoolfield J, Liechty EA. Early changes in plasma amino acid concentrations during aggressive nutritional therapy in extremely low birth weight infants. J Pediatr. 2011;158:543–8.e1. Blanco CL, Gong AK, Schoolfield J, et al. Impact of early and high amino acid supplementation on ELBW infants at 2 years. J Pediatr Gastroenterol Nutr. 2012;54:601–7. Blazer S, Reinersman GT, Askanazi J, Furst P, Katz DP, Fleischman AR. Branched-chain amino acids and respiratory pattern and function in the neonate. J Perinatol. 1994;14:290–5. Bulus N, Cersosimo E, Ghishan F, Abumrad NN. Physiologic importance of glutamine. Metabolism. 1989; 38:1–5.

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Castillo L, DeRojas-Walker T, Yu YM, et al. Whole body arginine metabolism and nitric oxide synthesis in newborns with persistent pulmonary hypertension. Pediatr Res. 1995;38:17–24. Cetin I, Corbetta C, Sereni LP, et al. Umbilical amino acid concentrations in normal and growth-retarded fetuses sampled in utero by cordocentesis. Am J Obstet Gynecol. 1990;162:253–61. Clark SE, Karn CA, Ahlrichs JA, et al. Acute changes in leucine and phenylalanine kinetics produced by parenteral nutrition in premature infants. Pediatr Res. 1997;41:568–74. Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics. 2003;111:986–90. Clark RH, Chace DH, Spitzer AR. Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a randomized, controlled trial. Pediatrics. 2007;120:1286–96. Denne SC. Regulation of proteolysis and optimal protein accretion in extremely premature newborns. Am J Clin Nutr. 2007;85:621S–4. Denne SC, Karn CA, Ahlrichs JA, Dorotheo AR, Wang J, Liechty EA. Proteolysis and phenylalanine hydroxylation in response to parenteral nutrition in extremely premature and normal newborns. J Clin Invest. 1996;97:746–54. Ehrenkranz RA, Younes N, Lemons JA, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics. 1999;104:280–9. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117:1253–61. Fomon SJ, Heird WC. Energy and protein needs during infancy. Orlando: Academic; 1986. p. xix, pp 248. Goldman HI, Goldman J, Kaufman I, Liebman OB. Late effects of early dietary protein intake on low-birthweight infants. J Pediatr. 1974;85:764–9. Gresham EL, Simons PS, Battaglia FC. Maternal-fetal urea concentration difference in man: metabolic significance. J Pediatr. 1971;79:809–11. Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition. 1997;13:295–302. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. 1984;4:409–54. Hay WWJ, Thureen PJ. Early postnatal administration of intravenous amino acids to preterm, extremely low birth weight infants. J Pediatr. 2006;148:291–4. Hay WW, Thureen P. Protein for preterm infants: how much is needed? How much is enough? How much is too much? Pediatr Neonatol. 2010;51:198–207. Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R, Krouskop RW. Aggressive early total parental nutrition in low-birth-weight infants. J Perinatol. 2004; 24:482–6.

1968 Kadrofske MM, Parimi PS, Gruca LL, Kalhan SC. Effect of intravenous amino acids on glutamine and protein kinetics in low-birth-weight preterm infants during the immediate neonatal period. Am J Physiol Endocrinol Metab. 2006;290:E622–30. Kalhan SC, Edmison JM. Effect of intravenous amino acids on protein kinetics in preterm infants. Curr Opin Clin Nutr Metab Care. 2007;10:69–74. Kennaugh JM, Bell AW, Teng C, Meschia G, Battaglia FC. Ontogenetic changes in the rates of protein synthesis and leucine oxidation during fetal life. Pediatr Res. 1987;22:688–92. Lemons JA, Adcock EW, Jones MD, Naughton MA, Meschia G, Battaglia FC. Umbilical uptake of amino acids in the unstressed fetal lamb. J Clin Invest. 1976;58:1428–34. Maggio L, Cota F, Gallini F, Lauriola V, Zecca C, Romagnoli C. Effects of high versus standard early protein intake on growth of extremely low birth weight infants. J Pediatr Gastroenterol Nutr. 2007; 44:124–9. McIntosh N, Mitchell V. A clinical trial of two parenteral nutrition solutions in neonates. Arch Dis Child. 1990;65:692–9. Meier PR, Peterson RG, Bonds DR, Meschia G, Battaglia FC. Rates of protein synthesis and turnover in fetal life. Am J Physiol. 1981;240:E320–4. Moss RL, Haynes AL, Pastuszyn A, Glew RH. Methionine infusion reproduces liver injury of parenteral nutrition cholestasis. Pediatr Res. 1999;45:664–8. Parimi PS, Kadrofske MM, Gruca LL, Hanson RW, Kalhan SC. Amino acids, glutamine, and protein metabolism in very low birth weight infants. Pediatr Res. 2005; 58:1259–64. Poindexter BB, Karn CA, Leitch CA, Liechty EA, Denne SC. Amino acids do not suppress proteolysis in premature neonates. Am J Physiol Endocrinol Metab. 2001;281:E472–8. Poindexter BB, Ehrenkranz RA, Stoll BJ, et al. Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants. Am J Clin Nutr. 2003;77:737–43. Poindexter BB, Ehrenkranz RA, Stoll BJ, et al. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics. 2004;113:1209–15. Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome. J Pediatr. 2006; 148:300–5. Ridout E, Melara D, Rottinghaus S, Thureen PJ. Blood urea nitrogen concentration as a marker of amino-acid intolerance in neonates with birthweight less than 1250 g. J Perinatol. 2005;25:130–3. Rivera AJ, Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism of preterm

C.L. Blanco and J.C. Hisey infants during the first three days of life. Pediatr Res. 1993;33:106–11. Scott PH, Sandham S, Balmer SE, Wharton BA. Dietrelated reference values for plasma amino acids in newborns measured by reversed-phase HPLC. Clin Chem. 1990;36:1922–7. Shah P, Shah V. Arginine supplementation for prevention of necrotising enterocolitis in preterm infants. Cochrane Database Syst Rev. 2007;18(3):CD004339 Shew SB, Keshen TH, Jahoor F, Jaksic T. Assessment of cysteine synthesis in very low-birth weight neonates using a [13C6]glucose tracer. J Pediatr Surg. 2005; 40:52–6. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics. 2009;123:1337–43. te Braake FW, van den Akker CH, Wattimena DJ, Huijmans JG, van Goudoever JB. Amino acid administration to premature infants directly after birth. J Pediatr. 2005;147:457–61. te Braake FW, Schierbeek H, Vermes A, Huijmans JG, van Goudoever JB. High-dose cysteine administration does not increase synthesis of the antioxidant glutathione preterm infants. Pediatrics. 2009;124: e978–84. Thureen P, Heird WC. Protein and energy requirements of the preterm/low birthweight (LBW) infant. Pediatr Res. 2005;57:95R–8. Thureen PJ, Melara D, Fennessey PV, Hay WWJ. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res. 2003;53:24–32. Tomlinson C, Rafii M, Ball RO, Pencharz PB. Arginine can be synthesized from enteral proline in healthy adult humans. J Nutr. 2011;141:1432–6. Trivedi A, Sinn JK. Early versus late administration of amino acids in preterm infants receiving parenteral nutrition. Cochrane Database Syst Rev. 2013; 7:CD008771. van den Akker CH, te Braake FW, Wattimena DJ, et al. Effects of early amino acid administration on leucine and glucose kinetics in premature infants. Pediatr Res. 2006;59:732–5. Van Goudoever JB, Colen T, Wattimena JL, Huijmans JG, Carnielli VP, Sauer PJ. Immediate commencement of amino acid supplementation in preterm infants: effect on serum amino acid concentrations and protein kinetics on the first day of life. J Pediatr. 1995; 127:458–65. van Veen LC, Teng C, Hay WWJ, Meschia G, Battaglia FC. Leucine disposal and oxidation rates in the fetal lamb. Metabolism. 1987;36:48–53. Vlaardingerbroek H, Vermeulen MJ, Rook D, et al. Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J Pediatr. 2013;163:638–44.e1-5.

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Vosatka RJ, Kashyap S, Trifiletti RR. Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate. 1994;66:65–70. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134:489–92. Yang S, Lee BS, Park HW, et al. Effect of high vs standard early parenteral amino acid supplementation on the growth outcomes in very low birth weight infants. J Parenter Enter Nutr. 2013;37:327–34.

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Yeh SL, Lai YN, Shang HF, Lin MT, Chen WJ. Effects of glutamine supplementation on innate immune response in rats with gut-derived sepsis. Br J Nutr. 2004; 91:423–9. Ziegler EE. Protein in premature feeding. Nutrition. 1994;10:69–71. Zlotkin SH. Intravenous nitrogen intake requirements in full-term newborns undergoing surgery. Pediatrics. 1984;73:493–6.

Parenteral Amino Acids in Preterm Infant and Impact on Bone Growth

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Martina Betto, Paola Gaio, Giorgia Rizzi, and Giovanna Verlato

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1972 Parenteral AAs in Perinatal Life . . . . . . . . . . . . . . . . . . . 1972 Bone Development and Metabolic Bone Disease in Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . 1973 Parenteral AAs Can Affect Growth and Bone Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parenteral AAs and Growth . . . . . . . . . . . . . . . . . . . . . . . . Parenteral AAs and Bone Health . . . . . . . . . . . . . . . . . . . Topics Needing Further Understanding . . . . . . . . . . . .

1975 1975 1976 1977

Applications to Critical or Intensive Care . . . . . . 1979 Applications to Other Conditions . . . . . . . . . . . . . . . . 1979 Guidelines and Protocols . . . . . . . . . . . . . . . . . . . . . . . . . 1979 Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1980 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1980

M. Betto • P. Gaio • G. Rizzi • G. Verlato (*) Department of Woman and Child’s Health, University of Padova, Padova, Italy e-mail: [email protected]; paola. [email protected]; [email protected]; [email protected]; [email protected] # Springer Science+Business Media New York 2015 R. Rajendram et al. (eds.), Diet and Nutrition in Critical Care, DOI 10.1007/978-1-4614-7836-2_104

Early nutrition and adequate growth can influence future adult health. Nonetheless, recommended nutrient intakes, which can affect growth and bone health, are rarely achieved in preterm infants during the first weeks of life. Peak fetal accretion of bone mineralization occurs during the last trimester of gestation, and preterm infants are exposed to a higher risk of developing metabolic bone disease with an increased bone fragility, a higher fracture risk, and a long-term reduced linear growth and childhood height. When earlier and higher doses of intravenous amino acids were provided to preterm newborns, improved anabolism and shortand long-term somatic growth were observed. Nonetheless, higher amino acid intakes need to be accompanied by adequate energy, phosphate, and calcium intakes to meet the increased requirements for these minerals following enhanced cell anabolism. Further studies, including analysys of plasma amino acid concentrations and markers of amino acid tolerance, will give more details on the upper limit of amino acids to be provided to preterm infants and which are the possible long term influences of amino acids on later growth, body composition, and neurodevelopmental outcome.

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List of Abbreviations

(T)PN AA DEXA ELBWI GA MBD mcBTT mcSOS MDI QUS VLBWI

(Total) parenteral nutrition Amino acid Dual energy x-ray absorptiometry Extremely low birth weight infant Gestational age Metabolic bone disease Metacarpal bone transmission time Metacarpal speed of sound Mental Development Index Quantitative ultrasound Very low birth weight infant

Table 1 List of essential, nonessential, and conditionally essential AAs Essential amino acids Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine

a

Introduction Parenteral AAs in Perinatal Life The aim of nutrition in preterm infants is to administer substrates from the first days of life in order to avoid or limit the period of early neonatal malnutrition and to achieve the rate of growth and body composition of a normal fetus of the same gestational age (GA) (American Academy of Pediatrics 2004). Essential and nonessential amino acids (AAs) play a fundamental role in normal fetal development (Table 1). They have several metabolic roles as purinic basis synthesis, hormone synthesis, and energy production through catabolic reaction, and they are important structural elements for growth for all tissues and particularly muscle and bone. AAs stimulate insulin secretion with the final result of promoting protein synthesis and protein accretion (Thureen et al. 2003). During fetal life, maximal increment in protein mass takes place before 32 weeks of gestation (Micheli and Schutz 1993), and fetuses receive large amounts of AAs, which are used for protein synthesis and are important substrates in fetal energy production. It has been demonstrated that fetal protein accretion is dependent on AAs supply and fetal plasma AA concentrations (Liechty et al. 1999) and that estimated placental transfer in the second and at the beginning of the third trimester of gestation is 3.6–4.8 g/kg/day. After preterm birth, nutrient placental transfer is suddenly interrupted and preterm infants have

Nonessential amino acids Alanine Argininea Asparagine Aspartic acid Cysteinea Glutamic acid Glutaminea Glycinea Prolinea Serine Taurinea Tyrosinea

Conditionally essential amino acids

poor energy stores to face malnutrition; fat accounts for only 2 % of their body weight, while glycogen for 1–2 % of their total protein stores each day (Kashyap 1990). Therefore, the administration of larger amounts of nutrients and particularly of AAs directly after birth is considered a strategy to improve anabolism (Van Goudoever et al. 1995), since it was found that early AA administration improved albumin synthesis (Van den Akker et al. 2007) without increasing the level of metabolic acidosis (Van Goudoever et al. 1995; Thureen et al. 2003; Porcelli and Sisk 2002; Maggio et al. 2007). Nonetheless, preterm babies still receive less of the recommended intakes (Lapillonne et al. 2009)

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though it is suggested that there are “critical windows” in early life where inadequate nutrition and growth can influence human health status in later life (Barker et al. 1993). Positive correlation between growth and neurodevelopmental outcome has been reported (Ehrenkranz et al. 2006), and preventing growth failure would protect from the risk associated with rapid catch-up growth later in life (Singhal et al. 2003, 2004). In this chapter, after defining the pattern of bone development, the role played by AAs in the developing preterm babies and their influence on growth and bone health will be particularly analyzed.

Bone Development and Metabolic Bone Disease in Preterm Infants Bone development is a process of bone mineral accretion and an increase in bone mass. The physiological process of mineralization consists in the incorporation of minerals into the preexistent organic bone matrix, synthesized and deposited by osteoblasts. Bone mineralization occurs in particular during the last trimester of gestation; then, after birth, there is a rapid reduction in bone density followed by a stabilization that lasts to the end of the first year of life. The decrease of physical density is mostly due to an increase in bone marrow cavity size, which is faster than the increase in thickness of the bone cortex (Rauch and Schoenau 2002). During childhood and adolescence, there is a progressive bone growth reaching peak bone mass (maximum total body bone mineral content) at about age 16 in girls and age 18 in boys; in the following years, there is a further small increase in bone mineral content, and final peak bone mass occurs between ages 25 and 30. After that, bone structure stays constant for 10–15 years and then begins to decline (Abrams and Hawthorne 2012). The mechanostat model of development consists in a feedback mechanism between bone deformation and bone stability: when deformation exceeds an acceptable limit, osteocytes might send out signals that could influence bone mass and architecture. In this model, other nonmechanical factors, such as nutrition,

1973

hormones, genetics, and behavioral and environmental factors (e.g., physical activity or drugs), have an effect on bone structure either modifying osteoblast and osteoclast activity or indirectly by influencing longitudinal bone growth or muscle force and mass (Rauch and Schoenau 2001). In particular, nutrition deficiency could act on bone metabolism through the losses in body mass but also through hormonal imbalances (Bass et al. 2005). Applying this model on gestational period, fetal bone development appears influenced by the regular fetal kicks against the uterine wall. In newborns and children, instead, bone stability is continuously adapted by the increased load that is the result of growth in length and increasing muscle force and muscle contraction (Rauch and Schoenau 2001). At term, newborn skeleton has a high cortical thickness and relative small marrow cavities. After birth there is a physiological change in bone metabolism resulting from various factors: disruption in maternal mineral and nutrient supplies, change in hormonal environment and secretions (decreased estrogen levels and increased parathyroid secretion), and reduction in mechanical stress due to kicks against the uterine wall (Rigo and Senterre 2006) resulting in an increase in endosteal bone resorption and a decrease in physical density (Rauch and Schoenau 2001). A rapid reduction of bone mineral apparent density from birth to the first months of life was reported in newborns by applying X-ray absorptiometry technology (DEXA) (Rigo and Senterre 2006; Rigo et al. 1998). To assess bone health in term and preterm newborns by quantitative ultrasound (QUS), Ritschl et al. used their longitudinal data to devise reference curves for metacarpal speed of sound (mcSOS) and metacarpal bone transmission time (mcBTT); these curves reflect the same bone remodeling process observed by DEXA (Ritschl et al. 2005). DEXA and QUS could have a role in the assessment of bone health and disease. QUS is a simpler, noninvasive, low-cost, and non-ionizing method that can be used at the bedside, and it is easily accessible, in particular in the neonatal intensive care unit (NICU). QUS assesses both qualitative and quantitative bone properties as structure, density, and

1974 Table 2 Physiopathological changes in bone metabolism at birth Disruption in placental mineral and nutrient supplies Change in hormonal environment and secretions: – Decreased estrogen levels – Increased parathyroid secretion Reduction in mechanical stress due to kicks against the uterine wall Enhanced catabolism Insufficient nutrient (protein and mineral supplies)

elasticity. The distance and the time elapsing between an emitting and a receiving probe are measured to calculate SOS and BTT. There are some differences in bone development between term and preterm infants. When birth occurs prematurely, estrogen supply is stopped earlier, and there is an abrupt interruption of the nutritional support (energy, proteins, minerals, and vitamins) from the mother through the placenta. About 80 % of calcium, phosphorus, and magnesium of the term infants are laid down during the third trimester of gestation, the time of peak fetal accretion of bone mineralization, so premature newborns could be at risk of having less-than-optimal normal bone mass due to the interruption of mineral supply (Atkinson and Tsang 2005). Furthermore, the physiological postnatal skeletal remodeling, characterized by a physical density deflection, occurs earlier with a lowest nadir than in term babies (Ritschl et al. 2005) (Table 2). Both osteopenia, resulting from diminished synthesis and/or increased resorption of organic bone matrix, and osteomalacia/rickets due to a deficient supply or uptake of mineral can occur after premature birth in a condition called metabolic bone disease (Rauch and Schoenau 2002). This condition can be accompanied by an increase in bone fragility and higher fracture risk, and in the long-term, it might adversely affect linear growth and childhood height. Preterm infants with biochemical evidence of bone disease (defined with a peak neonatal plasma alkaline phosphatase >1,200 IU) were shorter at the age of 9–12 years (Fewtrell et al. 2000). We can speculate that this compromised childhood bone mass could lead to an increased risk for osteoporosis in

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adulthood, as shown in a Finnish study where young adults born with very low birth weight had significantly lower bone mineral density than adults born at term (Hovi et al. 2009). Metabolic bone disease (MBD) occurs in 39 % of preterm infants with a birth weight under 1,500 g, and fractures are reported in 10.5 % of this population (Dabezies and Warren 1997). The etiology is likely multifactorial, an inevitable consequence of common illnesses, metabolic acidosis, use of diuretics and steroids, immobilization, malnutrition, prolonged use of total parenteral nutrition (TPN), and insufficient intakes of calcium, phosphorus, and vitamin D (Ryan 1996; Klein 1998). Use of TPN is likely associated with MBD; causes of this association could be an inadequate supply of proteins and energy that could compromise the synthesis of bone tissue (Rigo and Senterre 2006) and an inadequate amount of calcium and phosphate supplied by TPN to match the in utero mineral accretion rates, possibly due to limits in pharmacological preparations and the restriction of fluid intake. Moreover, other clinical conditions related to TPN use may influence bone status, for example, gastrointestinal and liver diseases, effect of hormones and renal control, immobilization, therapy with drug-induced alteration in bone metabolism, and lack of enteral nutrition (Klein 1998). Type of enteral nutrition could influence bone health in newborns. The duration of exclusive breastfeeding in neonates was positively related to lumbar spine DEXA in adolescence (Mølgaard et al. 2011), and a positive correlation between human milk intake and bone mass was found in 20-year-old subjects born preterm (Fewtrell 2011) suggesting the possible role of human milk nonnutritive factors on bone development. As supported by the mechanostat model, mechanical factors and muscle activities play a part in improving bone growth also in premature newborns. In a randomized controlled clinical trial, preterm infants between 26 and 34 weeks of GA in stable conditions were randomized into a control group that received routine care and a group that received physiotherapy, which consisted in 15 min of daily treatment, five times per week until hospital discharge. At the end of

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Table 3 Causes of metabolic bone disease in preterm infants Metabolic acidosis Therapy with drug-induced alteration in bone metabolism (e.g., diuretics and steroids) Prolonged use of total parenteral nutrition Inadequate nutrient supplies to match the in utero accretion rates Insufficient intakes of calcium, phosphorus, vitamin D Malnutrition and protein malnutrition Gastrointestinal and liver diseases Lack of enteral nutrition Hormones imbalance Lack of renal control Immobilization

the study, newborns into the physiotherapy group had significantly greater weight gain and length and better body composition values verified by DEXA (Vignochi et al. 2008). Positive effects of the physiotherapy were confirmed in a study where bone strength was determined by QUS: during the study period, bone SOS decreased in the control group but remained stable in the physiotherapy group (Litmanovitz et al. 2003). Some biochemical parameters of bone metabolism were collected in another randomized controlled trial, and the physiotherapy group had significantly lower level of urinary deoxypyridinoline than control group after applying the exercise protocol, showing that the imbalance between bone formation and resorption was mitigated by physiotherapy (Vignochi et al. 2012). Therefore, it appears important to limit immobilization and to optimize all nutrients that play a role in bone growth (Table 3).

Parenteral AAs Can Affect Growth and Bone Health Parenteral AAs and Growth Energy intakes and increment in protein accretion are deeply related; their relationship is curvilinear with most effect at 50–60 Kcal/kg/day, but increased protein intake leads to increased protein

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Table 4 Influences of different levels of AAs intakes (g/kg/day) early after birth g/kg/day 0 lose 1–2 %/day of protein stores (Kashyap 1990) 1.5 preventing catabolism (Thureen et al. 1998) 3 increase protein and leucine balances (Thureen et al. 2003) Better anthropometry at 36 weeks GA (Poindexter et al. 2006) 4 target in VLBWI (Ziegler 1994)

mass at all energy intakes, supposed we are above catabolism (Micheli and Schutz 1993). A protein intake of 1.5 g/kg/day is recommended for the preterm infant in order to prevent the breakdown of endogenous tissue (Thureen et al. 1998), and preterm receiving 3 g/kg/day of AAs also had significantly more positive protein and leucine balances (Thureen et al. 2003). Nonetheless, the requirements to attain intrauterine rates of protein deposition are around 4 g/kg/day in the smallest very low birth weight infants (VLBWI) (Ziegler 1994) (Table 4). Several studies found positive influence of early AA administration on growth. Already in the 1990s, randomized trial found that an aggressive nutrition (earlier and higher AAs intake) resulted in a significant reduction in the age that birth weight was regained and significant improvement in growth at hospital discharge without an increase in complications (Wilson et al. 1997). More recently, early higher protein intakes compared with standard intake control groups were associated with improved weight and length growth outcomes at discharge or at 40 weeks of postmenstrual age (Dinerstein et al. 2006; Maggio et al. 2007). Applying earlier and higher intakes of AAs resulted in fewer days to regain birth weight (Kotsopoulos et al. 2006; Radmacher et al. 2009), less postnatal weight loss (Radmacher et al. 2009), and less growth failure at discharge (Valentine et al. 2009). Parenteral AA intake at postnatal week 1 correlated directly with weight gain from birth to postnatal week 2 (Porcelli and Sisk 2002) and also with weight at 36 weeks of GA (Scattolin et al. 2013). The AA intake necessary to get a growth advantage was also studied. Olsen et al. found

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that the addition of 1 g of protein per kg per day could increase weight growth of 4 g/kg per day (Olsen et al. 2002). It has also been reported that infants who received 3 g/kg/day of parenteral AA within the first 5 days of life increased anthropometric parameters at 36 weeks of GA (better weight, length, and head circumference) and fewer male infants in the same group were found with head circumference below the 10th and 5th percentiles at the 18-month follow-up visit (Poindexter et al. 2006). Intrahospital growth positively correlated with neurologic outcome (Franz et al. 2009; Ehrenkranz et al. 2006). Furthermore, week 1 energy and protein intakes were each independently associated with Mental Development Index (MDI). Each gram per kilogram per day in protein intake was associated with an 8.2 point increase in the MDI; higher protein intake was also associated with lower likelihood of length 1,200) were correlated to final body height, and young adults born as VLBWI had significantly lower bone mineral density than adults born at term. Therefore, it seems mandatory to promote adequate growth and bone health since early life.

Guidelines and Protocols Guidelines on PN in children have been established (Koletzko et al. 2005) with the intent to serve as an aid to clinical judgment. In a recent

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survey (Lapillonne et al. 2013) exploring nutritional practices in the 74 % of NICUs in four European countries, a still high variability in the application of guidelines was found. In particular, for AA intakes, the target dose of AAs was reached in 91 % of the answering units; nonetheless, the day of starting AAs and the initial dose were adherent to guidelines only in the 63 % and the 38 %, respectively. It appears that most of the differences are found soon after birth when there is still a delay in the delivery of an adequate AA intake. The authors outline the need to improve guideline knowledge and dissemination and suggest the use of a web-based system reporting the adherence of local protocols with guidelines.

Summary Points • Preterm newborns need higher nutrient and in particular amino acid intakes to reach peak protein mass while they are subjected to higher proteolysis and lack in placental nutrient supplies and are exposed to enhanced catabolism in the neonatal intensive care units. • Early higher amino acid intakes showed advantages in terms of promoting anabolism and growth during hospitalization and also after hospital discharge. • Preterm infants are exposed to higher risk to develop metabolic bone disease that in the long term might adversely affect linear growth and childhood height. • Parenteral amino acids positively affect bone metabolism, but adequate phosphate and calcium intakes must be provided to avoid their release from bone and meet their increased needs following enhanced cell anabolism. • Future research will give more details on the upper limit of amino acids to be provided and which are the possible short- and long-term amino acid influences on later growth, body composition, and neurodevelopmental outcome.

M. Betto et al.

References Abrams SA, Hawthorne KM. What drives bone mineralization during puberty and what is meant by peak bone mass? In: Abrams SA, Hawthorne KM, editors. Bone health in children. Boca Raton: CRC Press Taylor & Francis Group; 2012. p. 90–3. American Academy of Pediatrics. Nutritional needs of the preterm infant. In: Kleinman RE, editor. Pediatric nutrition handbook, vol. 36. 5th ed. Elk Grove: American Academy of Pediatrics; 2004. p. 23–54. Ammann P, Bourrin S, Bonjour J, et al. Protein undernutrition-induced bone loss is associated with decrease IGF-I levels and estrogen deficiency. J Bone Miner Res. 2000;15:683–90. Atkinson SA, Tsang R. Calcium, magnesium, phosphorus and vitamin D. In: Tsang RC, Uauy R, Koletzko B, Zlotkin S, editors. Nutrition of the preterm infant. 2nd ed. Ohio: Digital Educational Publishing; 2005. p. 245–75. Barker DJ, Gluckman PD, Godfrey KM, et al. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341:938–41. Bass SL, Eser P, Daly R. The effect of exercise and nutrition on the mechanostat. J Musculoskelet Neuronal Interact. 2005;5:239–54. Blanco CL, Gong AK, Schoolfield J, et al. Impact of early and high amino acid supplementation on ELBW infants at 2 years. J Pediatr Gastroenterol Nutr. 2012;54:601–7. Bonsante F, Iacobelli S, Latorre G, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants – it is time to change the composition of the early parenteral nutrition. PLoS One. 2013;8: e72880. Bourrin S, Ammann P, Bonjour JP, et al. Dietary protein restriction lowers plasma insulin-like growth factors I (IGF-I), impairs cortical bone formation, and induces osteoblastic resistance to IGF-I in adult female rats. Endocrinology. 2000;141:3149–55. Chevalley T, Hoffmeyer P, Bonjour JP, et al. Early serum IGF-I response to oral protein supplements in elderly women with a recent hip fracture. Clin Nutr. 2010;29:78–83. Clark RH, Chace DH, Spitzer AR, et al. Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a randomized, controlled trial. Pediatrics. 2007;120: 1286–96. Dabezies EJ, Warren PD. Fractures in very low birth weight infants with rickets. Clin Orthop Relat Res. 1997;335:233–9. Denne SC. Regulation of proteolysis and optimal protein accretion in extremely premature newborns. Am J Clin Nutr. 2007;85:621S–4. Dinerstein A, Nieto RM, Solana CL, et al. Early and aggressive nutritional strategy (parenteral and enteral)

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decreases postnatal growth failure in very low birth weight infants. J Perinatol. 2006;26:436–42. Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117:1253–61. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics. 2001;107:270–3. Fewtrell MS. Does early nutrition programme later bone health in preterm infants? Am J Clin Nutr. 2011; 94(6 suppl):1870S–3. Fewtrell MS, Cole TJ, Bishop NJ, et al. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr. 2000;137:668–73. Fewtrell MS, Bishop NJ, Edmonds CJ, et al. Aluminum exposure from parenteral nutrition in preterm infants: bone health at 15-year follow-up. Pediatrics. 2009;124: 1372–9. Franz AR, Pohlandt F, Bode H, et al. Intrauterine, early neonatal, and postdischarge growth and neurodevelopmental outcome at 5.4 years in extremely preterm infants after intensive neonatal nutritional support. Pediatrics. 2009;123:e101–9. Ginty F. Dietary protein and bone health. Proc Nutr Soc. 2003;62:867–76. Heaney RP, Layman DK. Amount and type of protein influences bone health. Am J Clin Nutr. 2008;87 (suppl):1567S–70. Hoppe C, Molgaard C, Michaelsen KF. Bone size and bone mass in 10-year-old Danish children: effects of current diet. Osteoporos Int. 2000;11:1024–30. Hovi P, Andersson S, J€arvenp€a€a AL, et al. Decreased bone mineral density in adults born with very low birth weight: a cohort study. PLoS Med. 2009;6: e1000135. Javaid MK, Godfrey KM, Taylor P, et al. Umbilical venous IGF-1 concentration, neonatal bone mass, and body composition. J Bone Miner Res. 2004;19:56–63. Kalhoff H, Diekmann L, Rudloff S, et al. Renal excretion of calcium and phosphorus in premature infants with incipient late metabolic acidosis. J Pediatr Gastroenterol Nutr. 2001;33:565–9. Kashyap S. Nutritional management of the extremely-lowbirthweight infant. In: Cowett RM, Hay Jr WW, editors. The micropremie: the next frontier. Report of the 99th Ross conference on pediatric research. Columbus: Ross Laboratories; 1990. Kerstetter JE, O’Brien KO, Insogna KL. Dietary protein affects intestinal calcium absorption. Am J Clin Nutr. 1998;68:859–65. Klein GL. Metabolic bone disease of total parenteral nutrition. Nutrition. 1998;14:149–52. Koletzko B, Goulet O, Hunt J, et al. Paediatric parenteral nutrition. J Pediatr Gastroenterol Nutr. 2005;41 Suppl 2:S1–87.

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Kotsopoulos K, Benadiba-Torch A, et al. Safety and efficacy of early amino acids in preterm 2 calendar days on the date of the event, with day of device placement being Day 1, and a CVC or UC was in place on the date of the event or the day before. If a CVC or UC was in place for >2 calendar days and then removed, the LCBI criteria must be fully met on the day of discontinuation or the next day. If the patient is admitted or transferred into a facility with a central line in place (e.g., tunneled or implanted central line), day of first access is considered Day 1. LCBI must meet one of the following criteria:

• Catheter contamination: isolation of microorganisms in the distal segment of the catheter = 15 CFU/ml) and from the blood (preferably drawn from a peripheral vein) of a patient with accompanying clinical symptoms of BSI and no other apparent source of infection • Probable CRBSI: isolation of microorganisms from a semiquantitative culture in the distal segment of the catheter (>= 15 CFU/ml) or positive blood culture and culture of connection and/or positive skin culture for the same germ in a patient with accompanying clinical symptoms of BSI and no other apparent source of infection

1. Patient has a recognized pathogen cultured from one or more blood cultures and the organism cultured is not related to infection at another site. 2. Patient has at least one of the following signs or symptoms: fever (>38  C), chills, or hypotension, and positive laboratory results are not related to an infection at another site and the same common commensal is cultured from two or more blood cultures drawn on separate occasions. Criterion elements must occur within a timeframe that does not exceed a gap of 1 calendar day between two adjacent elements. 3. Patient 1 year of age has at least one of the following signs or symptoms: fever (>38  C core), hypothermia (85 %) removed due to this suspicion will be sterile (Ryan et al. 1974). In patients admitted to PICUs, the removal of a CVC represents the interruption of treatment, which in some cases can have serious consequences. Therefore, the decision to remove a catheter suspecting infection should be studied carefully. It is important not to forget that the direct cost of primary bloodstream infection in pediatric intensive care units is about $40,000, so extreme care must be taken trying to avoid this complication in order to save a great amount of economic resources (Elward et al. 2005). Particularly, the attributable cost of CRBSI is about $12,000 (Warren et al. 2006).

Risk Factors Identification of risk factors associated with CRBSI is essential to implement intervention programs in order to reduce the incidence of this complication. Duration of catheterization (Slonim et al. 2001; De Gaetano et al. 1999; Garcia-Teresa et al. 2007; Odetola et al. 2003; Van der Kooi et al. 2007; Yilmaz et al. 2007), exchange of CVC over a guide wire (Garnacho-Montero et al. 2008), insertion site (Gowardman et al. 2008), and parenteral nutrition (Ishizuka et al. 2008) were described as contributors to CRBSI in critically ill patients. PICUs differ from adult intensive care units (ICUs) in a number of ways, apart from the age of their patients. Therefore, specific studies in PICUs are of great value. Rey et al. found that PN (odds ratio 3.38 (1.40–8.19)) and indwelling time (odds ratio 1.08 (1.02–1.14)) were CRBSI risk factors (Rey et al. 2011). They introduced practice changes aimed at reducing PN and IT. After decreasing PN from 49.8 % (95% CI 49.7–49.9) to 26.7 % (95% CI 26.6–26.8) ( p 1 mg/dL by 24 h of life and 2 mg/dL by 3 days of life has been recommended (Brion et al. 2003; Brion et al. 2004; Henriksen et al. 2006). These levels should be attainable with the administration of

current PN MVI formulations, which would provide 2.8 mg/kg/day of vitamin E if given daily. A meta-analysis of low birth weight infants demonstrated that either enteral or parenteral supplementation with vitamin A reduced the risk of both death and oxygen requirement at 1 month of age, and the risk of oxygen requirement at 36 weeks corrected gestational age (Darlow and Graham 2011). Preterm infants are born with essentially no hepatic reserves of vitamin A (Darlow and Graham 2011); therefore, vitamin A needs to be provided consistently from PN. In cases where MVI administration is being limited to 3 times a week due to shortages, it may be possible to eliminate weight-based guidelines and provide larger doses intermittently in a neonatal or pediatric population. Poor outcomes due to deficiency in adults have been reported as well; a 2005 case study described a patient on long-term PN due to bowel resections who presented with subacute vision disturbances due to vitamin E deficiency. This patient was only receiving electrolyte supplementation, as it was believed he had undergone bowel adaptation sufficient to meet micronutrient needs (Porter et al. 2005). Although this case was not directly related to shortages, it highlights the potential adverse events that can be associated with restriction of MVI.

Applications to Critical or Intensive Care Shortages of PN components may have the greatest impact on patients in critical care units, as they may be the most likely population to require PN. In situations where health care providers are forced to deal with shortages of parenteral components, it is critical that thorough nutritional assessments and monitoring be conducted on a routine basis to monitor for potential poor patient outcomes and to intervene whenever possible to minimize the impact of nutritional deficiencies. Enteral nutrition is always the preferred route of feeding, and any patient capable of tolerating enteral nutrition should have feedings initiated via this route, even if enteral nutrition

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cannot meet 100 % of nutritional needs. Indeed, many studies have documented the tolerance of critical care patients to enteral feeds (National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network et al. 2012), and enteral feeding in critical care appears to have many benefits, including a reduction in infections and mortality in critically ill patients (Strack van Schijndel et al. 2009). However, for patients unable to consume or absorb nutrition enterally, including many patients in critical care units, nutrient administration during parenteral shortages remains a significant challenge; and unfortunately these patients are often at the highest risk for nutrient deficiencies.

Applications to Other Conditions In clinical experience, there are two primary patient populations at the highest risk for nutrient deficiencies, which include low birth weight premature infants and patients with severe short bowel syndrome. Furthermore, these populations are least likely to benefit from enteral nutrient supplementation during parenteral shortages. It is therefore crucial that protocols be in place to allow for prioritization of recipients receiving parenteral nutrition products during periods of low supply. In addition, it is essential that practitioners only use parenteral nutrition when there are strong indications, as inappropriate use of parenteral nutrition may further deplete crucial products. The challenge of providing adequate nutrition to premature infants during parenteral shortages is due to their significant initial reliance on parenteral nutrition to meet nutritional needs. ASPEN recommends the use of enteral supplementation when parenteral products are unavailable. However, low birth weight infants are born with immature gastrointestinal functions and poor intestinal motility, so enteral feedings are increased slowly over the course of one to several weeks to ensure tolerance and avoid complications. Therefore, it is often unfeasible to add oral vitamin or mineral supplements to enteral feedings during this time, as daily enteral volumes may not exceed more

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than one-half or one ounce daily. Adding supplements to these small volumes also increases the osmolarity of the feedings, which may contribute to feeding intolerance or more serious complications like necrotizing enterocolitis. Patients with severe short bowel syndrome, whether pediatric or adult, often require longterm parenteral nutrition. Some of these patients may be allowed enteral intake to prevent cholestasis, but for some, these feedings are a minimal source of nutrition. If essential nutrients cannot be added parenterally for these patients, enteral supplementation is likely of minimal benefit if there is limited absorptive capability. Some clinicians working with this population will add large enteral doses of certain vitamins or minerals to promote some absorption. However, it is unclear if this provides significant benefits. In one case at an institution, a home care company did not have any calcium or phosphorus available for a parenterally dependent young pediatric patient. As this patient had less than 10 cm of small bowel remaining, the medical team questioned if the patient should be hospitalized in an institution with these parenteral products available. Though far from an ideal situation, this is an example of the significant impact parenteral shortages can have on medical management decisions.

Guidelines and Protocols For patients on prolonged parenteral nutrition, there are suggested guidelines for the type and frequency of monitoring as seen in Table 5. Of note, these guidelines are recommended for stable patients receiving appropriate amounts of all parenteral nutrients. If parenteral nutrients are eliminated or reduced from baseline needs, more frequent monitoring will be required. During extreme shortages, it may also be of benefit to use physical assessment of a patient more frequently, to help detect signs of severe nutrient deficiencies. A partial list of physical signs and associated micronutrient deficiencies is shown in Table 6. As always, type and timing of monitoring will depend on each patient’s status and risk factors.

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C. Hanson et al.

Table 5 Suggested laboratory and physical monitoring schedule for patients receiving parenteral nutrition support (online Pediatric Nutrition Care Manual; ASPEN Nutrition Support Core Curriculum, Chap. 36, ASPEN Pediatric Nutrition Support Core Curriculum, Chap. 36) Growth: weight Growth: height/length Growth: head circumference Electrolytes

Glucose

Infants

Pediatric

Adults

Daily

Weekly

Weekly

Weekly

Monthly

N/A

Weekly

Monthly

N/A

Daily until stable, then every 1–2 weeks

Daily until stable, then every 1–4 weeks

As indicated

As indicated and daily until stable, every 1–4 weeks

Daily until stable, then weekly for 1–2 weeks, monthly for 3 months, then every 6 months As indicated and daily until stable, weekly for 1–2 weeks, monthly for 3 months, then every 6 months Weekly for 1–2 weeks, monthly for 3 months, then every 6 months Optional at baseline depending on underlying disease status, then as indicated

Calcium, magnesium, phosphorus

Every 1–2 weeks

Every 1–4 weeks

Vitamins/ minerals/trace elements

As indicated

Vitamin B12 and folic acid at 6 months, then yearly; zinc, selenium, copper, chromium, and manganese at 3 months, then every 3–6 months; molybdenum and vitamin D yearly; others as

(continued)

Table 5 (continued) Infants

Pediatric clinically indicated Every 1–4 weeks

Serum urea nitrogen/ creatinine

Every 1–2 weeks

Serum proteins

Every 2–3 weeks

Monthly

Liver enzymes

Every 2–3 weeks

Every 1–4 weeks

Alkaline phosphatase

Every 2–3 weeks

Every 1–4 weeks

Hematocrit Blood cell count

Every 2–3 weeks

Every 1–4 weeks Every 1–4 weeks

Adults

Weekly for 1–2 weeks, monthly for 3 months, then every 6 months Weekly for 1–2 weeks, monthly for 3 months, then every 6 months Weekly for 1–2 weeks, monthly for 3 months, then every 6 months Weekly for 1–2 weeks, monthly for 3 months, then every 6 months Every 6 months Every 6 months

Summary Points • Shortages of components for parenteral nutrition are a major concern for patients in the critical care unit, who may be more likely to be PN dependent • Inadequate administrations of several nutrients currently in short supply are linked to poor critical care outcomes. • During parenteral nutrition component shortages, it is crucial to carefully monitor patients receiving PN to identify potential nutrient deficiencies and to identify possible intervention strategies.

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Table 6 Physical signs of micronutrient deficiency and biochemical indications of deficiency (Adapted from the ASPEN Nutrition Support Core Curriculum, Chaps. 7, 8, and 36) Micronutrient Biotin

Possible deficiency signs Alopecia, dermatitis

Chromium

Glucose intolerance, hypertriglyceridemia

Copper

Depigmentation, microcytic anemia

Folic Acid Iron

Macrocytic anemia, peripheral neuropathy Microcytic anemia

Magnesium Manganese Molybdenum

Anorexia, weakness Abnormal clotting, depigmentation, dermatitis Confusion

Niacin

Dementia, dermatitis, diarrhea

Riboflavin

Cheilosis, glossitis, scaly skin, weakness

Selenium

Diarrhea, heart failure, weakness

Thiamine

Anorexia, dyspnea, heart failure, hepatomegaly, lactic acidosis, peripheral neuropathy, oliguria Alopecia, night blindness, scaly skin Bleeding gums, petechiae Bleeding gums, retinal degeneration Osteomalacia Hemorrhage Glossitis, macrocytic anemia, peripheral neuropathy Delayed wound healing, dermatitis, dysgeusia, glossitis, growth retardation, immunoincompetence, night blindness, photophobia, scaly skin

Vitamin A Vitamin C Vitamin E Vitamin D Vitamin K Vitamin B12 Zinc

Biochemical indication of deficiency Urine biotin