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z.f • • r1t1ca Care SECOND EDITION •' , - ~ > ~ ,> ~ ' - - ~' ·- - - '>"" ··~ < Oxford Textbook of Critical Care Free personal online access for 12 months Individual purchasers of this book are also entitled to free personal access to the online edition for 12 months on Oxford Medicine Online (www.oxfordmedicine.com) Please refer to the access token card for instructions on token redemption and access Online ancillary materials, where available, are noted at the end of the respective chapters in this book Additionally, Oxford Medicine Online allows you to print, save, cite, email, and share content; download high-resolution figures as Microsoft PowerPoint slides; save often-used books, chapters, or searches; annotate; and quickly jump to other chapters or related material on a mobile-optimized platform We encourage you to take advantage of these features If you are interested in ongoing access after the 12-month gift period, please consider an individual subscription or consult with your librarian Oxford Textbook of Critical Care SECOND EDITION Edited by Professor Andrew Webb, MD, FRCP, MFMLM Clinical Professor, Division of Critical Care, Faculty of Medicine, The University of British Columbia, Canada Professor Derek C. Angus, MD, MPH, FRCP Distinguished Professor and Mitchell P. Fink Endowed Chair Department of Critical Care Medicine University of Pittsburgh and UPMC Health System Professor Simon Finfer, MBBS, FAHMS, FRCP, FRCA, FCICM, DrMed Professor of Critical Care, The George Institute for Global Health, University of Sydney Senior Staff Specialist in Intensive Care, Royal North Shore Hospital, Sydney Professor Luciano Gattinoni, MD FRCP Chief of the Department of Anaesthesia, Resuscitation and Emergency Medicine, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico Full Professor in Anesthesiology and Intensive Care Medicine, Department of Pathophysiology and Transplantation, University of Milan Professor Mervyn Singer, MD FRCP, FRCP, FFICM Professor of Intensive Care Medicine, University College London 1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2016 The moral rights of the authorshave been asserted First Edition Published in 1999 Second Edition Published in 2016 Impression: 1 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2015939284 ISBN 978–0–19–960083–0 Printed in China through Asia Pacific Offset Ltd Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations The authors and the publishers not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding Links to third party websites are provided by Oxford in good faith and for information only Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work Foreword One may ask in today’s internet-based world whether there is still a need for textbooks when there is so much opinion and advice already available online Although possibly not able to capture and include the very latest research results, textbooks provide a solid basis and background of the subject in question giving an essential framework of understanding on which to build This Oxford Textbook of Critical Care is a true example of quality All the authors are well-known experts in their field, the chapters have all been carefully reviewed and the contents are, therefore, relevant and reliable What is more, as with many recent publications, this textbook is also available as an online version for easy reference This completely revised and comprehensive version of the 1999 edition covers all possible aspects of intensive care medicine making it an impressive tome The chapters are short, concise and to the point, and thus easy to read and understand The book is wellillustrated and the layout is fresh and attractive The key points, highlighted at the start of each chapter, provide a useful summary of each topic and the book in general is clinically-orientated, making it of value for the practicing clinician, as well as physicians in training The book benefits from an impressive list of true experts from around the globe, giving it international appeal and insight— it is a real credit to the editors that so many leading authorities have contributed! I believe textbooks still have an important role in providing a trustworthy source of knowledge As different textbooks will have a slightly different focus, include different authors, and use various presentation formats they can complement each other This book will occupy an important place in this field and is a highly recommended reference for all involved in the care of critically-ill patients Jean-Louis Vincent, MD PhD Professor of Intensive Care Medicine, Université Libre de Bruxelles Preface Since the first edition of the Oxford Textbook of Critical Care was published there have been many advances in our understanding and management of critical illness We prefaced the first edition with a note on the exacting nature of critical care; the holistic complexity of the patient with multisystem dysfunction, the out-of-hours commitment, the often stressful and highly charged situations requiring considerable agility of brain and hand, and the continuing evolution (and occasional revolution) in perceived ‘best practice’ However, these challenging demands are precisely what attract the critical care practitioner to the specialty The importance of strong support mechanisms—from colleagues, from national and international societies, and from robust educational and research outputs—is paramount to not only sustain but also enhance the quality of care given Recognizing the increasing use of electronic media for reference, we have continued the format used in the first edition The traditional chapter layout of a textbook gave way to system-orientated sections Each section has been subdivided into short topics grouped within the section according to clinical problems We believe the reader will often come to this book, in paper or electronic format, wishing to update on a specific clinical problem that matches an issue experienced at the bedside Furthermore, this layout facilitates manageable and relevant searches in electronic media The Oxford Textbook of Critical Care is a single-volume major reference book aiming to cover the breadth of clinical and organizational aspects of adult critical care medicine in readable chunks We clearly acknowledge that every single topic cannot possibly be covered in detail, but hope its comprehensive nature will be found useful by all health care providers who look after critically-ill patients We recognize there are often local, national, and international differences in philosophy and management strategy Some of these differences are seemingly contradictory and it is often difficult for physicians in one country to assimilate information produced for another We intended from the outset to offer the Oxford Textbook of Critical Care as an international text We have attempted to give a balanced view where international differences exist and, in many cases, have sat squarely on the fence We make no apology for this since we believe the book should inform rather than dictate Producing this edition has been a mammoth task, co-ordinating the efforts of over 600 authors from all corners of the world We thank all those who have contributed to this project and to members of the staff of Oxford University Press for persuading us to take on this second edition, and whose skill and support have been essential to the editorial and production process Finally, the editors are saddened to hear of the passing of Dr Mitchell Fink, Prof Albert Jaeger and Dr Jan Kornder since the submission of their contributions to the book Andrew Webb Derek C Angus Simon Finfer Luciano Gattinoni Mervyn Singer Contents Abbreviations xxvii PART 1.2 Contributors xxxix Communication SECTION 1 ICU organization and management PART 1.1 The intensive care unit Design of the ICU Neil A. Halpern Staffing models in the ICU Tim Buchman and Michael Sterling Rapid response teams for the critically ill 11 Ken Hillman and Jack Chen In-hospital transfer of the critically ill 14 Lorna Eyre and Simon Whiteley Pre- and inter-hospital transport of the critically ill and injured 19 Kelly R. Klein and Paul E. Pepe Regional critical care delivery systems 24 Theodore J. Iwashyna and Colin R. Cooke Integration of information technology in the ICU 28 Daniel Martich and Jody Cervenak Multiple casualties and disaster response in critical care 32 Yoram Weiss and Micha Shamir Management of pandemic critical illness 37 Robert Fowler and Abhijit Duggal 10 Effective teamwork in the ICU 43 Peter G. Brindley 11 Communication with patients and families in the ICU 46 Leslie P. Scheunemann and Robert M. Arnold 12 Telemedicine in critical care 51 Bela Patel and Eric J Thomas PART 1.3 Training 13 Clinical skills in critical care 56 Graham Nimmo and Ben Shippey 14 Simulation training for critical care 60 Ben Shippey and Graham Nimmo 15 Leadership skills in the ICU 64 Carole Foot and Liz Hickson PART 1.4 Safety and quality 16 Patient safety in the ICU 71 Bradford D. Winters and Peter J. Pronovost 17 Policies, bundles, and protocols in critical care 75 Jeffrey Mazer and Mitchell M. Levy 18 Managing biohazards and environmental safety 78 Ferenc Kovari and Gilbert Park x contents 19 Managing ICU staff welfare, morale, and burnout 81 Gavin G Lavery and Linda-Jayne Mottram PART 1.5 Governance 20 ICU admission and discharge criteria 86 Julian Bion and Anna Dennis 21 Resource management and budgeting in critical care 90 Jukka Takala 22 Costs and cost-effectiveness in critical care 94 SECTION 2 Pharmacotherapeutics PART 2.1 Respiratory drugs 32 Oxygen in critical illness 139 James N. Fullerton and Mervyn Singer 33 Bronchodilators in critical illness 144 Rajiv Dhand and Michael McCormack PART 2.2 Cardiovascular drugs David J. Wallace and Derek C. Angus 34 Vasopressors in critical illness 149 PART 1.6 35 Vasodilators in critical illness 153 Research 23 Evidence-based practice in critical care 100 Marius Terblanche and Damon C. Scales 24 Research ethics in the ICU 104 Neal W. Dickert and Scott D. Halpern Daniel De Backer and Patrick Biston A B. J Groeneveld and Alexandre Lima 36 Inotropic agents in critical illness 158 Abdallah Fayssoil and Djillali Annane 37 Anti-anginal agents in critical illness 161 Ajay Suri and Jean R. McEwan 38 Anti-arrhythmics in critical illness 165 PART 1.7 Medico-legal and ethical issues 25 Informed consent in the ICU 108 Henry J. Silverman 26 Patient rights in the ICU 113 Thaddeus M. Pope and Douglas B. White 27 Medico-legal liability in critical care 117 Michael A. Rie PART 1.8 Critical illness risk prediction 28 The role and limitations of scoring systems 121 Hannah Wunsch and Andrew A. Kramer 29 Severity of illness scoring systems 125 Graeme K. Hart and David Pilcher 30 Organ failure scoring 130 Rui Moreno 31 Genetic and molecular expression patterns in critical illness 133 Anthony F. Suffredini and J Perren Cobb John LeMaitre and Jan Kornder 39 Pulmonary vasodilators in critical illness 170 Benjamin Chousterman and Didier Payen PART 2.3 Gastrointestinal drugs 40 Gastrointestinal motility drugs in critical illness 175 Sonja Fruhwald and Peter Holzer 41 Stress ulcer prophylaxis and treatment drugs in critical illness 180 Waleed Alhazzani and Deborah J. Cook PART 2.4 Nervous system drugs 42 Sedatives and anti-anxiety agents in critical illness 185 Curtis N. Sessler and Katie M. Muzevich 43 Analgesics in critical illness 189 Mayur B. Patel and Pratik P. Pandharipande 44 Antidepressants in critical illness 193 Scott R. Beach and Theodore A. Stern contents 45 Antiseizure agents in critical illness 198 Sebastian Pollandt and Lori Shutter 46 Inhalational anaesthetic agents in critical illness 202 Laurent Beydon and Flavie Duc 47 Muscle relaxants in critical illness 206 Brian J. Pollard 48 Neuroprotective agents in critical illness 210 Jerrold L Perrott and Steven C Reynolds PART 2.5 Hormonal drugs 49 Hormone therapies in critical illness 215 Mark S. Cooper 50 Insulin and oral anti-hyperglycaemic agents in critical illness 218 Roosmarijn T M. van Hooijdonk and Marcus J. Schultz PART 2.6 Haematological drugs 51 Anticoagulants and antithrombotics in critical illness 223 Vickie McDonald and Marie Scully 52 Haemostatic agents in critical illness 229 Beverley J. Hunt PART 2.7 Antimicrobial and immunological drugs 53 Antimicrobial drugs in critical illness 234 A P. R Wilson and Preet Panesar 54 Steroids in critical illness 241 Didier Keh 55 Immunotherapy in critical illness 244 Hans-Dieter Volk and Levent Akyüz PART 2.8 Fluids and diuretics 56 Colloids in critical illness 248 Andrew Webb 57 Crystalloids in critical illness 252 Karthik Raghunathan and Andrew Shaw 58 Diuretics in critical illness 256 Marlies Ostermann and Ruth Y. Y. Wan SECTION 3 Resuscitation PART 3.1 Respiratory management 59 Airway management in cardiopulmonary resuscitation 263 Jerry P. Nolan and Jasmeet Soar 60 Artificial ventilation in cardiopulmonary resuscitation 268 Jasmeet Soar and Jerry P. Nolan PART 3.2 Circulatory management 61 Pathophysiology and causes of cardiac arrest 273 Peter Thomas Morley 62 Cardiac massage and blood flow management during cardiac arrest 277 Gavin D. Perkins 63 Defibrillation and pacing during cardiac arrest 280 Charles D Deakin 64 Therapeutic strategies in managing cardiac arrest 284 John Field 65 Post-cardiac arrest arrhythmias 289 Marwan F. Jumean and Mark S. Link 66 Management after resuscitation from cardiac arrest 294 Jerry P. Nolan and Michael J. A. Parr 67 Ethical and end-of-life issues after cardiac arrest 299 Carolyn Benson and G Bryan Young PART 3.3 Fluid management 68 Physiology of body fluids 304 Anthony Delaney 69 Choice of resuscitation fluid 308 John Myburgh and Naomi E. Hammond 70 Therapeutic goals of fluid resuscitation 313 Bashar S Staitieh and Greg S. Martin xi CHAPTER 198 Extracorporeal liver support devices in the ICU Rajiv Jalan and Banwari Agarwal Key points ◆ There is an unmet need for a liver support system because of the increasing shortage of organs for transplantation and the complications associated with the procedure ◆ In theory, acute liver failure and acute decompensation of chronic liver disease secondary to a precipitating event are potentially reversible In this context, an extracorporeal liver support can temporarily substitute liver functionality to allow natural recovery through regeneration of hepatocytes and elimination of the precipitating event ◆ Goals of liver support system are to provide all functions of the liver, including synthetic and metabolic functions, and to remove as well as reduce the production of pro-inflammatory mediators to attenuate the inflammatory process ◆ Currently existing devices are either purely mechanical and/ or cell-based Detoxification is provided by both systems, but biological activities are limited only to the cell-based systems Albumin dialysis is the major component of mechanical devices because albumin is irreversibly destroyed in liver failure ◆ Cell-based or bio-artificial systems are essentially ‘mini-livers’, but their success is limited by the lack of a continuous and abundant supply of high-quality hepatocytes Introduction The burden of liver disease continues to rise, with 10% of the current world population estimated to suffer from chronic liver disease Annually, over a million people die from liver-related illnesses; severe acute liver failure is associated with 50–60% mortality, while deaths from cirrhosis-related complications are projected to be the ninth most common in the developed world by 2015 [1] Liver transplantation (LT) remains the only optimal treatment for the majority of patients, but the expanding gap between organ availability and increasing waiting lists results in a significant mortality for patients awaiting transplantation In the UK the average waiting time for chronic liver disease patients is between and 18 months; >500 patients are on the waiting list at any one time with 15–20% dying without LT becoming available [2] There is an urgent need for an extracorporeal liver assist device with the capacity to support liver function and provide a temporary holding measure as a bridge to transplantation, or ideally, facilitate natural recovery of native liver function The quest for such devices dates back to the 1960s, but the realization of developing an ideal liver device has only been partially achieved Liver failure syndromes Liver failure can be broadly viewed as a spectrum of disease ranging from acute to acute-on chronic and end-stage liver failure This classification captures different clinical phenotypes of liver illness and allows formulation of appropriate treatment plans Acute liver failure Acute liver failure (ALF) is characterized by a rapid decline in liver function (within days to weeks) secondary to massive necrosis of hepatocytes following an acute insult (infective, metabolic, vascular, or drug-induced) This occurs in patients with previously normal liver function, and results in varying degrees of coagulopathy and hepatic encephalopathy (HE), eventually progressing to extrahepatic organ involvement and failure Cerebral complications, superimposed sepsis and the multiple organ dysfunction syndrome account for most deaths in these patients ALF stratification, based upon the length of time elapsed between the appearance of first symptoms and the development of HE, into the hyperacute (1–7 days), acute (8–28 days), and subacute (28 days–24 weeks) subvarieties, in conjunction with markers of acute physiological derangement (blood pH and lactate levels), patient age, and the aetiology of ALF, informs prognosis and identifies patients unlikely to survive without emergency or super-urgent LT [3] LT is a life-saving procedure, but is a major intervention with attendant morbidity and mortality, requires life-long immunosuppression, is expensive and limited by organ availability Acute on chronic liver failure Acute on chronic liver failure (ACLF) is an increasingly recognized clinical entity referring to the coincidence of either an identified or unidentified acute precipitating event (either superimposed liver injury or extra hepatic factors, such as infection) in patients with existing compensated or decompensated cirrhosis, culminating in further deterioration of liver function, and development of end-organ damage leading to high short term mortality [4] The final common pathway of a precipitating event—infection, variceal bleed, or additional liver injury—seems to be the development of an unquenched dysregulated systemic and hepatic inflammation resulting in worsening encephalopathy, aggravation of portal Chapter 198 extracorporeal liver support devices hypertension, development of renal dysfunction and haemodynamic embarrassment, and retardation of liver regeneration Box 198.1 Potential indications for liver supportive therapy End-stage liver disease ALF patients End-stage liver disease is an irreversible condition representing the terminal phase of liver failure, with little capacity for regeneration by the native liver The only treatment known to improve survival in this situation is LT ◆ Failure to reach criteria for emergency LT, but remain at high risk of dying (10–15% of non-survivors not fulfil King’s College Criteria for emergency transplantation) Liver support systems: types, technical issues, operational and functional characteristics, and current clinical evidence The liver is a complex organ, central to the body’s metabolic processes It has an unparalleled ability to handle multiple tasks required to maintain metabolic homeostasis and to act as the major regulatory player in the organ cross-talk framework Hepatocytes perform a range of functions including: ◆ Detoxification and lactate) (of drugs, toxins and chemicals such as ammonia ◆ Metabolic and biotransformation activities (e.g drug metabolism, maintenance of glucose homeostasis and thermogenesis) ◆ Synthesis (of coagulation proteins, albumin, globulins, acute phase and transporter proteins ◆ Immune modulation functions Hepatocellular failure results in toxin (ammonia, bilirubin, lactate, mercaptans, and bile acids) accumulation, an imbalance of metabolic substrates, and increased levels of inflammatory mediators The premise and concept behind an ideal extracorporeal liver support device therefore hinges on its ability to detoxify blood, perform synthetic, metabolic and immune functions, and to remove and/ or inhibit production of inflammatory signalling molecules (e.g cytokines) This breaks the vicious circle of liver injury characterized by production of inflammatory mediators and propagation of further liver injury, the ultimate aim being stimulation and promotion of liver regeneration Because of the temporary nature of the support offered by the currently available devices, their clinical application is targeted largely to situations where liver injury is acute, as in ALF and ACLF In addition, these devices can be used to improve and alleviate symptoms arising from cholestasis such as pruritus (Box 198.1) There are two types of liver support systems, namely artificial (non-biological) systems, which are purely mechanical dialysis devices based on blood detoxification, and bio-artificial devices, which are cell-based devices incorporating hepatocyte-derived cells that can potentially substitute liver metabolic function Blood purification devices are also added to some of these systems For a summary of this section, see Tables 198.1 and 198.2 Artificial devices Conventional blood purification methods, such as continuous haemofiltration or haemodiafiltration, although highly effective in removing small, water-soluble toxins, are no longer used as the sole means of detoxification in liver failure patients This is due to their inability to remove protein-bound substances and their ineffectiveness in liver failure They are still used in conjunction with ◆ Patients either precluded from LT due to medical, surgical, or psychological reasons, or those who continue to deteriorate rapidly, while on the emergency transplant list ACLF patients ◆ These patients are currently not considered for emergency LT in the UK, so a device can provide support until spontaneous recovery to pre-injury levels of liver function ◆ As a bridge to LT, especially for those patients who are high up on the waiting list and would receive LT within the next few weeks End stage liver disease Patients with ESLD lack reversibility Since currently available liver assist devices are unable to sustain liver support for longer than a few weeks, the only role of liver devices pertains to symptom reduction and quality of life improvement as in: ◆ Intractable pruritus ◆ Hepatic encephalopathy ◆ Severe chronic fatigue Other indications ◆ Primary graft non-function after transplantation, and waiting for super-urgent re-transplant ◆ Small-for-size syndrome: • Development of liver failure following extensive resection for malignancy • Following donor hepatectomy in living donation liver transplantation liver support devices to augment elimination of water-soluble toxins The first generation of liver devices utilized activated charcoal haemoperfusion as the basis for toxin adsorption, but failed to demonstrate significant benefit and is now largely superseded by albumin-based systems Albumin is the most abundant circulating plasma protein and maintains plasma oncotic pressure In addition, current literature consistently points towards a number of other biological functions such as fatty acid transport, drug binding, metal chelation, and antioxidant activity performed by albumin, rendering it an important detoxification molecule and a candidate protein to be targeted in liver dialysis systems [5] In addition to quantitative hypoalbuminaemia in liver failure, there is a severe functional impairment of the available albumin rendering it an inefficient transporter protein [6] The two most commonly used artificial systems are the molecular adsorbent recirculating system (MARS) and the fractional separation of plasma and albumin dialysis (Prometheus) Both forms of treatment are relatively new; MARS was used clinically for the first time in 1993 and Prometheus in 2003 935 936 Section 6 the gastrointestinal system: acute hepatic failure Table 198.1 Artificial devices Device Principles of therapy Clinical studies SPAD (single-pass albumin dialysis) Albumin dialysis against 2–5% albumin Improvement in biochemical parameters, comparable with MARS Only single case studies available [13], no RCTs MARS (molecular adsorbent recirculating system) Albumin dialysis against 20% albumin Improved hepatic encephalopathy [14], improved quality of life, no significant survival benefit [9] Prometheus (fractionated plasma separation and adsorption—Prometheus) Plasma separation, adsorption using neutral resin, and anion adsorbers Improvement in biochemical parameters No significant benefit at 28 days [10] SEPET (selective plasma filtration technology) 100 kDa hollow fibre membrane, albumin, and fresh-frozen plasma mixture as replacement fluid No human RCTs Animal models show improved survival [15] HVPE (high volume plasma exchange) Patient’s plasma removed and replaced with fresh frozen plasma Improved transplant-free survival in ALF [7] Data from various studies (see references) MARS (Gambro, Sweden) combines albumin dialysis with conventional haemodialysis to remove both water-soluble and protein-bound toxins The patient’s blood is detoxified of protein-bound substances via an albumin-impregnated polysulfone dialysis membrane (50 kDa) against a concentration gradient exchange mechanism by the albumin solution stored in the adjacent chamber (600 mL 20% human albumin) The selective pore size stops the patient’s own toxin-laden albumin from crossing the membrane The albumin dialysate is passed through an activated charcoal and anion exchange resin to regenerate the protein to allow its continued use as a detoxification medium (Fig 198.1a) The haemodialysis circuit in the system removes water-soluble substances Prometheus (Fresenius, Germany) combines plasma separation and adsorption in a double circuit design A high cut-off membrane of 250 kDa filters the patient’s albumin into a secondary plasma circuit The albumin-rich plasma then passes through two columns of adsorbent resins (neutral and anion exchange, see Fig 198.1b), to remove bound toxins before recombining with the cell fraction prior to return to the patient A high-flux dialysis system is applied to the blood circuit to enhance elimination of water-soluble toxins Single-pass albumin dialysis (SPAD) is a non-commercial simplified system of albumin dialysis designed to remove protein-bound toxins using an albumin solution (typically 5%) as the dialysate separated from the patient’s blood by a high-flux albumin-impermeable membrane Unlike MARS where the albumin dialysate is re-circulated, it is discarded after a single pass (Fig. 198.1c) Continuous veno-venous haemodiafiltration can be added to augment removal of water-soluble substances The SPAD system is simple, safe, and has similar efficiency to MARS in removing bilirubin, ammonia, bile acids, and creatinine Plasmapheresis (plasma exchange) separates the patient’s plasma from cellular blood components to be then replaced by donor freshfrozen plasma and/or albumin It is effective in removing circulating antibodies, inflammatory cytokines, and other toxic substances, as well as toxins bound to tissue sites, and is used for a number of autoimmune conditions In liver failure, enhanced or high volume plasmapheresis (>10 L of plasma removed and replaced per day) has demonstrated clinical improvement in hepatic encephalopathy, hepatic and cerebral blood flow, and even a survival benefit in patients with ALF [7] SEPET (selective plasma filtration technology) incorporates a 100 kDa hollow-fibre membrane where the ultrafiltrate is replaced by a mixture of electrolyte, albumin, and fresh-frozen plasma solutions Table 198.2 Bio-artificial devices Device Principle and cell type Main concern Clinical studies Hepat Assist Plasma separation, charcoal adsorption, porcine hepatocytes Zoonoses 176 patients, no survival advantage in fulminant and sub-fulminant [16] MELS (modular extracorporeal liver system) Plasma separation, then plasma passed through human hepatocytes Supplies low, function difficult to maintain Eight patients, successfully bridged to transplant [17] ELAD (extracorporeal liver assist device) Human hepatoblastoma cell (C3A cells) Tumourogenicity Six human studies, 150 patients treated Survival benefit in ACLF study in 49 patients [18] BLSS (bio artificial liver support system) Porcine hepatocytes Zoonoses Phase I study in four patients, no serious adverse events [19] AMC-BAL Porcine hepatocytes Zoonoses 12 patients treated, 11 bridged to transplant [20] Data from various studies (see references) Chapter 198 (a) Blood return 50K Da filter Albumin dialysate solution Anion Activated exchange carbon Renal dialysis circuit Blood from patient (b) Blood return Albumin fraction filter Renal dialysis circuit extracorporeal liver support devices between the modest cytokine elimination ability of these systems, and their continuous production during liver failure [8] Both systems lose detoxification capability significantly after hours’ use Most of the published evidence relates to these two main artificial devices The MARS system has received US FDA approval as a therapy for use in hepatic encephalopathy, in addition to previous approval for the management of drug toxicity Both MARS and Prometheus are effective in supporting patients with severe liver dysfunction either following surgery or as a bridge to transplantation Crucially, neither system could show an independent survival benefit (in the absence of transplantation) in phase III multicentre trials [9,10] Albumin dialysis/detoxification has been shown to be very effective for intractable pruritus and provides symptom relief for prolonged periods (3–4 months) [11] As these patients often will not qualify for LT based on their liver function, this treatment option can play a vital role in improving their quality of life (Table 198.1) Biological or bio-artificial liver system Anion exchange Neutral Resin Blood from patient Albumin fraction (c) A bio-artificial liver system (BAL) system employs biochemically active cells contained in a bioreactor In theory, it is capable of carrying out a proportion of the metabolic, synthetic, and immune function provided by the liver A blood purification device is often added to improve efficacy The essential pre-requisites for a functioning BAL system are: ◆ High quality, well-differentiated cells retaining a high degree of hepatocyte function, which are stable in vitro ◆ Sufficient quantities of these cells equating to up to one-third of normal liver mass as extrapolated from data on large liver resections Blood return Albumin solution Waste Blood from patient Fig. 198.1 Schematic representations of (a) molecular adsorbent recirculating system (MARS) (b) Fractional separation of plasma and albumin dialysis (Prometheus) (c) Single pass albumin dialysis (SPAD) artificial systems Safety profile and clinical efficacy of artificial devices MARS is the most studied device with over 5000 patients having been treated for more than 20,000 therapy sessions, followed by Prometheus that has also been used extensively These are largely safe procedures, with no serious side effects reported for either treatment Reported complications have included modest thrombocytopenia, bleeding episodes, transient haemodynamic instability, a need for more anticoagulation treatment, and reversible leukocytosis unrelated to sepsis Both MARS and Prometheus effectively remove water-soluble and albumin-bound toxins, as well as cytokines, but without significant reduction in plasma cytokine levels, reflecting an imbalance ◆ Ready and unlimited availability of these cells at any time Cell sources most commonly studied have been derived from primary human and porcine sources, immortalized human cells, and cells derived from hepatic tumours such as hepatoblastoma The cells are used as either tissue slices, homogenates or as single cell layer columns supported on matrices similar in appearance to dialysis filters The disadvantages of human cells are limited availability, while porcine hepatocytes tend to be less stable and carry a theoretical risk of xenozoonosis, which although not yet reported, will prevent their use in Europe and the USA On the other hand, cell lines such as C3A derived from human hepatoblastomas lose functionality following transformation, e.g their ureagenesis capacity is limited only to the arginine aspect of the urea cycle and thus cannot completely detoxify ammonia Currently available BAL systems The ELAD C3A-based BAL system is currently under development and undergoing clinical trials (Vital Therapies, San Diego, USA) Small-scale studies have shown survival benefit or use as a bridge to transplantation, although a large-scale pivotal survival study has not yet been undertaken Other systems are in varying stages of development, seeking to optimize the bioreactor design or the cell type contained within them It is not yet clear as to how successful these technologies will be A major limiting factor in whether BAL systems will be adopted widely would be the considerable cost of therapy associated with generating, shipping, and 937 938 Section 6 the gastrointestinal system: acute hepatic failure maintaining bioreactors Clinical studies therefore need to demonstrate clear, unequivocal survival benefit of ELAD over other treatment options before acceptance into the majority of healthcare systems (Table 198.2) Conclusion Specific therapies aimed at targeting factors identified in relation to the progression of liver injury are being developed for the next generation of liver dialysis systems Proof-of-principle systems have shown clinical benefit by combining endotoxin removal filters with albumin dialysis [12] These endotoxin filters, developed as therapies for sepsis, are used to reduce the ongoing inflammatory stimulus associated with end-stage liver disease Another approach is to improve the quality and functional capacity of the patient’s albumin during therapy The disease process damages albumin binding and transport capability, so methods to replace the damaged protein to restore function rather than just to dialyse the bound toxins is the next logical step in system design Improved BAL systems may be able to demonstrate a large functioning cell mass that can effectively replace liver function for a prolonged period, though this would still appear to be some way from the clinic Current artificial liver dialysis systems offer effective support for a number of applications Though they are not able to replace the failing liver, they offer detoxification functions and can act as a bridge to transplantation References Mathers C, Fat DM, Boerma JT, and the World Health Organization (2008) The Global Burden of Disease: 2004 Update Geneva: World Health Organization NHS Blood and Transplant (2011) Transplant Activity in the UK Report 2010/2011: Statistics and Clinical Audit London: NHS Blood and Transplant Lee WM, Stravitz RT, and Larson AM (2012) Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011 Hepatology, 55, 965–7 Moreau R, Jalan R, Gines P, et al (2013) Acute-on-chronic liver failure is a distinct syndrome developing in patients with acute decompensation of cirrhosis Gastroenterology, 144, 1426–37 Quinlan GJ, Martin GS, 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Journal of Artificial Organs, 25, 950–9 PART 6.9 Acute on chronic hepatic failure 199 Pathophysiology, diagnosis, and assessment of acute or chronic hepatic failure 940 Alastair O’brien 200 Management of acute or chronic hepatic failure in the critically ill 944 Alastair O’Brien CHAPTER 199 Pathophysiology, diagnosis, and assessment of acute or chronic hepatic failure Alastair O’Brien Key points ◆ Cirrhosis is an increasing problem and prognosis following ICU admission is poor ◆ Acute on chronic liver failure (ACLF) is a separate entity to cirrhosis with organ failure at the core of this syndrome ◆ ACLF results from an acute ‘new’ insult that may/may not be related to the original cause of chronic liver disease ◆ Infection and the associated SIRS response are the most important precipitants of ACLF ◆ Clinical assessment should follow the standard ABCDE approach to the critically-ill patient Introduction Cirrhosis is the end result of liver damage caused by a wide variety of insults including alcohol, chronic viral infection, non-alcoholic fatty liver disease, autoimmune disease, certain genetic conditions, and other less common conditions It represents a leading cause of death worldwide In the UK it is currently the fifth leading cause of death and, unlike many other common diseases, there is an upward trend in mortality The average age of death from liver disease is only 59 years, compared with 82–84 years for cardiovascular and lung diseases Cirrhosis and intensive care unit admission Cirrhosis is rarely reversible and the natural progression from compensated to decompensated disease results in a significant increase in morbidity and mortality, and a much decreased quality of life This is a direct consequence of the impairment in liver function secondary to decreased functional hepatocytes and the architectural disruption that impairs a normal hepatic and enteric circulation Management of the complications of cirrhosis, such as gastrointestinal bleeding, sepsis, and renal failure, frequently involves ICU admission All studies in ICU patients report a poor prognosis with an overall hospital mortality of 44–71%, although a small improvement in mortality has been described over time Patients admitted for airway protection following an upper gastrointestinal bleed fare well with a mortality of 20% However, mortality in those with organ failure, septic shock, or hepatorenal syndrome may approach 85–100% Liver transplantation is the only curative therapy for established cirrhosis, giving excellent 5-year survival rates of 75% However, the limited number of available organs dictates that the vast majority of patients will not be considered For example, approximately 600-800 transplants are performed annually in the UK, while over 550,000 patients were admitted with complications of cirrhosis during 2012 This mismatch results in a large number of intensive care unit (ICU) admissions of patients that will never be considered suitable for transplantation The estimated number of ICU admissions related to cirrhosis in the United States is in excess of 26,000 per year with an estimated cost of $3 billion In the UK this represents approximately 2.6% of total admissions per year (approximately 1250 patients) Acute on chronic liver failure: definition Acute on chronic liver failure (ACLF) refers to an acute deterioration in liver function in cirrhotic patients secondary to superimposed hepatic or extrahepatic injury, such as infection [1] The most recent definition by the EASL-CLIFF consortium refers to an acute decompensation (ascites, encephalopathy, gastrointestinal bleeding, bacterial infection) associated with organ failure (worsening of liver function, and/or kidney failure or other organs) The previous definition proposed by a working group from the American Association for the Study of Liver Disease (AASLD) and the European Association for Study of the Liver (EASL) is ‘acute deterioration of pre-existing, chronic liver disease, usually related to a precipitating event and associated with increased mortality at months due to multisystem organ failure’ Ongoing studies are aimed at further refinements, however the most important message from studies published thus far is that in ACLF it is the degree of organ failure that determines outcome, rather than the severity of liver disease ACLF must be contrasted with acute or ‘fulminant’ liver failure that develops in patients without pre-existing liver disease and is described elsewhere Distinction between the two is important as the treatment and prognosis is, in most cases, dissimilar Precipitating event ACLF results from an acute ‘new’ insult that may/may not be related to the original cause of chronic liver disease [1,2] This separates it Chapter 199 from cases of cirrhosis in which continued hepatocellular damage leads to progression and worsening of disease Although this distinction has been made between ACLF and advanced cirrhosis for the purposes of this chapter and the ACLF management chapter, the recommendations made for assessment and management can be applied to any critically-ill patient with cirrhosis Precipitants include bacterial infections, alcoholic hepatitis, superimposed viral hepatitis, drug (or hepatotoxin)-induced liver injury, variceal bleeding, ischaemia, and surgery There is global variation, for example, viral infections are more common in Asia, while alcoholic and non-alcoholic fatty liver disease (NAFLD) are more common in Europe and the United States Reversibility In contrast to the natural progression of cirrhosis, a key defining principle of ACLF is the element of reversibility if the patient is identified early and aggressive intensive care support given [1] However, full recovery to the previous baseline is not likely Indeed, in patients who survive to hospital discharge, there is a median survival of only months if their admission APACHE III (Acute Physiology and Chronic Health Evaluation) score exceeded 90, and 17 months if