Startseite Organ donation and transplantation after cardiac death
Organ donation and transplantation after cardiac deathTalbot, David, D'Alessandro, Anthony M., Muiesan, Paolo
With the success of organ transplantation and the declining number of heart beating cadaver doctors, the number of patients awaiting a transplant continues to rise. This means that alternative sources of donors have been sought, including donors after cardiac death. Such donors sustain rapid damage to their organs due to ischaemia, and as a consequence, some organs do not work initially and some none at all. The proportion of such transplants has increased dramatically in recent years--25% of kidney transplants in the UK were from such donors in 2006, highlighting how much progress has been made.
Written by international experts, this book lays out the moral, legal, and ethical restraints to using such donors for organ transplant together with the techniques that have been adpoted to improve their outcome. The different approaches and results of renal transplant according to country are covered together with the procedures and outcomes adopted to use other organs, notably the liver and lungs.
Written by international experts, this book lays out the moral, legal, and ethical restraints to using such donors for organ transplant together with the techniques that have been adpoted to improve their outcome. The different approaches and results of renal transplant according to country are covered together with the procedures and outcomes adopted to use other organs, notably the liver and lungs.
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Organ Donation and Transplantation after Cardiac Death This page intentionally left blank Organ Donation and Transplantation after Cardiac Death Edited by David Talbot Anthony M. D’Alessandro Assistant Editor Paolo Muiesan 1 1 Great Clarendon Street, Oxford OX2 6DP 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 in Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Published in the United States by Oxford University Press Inc., New York © Oxford University Press 2009 The moral rights of the author have been asserted Database right Oxford University Press (maker) First published 2009 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, 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 book in any other binding or cover and you must impose this same condition on any acquirer British Library Cataloguing in Publication Data Data available Library of Congress Cataloguing in Publication Data Data available Typeset by Cepha Imaging Private Ltd., Bangalore, India Printed and bound in Great Britain by Biddles Ltd., King’s Lynn ISBN 978–0–19–921733–5 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 procedure with the most up to date published product information and data sheets provided by the manufactures and the most recent codes of conduct and safety regulations. The authors and publishers do 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. Foreword In 1999 Paul Terasaki wrote an editorial on non-heart-beating (NHB) donation in clinical transplantation. He stated that NHB donation had the potential to eradicate the shortage of kidneys that had frustrated the transplant community ever since the early days. How close was Paul at that date and has NHB donation done what he expected? This book, an initiative of two early believers in and supporters of NHB donation, depicts the wording of this special source of organs for transplantation and presents the current situation, not only for kidneys, but for other organs as well. The book is rich in information on physiology of ischemia, and preservation both in general and specific for NHB organs. Viability testing has become crucial in NHB donation and the chapter by David Talbot is leading in this respect. It starts with the intriguing statement that NHB kidneys might actually be in a better condition then HB kidneys! Advanced procedures used to improve the preservation of organs ‘touched’ by warm ischemia are presented by experts in the field over several chapters. What makes this book so exceedingly interesting is the fact that the chapters are written by authors of different disciplines—for example, an ethicist and a paediatric intensive care specialist write together on the legal and moral issues of NHB donation. The chapters on the European, the USA, and the Japanese settings are very informative and illustrate a certain diversity, but also that the number of available organs in all settings has increased! NHB and DCD are used interchangeably without confusion. I am convinced that this book will receive a welcome in the transplantation world as it presents a unique opportunity to increase the availability of organs for our patients. Gauke Kootstra, Maastricht. This page intentionally left blank Preface Transplantation has been one of the most significant advances in health care over the last 40 years. This success has resulted in a marked increase in the numbers of patients who can benefit from transplantation as indicated by the ever increasing size of waiting lists throughout the world. While there has been a modest increase in the number of organ donors worldwide the disparity between the number of potential recipients and the number of deceased donors remains significant. Transplant practitioners have therefore searched for alternative sources of deceased donors including expanding the criteria for brain dead donors as well as returning to cardiac death donors, which formed the foundation of transplantation before the establishment of brain death criteria. As there have been a number of improvements in surgical recovery, organ preservation, immunosuppression and post trasplant patient management, donation after cardiac death and transplantation has become one way to provide more recipients the opportunity to experience the benefits of transplantation. Recovery of organs from cardiac death donors requires the cessation of cardiocirculatory function, a stand-off period followed by declaration of death before organs can be recovered. After the heart has stopped beating all organs that depend upon oxygenated blood begin to deteriorate very rapidly. Using organs for transplantation after such damage carries a risk that they may never work after they are reperfused in the recipient. A number of techniques have been developed to allow transplantation from cardiac death donors to be done successfully. This book has been written by internationally renowned experts in order to share this knowledge in a rapidly evolving field. While there are many practicalities of transplanting such donor organs there are also many ethical issues which relate largely to the issues of organ donation in a non brain dead patient such as: when does death actually occur? This book also covers these topics. David Talbot Anthony D’Alessandro This page intentionally left blank Contents Contributors xi 1 History of non-heart-beating donation 1 Gauke Kootstra 2 Legal, moral, and ethical issues 7 Sam D. Shemie, Michael De Vita 3 History of organ perfusion in organ transplantation 31 Diethard Monbaliu, Qiang Liu, Katrien Vekemans, Jacques Pirenne 4 Viability testing of kidneys from non-heart-beating donors 51 David Talbot 5 Perfusate development for the NHBD 67 Colin Wilson 6 Thrombolysis in the non-heart-beating donor 103 David Talbot, Mohamed Gok, Thomas Minor 7 Supplemental cryopreservation of the donor by peritoneal cooling 117 John Asher, Alex Navarro 8 Gaseous oxygen to improve viability of marginal or pre-damaged organ grafts during hypothermic storage 131 Thomas Minor 9 Extracorporeal circulatory-assisted non-heart-beating organ donation 153 Jeff Punch 10 Patient selection and management 161 Julio Pascual, John D. Pirsch 11 The renal biopsy in non-heart-beating organ transplantation 173 M Snoeijs, R. Matthijsen, M.H. Christiaans, J.P. van Hooff, E. van Heurn, W. Buurman, R.J. van Suylen, C.J. Peutz-Kootstra 12 Early results for renal transplants from non-heart-beating donors 203 Alex Navarro 13 Liver transplantation using non-heart-beating donors 213 Paolo Muiesan x CONTENTS 14 Lung transplantation from non-heart-beating donors—donation after cardiac death (DCD) 231 Chris Wigfield, Robert Love, John Dark 15 Donors without a heart beat in the United States 255 Anthony D’Alessandro 16 Non-heart-beating donation in Europe 271 Ernest van Heurn, David Talbot 17 Renal and islet transplantation from non-heart-beating donors in Japan 289 Hirofumi Noguchi, Nobuyo Hatanaka, Shinichi Matsumoto 18 The current situation and further development 307 David Talbot, Anthony D’Alessandro Index 313 Contributors John Asher Department of Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. Ernest van Heurn Department of Surgery, University Hospital Maastricht, The Netherlands. Wim Buurman Department of Surgery, University Hospital Maastricht, The Netherlands. Hans P. van Hooff Department of Nephrology, University Hospital Maastricht, The Netherlands. Maarten H. Christiaans Department of Nephrology, University Hospital Maastricht, The Netherlands. Gauke Kootstra Emeritus Professor of Surgery, University Hospital Maastricht, The Netherlands. Anthony M. D’Alessandro Department of Surgery, University of Wisconsin, USA. Qiang Liu Department of Transplant Surgery, University of Leuven, Belgium. John H Dark Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle upon Tyne, UK. Robert B. Love Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Maywood, Illinois, USA. Michael DeVita Associate Medical Director, University of Pittsburgh Medical Center, Professor of Critical Care Medicine and Internal Medicine, University of Pittsburgh, USA. Mohamed Gok Department of Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. Nobuyo Hatanaka The University of Tokyo, The Institute of Medical Science, Exploratory Research University, Tokyo, Japan. Shinichi Matsumoto Baylor Institute for Immunology Research, Baylor Research Institute, Dallas and Fort Worth, USA. Robert Matthijsen Department of Surgery, University Hospital Maastricht, The Netherlands. Thomas Minor Department of Surgical Research, University of Bonn, Germany. Diethard Montbaliu Department of Transplant Surgery, University of Leuven, Belgium. xii CONTRIBUTORS Paolo Muiesan Queen Elizabeth and Birmingham Children’s Hospital, Birmingham, UK. Martin Snoeijs Department of Surgery, University Hospital Maastricht, The Netherlands. Alex Navarro Department of Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. Robert Jan van Suylen Department of Pathology, University Hospital Maastricht, The Netherlands. Hirofumi Noguchi Baylor Institute for Immunology Research, Baylor Research Institute Dallas and Fort Worth, USA. David Talbot Department of Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. Julio Pascual Department of Nephrology, Hospital Ramon y Cajal, Madrid, Spain. Katrien Vekemans Postdoctoral Researcher of the Fund for Scientific Research, Flanders, Department of Transplant Surgery, University of Leuven, Belgium. Carine J. Peutz-Kootstra Department of Pathology, University Hospital Maastricht, The Netherlands. John D. Pirsch Departments of Medicine and Surgery, University of Wisconsin, USA. Jacques Pirenne Department of Transplant Surgery, University Leuven, Belgium. Jeffrey D. Punch Department of Surgery, University of Michigan, USA. Sam D. Shemie Division of Pediatric Critical Care, Montreal Children’s Hospital, McGill University Health Centre The Bertram Loeb Chair in Organ and Tissue Donation, Faculty of Arts, University of Ottawa, Canada. Christopher Wigfield Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Maywood, Illinois, USA. Colin Wilson Department of Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK. Chapter 1 History of non-heart-beating donation Gauke Kootstra The history of non-heart-beating (NHB) donation is as old as human kidney transplantation. At the first human to human kidney transplant by Voronoy (1), at Cherson (Kherson), Ukraine, 3 April 1933, the kidney was procured from a 60 year old man who had died of a skull fracture. Voronoy took the kidney 6 hours after death of the donor and transplanted it into a lady of 26 years who was uraemic after attempting suicide by sublimate drinking. With our current knowledge, it is not surprising that the kidney never functioned; neither did the five other kidneys Voronoy transplanted until 1949. In fact, all the early kidney transplants in the USA (1947) (2) and France(1951) (3) were from donors who were clinically dead, usually after a cardiac arrest from varying causes. This certainly holds for the early French donors who had been decapitated by the ‘guillotine’ and so were both brain dead and non-heart beating! Before the concept of brain death was introduced with the Harvard criteria in 1968 (4), all post-mortem kidneys were procured after cardiac arrest of the donor. Subsequently, when brain dead donors failed to provide sufficient kidneys, additional sources were explored including living and NHB donation. The ‘reformed’ NHB donor programmes on restarting used donors who were not brain dead. In contrast, the normal cadaver donors prior to the Harvard Criteria were usually those subjects who were first brain dead and then after withdrawal of supportive measures were also dead by cardio-pulmonary definition. These were later defined as the Maastricht IV NHB donor group, which will be discussed later. When can one then speak of the restarting of NHB donation? Probably it is best to take the start of NHB donation as the moment when the aim was to enlarge the donor pool due to the persistent shortage of post-mortem kidneys from braindead donors. In NHB donors, the heart ceases beating, this being an irreversible process. Kidneys from NHB donors are always, therefore, subjected to a period of warm ischaemia. This period of warm ischaemia is considered to be unfavourable for the outcome and function of kidneys after transplantation. Therefore, ‘heart beating’ as in ‘brain dead’ donors are not only supposed to give better results for kidney transplantation, but also should result in access to other organs such as liver, lungs, and hearts. 2 HISTORY OF NON-HEART-BEATING DONATION In the US and Canada, the term ‘donation after cardiac death’ (DCD) (5) is generally used to describe NHB donation. The term is used to contrast with ‘donation after brain death’ (DBD), which is equivalent to heart-beating donation from brain-dead donors. The term ‘asystolic donor’ has appeared in a few publications from the UK (6). There have been cases where the parents of a brain-dead child could not bring themselves to consent to organ donation, but they changed their opinion when it was proposed that they could await cardiac arrest and then proceed to kidney donation. Between 1970 and 1979 at the University Hospital in Groningen, 38 nephrectomies were performed in NHB donors, parallel to the larger heart beating programme. The kidneys were transplanted in several centres in and outside of the Eurotransplant area. The experience was published in 1980 in the ‘Proceedings of the European Dialysis and Transplantation Association’ (7). The results were as good as a large control group of heart-beating kidneys collected by the Eurotransplant organisation. The transplant programme led by the late Fred Belzer (8) in San Francisco and later on in Madison (Wisconsin) held to the principle that kidneys were only taken after cardiac arrest, even when the donor was declared brain dead. The reason was that Belzer felt insecure about the definition of brain death as diagnosed by Hospital physicians other than his own University Hospital doctors. In the opinion of Belzer, the damage incurred by the warm ischaemia was compensated for by machine preservation. The first international workshop on NHB donors in Maastricht In March 1995, we organised in Maastricht a workshop on NHB donation. Participants came from Europe, the Middle East and the USA and included surgeons, nephrologists and ethicists. In a lively discussion, the use of NHB donation was further defined and sharpened. Three major topics were discussed: 1. The classification of NHB donors into four categories. 2. The criteria needed for the establishment of death and the irreversibility of cardiac death. 3. The waiting time between cardiac arrest and the start of procurement of the organs. The classification of NHB donors into four categories (9) Kidneys from NHB donors are subjected to a variable duration of warm ischaemia. Four categories of NHB donors were proposed and accepted (Table 1.1). Organs from category I donors have the longest warm ischaemic time, whereas those from category 3 and 4 donors have the shortest. Later, because of some uncertainties regarding the practical role of such a classification ‘uncontrolled’ was added for categories 1 and 2, whilst categories 3 and 4 were identified as ‘controlled’. These categories later received the epithet ‘Maastricht’. THE FIRST INTERNATIONAL WORKSHOP ON NHB DONORS IN MAASTRICHT Table 1.1 The classifications of NHB donors as described by the First International Workshop on NHB Donors, Maastricht (9). The terms ‘Controlled’ and ‘Uncontrolled’ were not used at the workshop but added later Category Alternative categorisation Status of potential donor Hospital department Category I Uncontrolled Dead upon arrival Accident and emergency Process Viability testing Category II Uncontrolled Resuscitation attempted without success Accident and emergency Viability testing Category III Controlled Awaiting cardiac arrest Intensive care Transplantation Category IV Controlled Cardiac arrest while brain dead Intensive care Transplantation The criteria for death and the irreversibility of cardiac death The ethical aspects of these two key principles in NHB donation were addressed by Arnold and Youngner (10), two American ethicists. Before the practice of organ donation, there was no need for a quick diagnosis of death. This has changed since organ donation because a donor has to be dead before the organs are taken, according to the dead donor rule (11, 12). Cardiac arrest is not the moment of death per se because the brain stem may still be functional. After the heart has stopped and the circulation to the brain ceases, the brain stem, if functioning before, will rapidly deteriorate and activity will cease. To observe whether the arrest is irreversible, one needs time, but time is of the essence with regard to warm ischaemic damage to the organs. The ethical issues will be further discussed in chapter two. The waiting time between cardiac arrest and the start of procurement of the organs This topic was discussed in depth because for category 3 donors supportive treatment is withdrawn, e.g. artificial ventilation, and then after a few minutes the heart stops. Is the patient dead at that very moment? It was concluded that this was not the case. If at the moment of cardiac arrest, heart massage, and artificial ventilation were started, it is likely that heart could be restarted and thus the patient would not be ‘dead’ immediately after cardiac arrest. Although resuscitation is not intended to be given at this precise time, it was felt that one could not declare somebody to be dead at the moment of cardiac arrest. A period of ‘no touch’ time had to elapse, i.e. of doing nothing to the body, before death could be confirmed. The brain would ‘die’ during this period and so the patient could then be declared dead. Though consensus on this point was straight forward, protracted and heated discussions took place on the required length of this ‘no touch’ period. The liver group from Pittsburgh 3 4 HISTORY OF NON-HEART-BEATING DONATION (13) proposed two minutes, the ethicists and others considered two minutes too short. Ten minutes was then agreed but with protest from the liver group. The background to the discussion was that a ‘no-touch’ period meant ‘warm ischaemia’ for all organs. Early function after transplant is particularly vital for the liver, whereas the renal transplant patient can be supported by dialysis. Therefore, with more protracted warm ischaemia, either the livers could not be used from these donors or there would be a greater risk of recipient death if the liver was transplanted. Nevertheless, since the Maastricht consensus meeting, transplant groups using NHB donors adhered to the 10 minutes ‘no touch’ period after cardiac arrest before cannulation. In 1998, the Institute of Medicine from the United States published a consensus statement on NHB donor organ transplantation and recommended in their report a 5 minute period of ‘no-touch’ (14). Since then ‘5 minutes’ of no-touch has become the standard approach. The Double-Balloon-Triple-Lumen (DBTL) catheter In November 1975, Garcia-Rinaldi et al. (15) published the design of a catheter for in situ preservation of cadaver kidneys for transplantation. This catheter was designed to be introduced through the femoral artery into the aorta and by inflating two balloons the segment of the aorta, where the renal arteries have their origin, is isolated. Through a third lumen the kidneys can be perfused with a cold solution and so the kidneys are preserved ‘in situ’ inside the body. The DBTL catheter can therefore be introduced at the bedside, in the Accident and Emergency unit, the Intensive Care Unit or in the operating room. Later on some minor modifications (16) were made, but the principle has not changed. Anaise et al. (17) added peritoneal cooling to early preservation via catheters inserted into the abdominal cavity. Light (18) applied the use of this principle as well and observed better kidney function after transplantation as a result (see chapter seven). The future of NHB donation Currently, livers, lungs, and pancreases of NHB donors are used for transplantation in a rather small numbers, although the interest in developing this area is increasing. In separate chapters, the current status of the transplantation of these organs from NHB donors will be presented. The number of NHB donors and the experience gained between centres and countries differ markedly! In the Netherlands, nearly 50 per cent of the cadaver kidneys are from NHB donors and so it would be expected that transplant numbers would have increased. Unfortunately, instead of an increase in kidneys for transplantation there has been a substitution of the heart-beating kidneys for NHB kidneys and so the numbers have remained the same. Therefore, one could postulate that NHB donation as an improvement to the shortage of organs has not worked. However, heart-beating donors have declined for a number of reasons including the reduction in head injuries due to better road safety and also an increase in relative refusal rates. Therefore, if the source of NHB donors was to cease, there wouldn’t necessarily be a reciprocal rise in heart-beating donors and there would be a catastrophic increase in the numbers of patients on dialysis. REFERENCES Most of the clinical and basic research into NHB donation has been done in the UK, where several centres have provided data from single centre and multi-centre studies. Currently, the vast majority of NHB kidneys are from category 3 donors; however, these are scarce. The potential number of category 1 and 2 donors is immense but will only be realised when adequate viability testing is available and the inevitable ischaemic damage present can be repaired. Hereto, warm perfusion with a blood substitute is the way forward as it offers the potential to both test and repair the damaged organ, and research should be directed into this intriguing field of warm preservation (15). References 1. Voronoy, Y. ‘Sobre el bloque del aparato reticuloendotelial del hombre en algunas formas de intoxicacion por el sublimado y sobre la transplantacion del rinon cadaverico como metodo de tratamiento de la anuria consecutive a aquella intoxicacion’. Siglo Medico 1936;97:296–8. 2. Hume, D., Merril, J., Miller, B., & Thorn, G. ‘Experiences with renal homotransplantations in the human: report of nine cases’. J Clin Investigation 1955;34:327–82. 3. Kuss, R., Teinturier, J., & Millieaz, P. ‘Quelques essais de greffe rein chez l’homme’. Memoire Acad Chir 1951;77:754–64. 4. Beecher, H. ‘A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to examine the definition of brain death’. JAMA 1968;205:337–40. 5. Howard, R., Schold, J., & Cornell, D. ‘A 10-year analysis of organ donation after cardiac death in the United States’. Tranplantation 2005;80:569–70. 6. Koffman, C., Bewick, M., Chang, R., & Compton, F. ‘Comparitive study of the use of systolic and asystolic kidney donors between 1988 and 1991’. Transplantation Proceedings 1993;25:1527–9. 7. van der Vliet, J., Slooff, M., Kootstra, G., Krom, R., & Rijkmans, B. ‘Non-heartbeating donors, is it worthwhile?’. Proc Eur Dial Transplant Assoc 1980;17:445–9. 8. Belzer, F. Personal communication. 9. Kootstra, G., Daemen, J., & Oomen, A. ‘Categories of non-heart-beating donors’. Transplant Proc 1995;27(5):2893–4. 10. Arnold, R. & Youngner, S. ‘Time is of the essence: the pressing need for comprehensive non-heart-beating cadaveric donation policies’. Tranplantation Proc 1995;27:2913–17. 11. Robertson, J. ‘The dead donor rule’. The Hastings Center Report 1999;29(6):6–14. 12. Robertson, J. ‘Death: merely biological?’. The Hastings Center Report 1999;29(1):4. 13. Casavilla, A., Ramirez, C., Shapiro, R., Nghiem, D., Miracle, J., Fung, J., et al. ‘Experience with liver and kidney allografts from non-heart-beating donors’. Tranplantation Proc 1995;27:2898. 14. Herdman, R., Beauchamp, T., & Potts, J. ‘The Institute of Medicine’s report on non-heartbeating organ transplantation’. Kennedy Inst Ethics J 1998;8:83–90. 15. Garcia-Rinaldi, R., Lefark, E., Defore, W., Feldman, L., Noon, G., Jachimczyk, J., et al. ‘In situ preservation of cadaver kidneys for transplantation: laboratory observations and clinical application’. Ann Surg 1975;182:576–84. 16. Kootstra, G. & van Heurn, E. ‘Non-heartbeating donation of kidneys for transplantation’. Nature Clin Pract Nephr 2007;3:154–63. 5 6 HISTORY OF NON-HEART-BEATING DONATION 17. Anaise, D., Smith, R., Ishimaru, M., Waltzer, W., Shabtai, M., Hurley, S., et al. ‘An approach to organ salvage from non-heartbeating cadaver donors under existing legal ethical requirements for transplantation’. Tranplantation 1990;49:290–4. 18. Light, J., Sasaki, T., Aquino, A., Barhyte, D., & Gage F. ‘Combined intravascular and intraperitoneal cooling in the non-heart-beating donor improves kidney function following transplantation’. Transplantation Proc 2000;32(1):188. Chapter 2 Legal, moral, and ethical issues Sam D. Shemie and Michael De Vita Controlled and uncontrolled donation after cardiac death Post-mortem organ donation falls into two broad categories, based on the criteria for death determination. When procurement occurs after death determination using neurologic criteria, it is termed ‘donation after brain death’ (DBD). When procurement follows death determined using absence of respiration, circulation, and responsiveness, it is termed ‘donation after cardiac (or cardiopulmonary, or cardiocirculatory) death’ (DCD). For the purposes of this discussion and from a practical clinical perspective, it is useful to classify DCD into two subgroups, controlled and uncontrolled (Figure 2.1) (1). These terms should not be misunderstood as a reflection of professional behaviour or the organisation of clinical services. The degree of ‘control’ refers to the ability to control temporal and geographic constraints for the procurement. Controlled DCD refers to donation following a death that is anticipated but has not yet occurred, and follows a planned removal of life-sustaining treatment. This will usually take place in an intensive care or special care unit. Prior to considering donation, the patient should be judged to have a non-recoverable injury/illness with dependence on life-sustaining therapy. In this circumstance, medical care may be considered futile or the treatment burden exceeds the perceived benefit, and a consensual decision to withdraw life-sustaining therapy has been made. Death is anticipated after withdrawal of life-sustaining therapy. Organ procurement is performed after death has been diagnosed according to objective criteria. Patient conditions may include, but are not limited to, catastrophic brain injury of diverse etiology, cervical spinal cord injury, and end-stage neuromuscular diseases. These patients, previously designated as Maastricht (2) category III, constitute the majority of identifiable DCD donors in the United States, United Kingdom, The Netherlands and Canada. Maastricht IV donors are the predominant form of DCD in Japan. Uncontrolled DCD refers to donation after a death that occurred suddenly and was not anticipated. The typical patient has an unexpected cardiac arrest, which may occur in the emergency department, hospital wards, ICU/special care unit or pre-hospital locations. A decision will have been made to terminate or not to initiate cardiopulmonary resuscitation (CPR). While the duration of cardiac arrest may or may not be known, there is time pressure to perform procurement as quickly as possible after death determination to limit ischaemic injury. Conditions include the patient 8 LEGAL, MORAL, AND ETHICAL ISSUES Controlled Uncontrolled Dependence upon Life-Sustaining Therapy and Consensual Decision to Withdraw Life-Sustaining Therapy Cardiocirculatory Arrest and Decision to Terminate or Not Initiate Resuscitation Option of Organ Donation and Consent Determination of Death Withdrawal of Life-Sustaining Therapy Determination of Death Option of Organ Donation and Consent Organ Procurement Organ Procurement Fig. 2.1 Sequences of care in DCD (1) being dead on arrival to the emergency department (Maastricht category I), and unsuccessful resuscitation after cardiac arrest (Maastricht category II). Worldwide, the majority of uncontrolled DCD are Category I and II patients and constitute the bulk of patients considered eligible for DCD in Spain, France, and the Netherlands. Management is complicated by the fact that death is sudden or unanticipated and may not have occurred within the medical setting. As donation interventions should be initiated as soon as possible, the surrogate decision makers or advance directives may not be immediately available to provide consent. Cardiac arrest following the determination of brain death in the ICU (Maastricht Category IV) is also considered uncontrolled because of unexpected circumstances. However, in this situation, consent for donation may have been previously obtained, thus substantially reducing the ethical issues surrounding consent. The determination of death Medicine and society continue to thoughtfully struggle with the definition of and criteria for death, especially in view of advances in complex life and organ support systems. This is not new. Death determination has been the subject of medical, legal, and social debate for centuries. While diagnostic modalities and physiologic understanding have advanced, the ‘fixed point’ when death is said to have occurred is still mired in controversy. Our ability to support organ failure with technology and transplantation raises important questions of when a disease is irreversible (and indeed what ‘irreversible’ means), when further treatment is no longer effective and when death can be said to have occurred. Complicating the issue is the lack of clear distinction between the different domains in which death may be defined, e.g., medical, legal, THE DETERMINATION OF DEATH religious, spiritual, existential, philosophical, supernatural and even the mystical. ICU practitioners remain confused (3). Death is a biological event based on the permanent cessation of brain or cardiocirculatory function. However, there are also social, legal, and cultural factors impacting on its determination. In medicine and law, the separation between being alive and dead cannot be ambiguous. It marks the point in time after which consequences occur, including no legal or medical requirement to provide resuscitation or life support technologies, loss of personhood and most individual rights, the opportunity for organ donation and autopsy proceedings, execution of the decedent’s legal will, estate and property transfer, payment of life insurance, final disposition of the body by burial or cremation, and of course religious or social ceremonies to mark the end of a life. Almost uniformly throughout the world, precise statutory criteria for death determination are not incorporated in legislation. Most laws only mention the requirement that criteria are met and leave the practical aspects of determining criteria and describing methods for diagnosing death to the medical profession. For example, Canadian law states that ‘for the purposes of post-mortem transplantation, the fact of death shall be determined by two physicians in accordance with accepted medical practice’ (1). The US Uniform Determination of Death Act (UDDA) (4, 5) specifies that death may be ascertained either by the irreversible loss of all brain function or by the irreversible cessation of cardio-respiratory function. The UDDA specifies three criteria for death by cardio-respiratory criteria: unresponsiveness, apnoea, and permanent cessation of circulation. However, the UDDA has never provided criteria for the determination as death should be declared based upon current standards established by the medical community. There are no clear definitions of ‘accepted medical practice’ and the meaning of the term ‘irreversible’ is subject to interpretation. Nor is there legal guidance for the tests or mechanisms that should be employed to determine this death. Finally, the UDDA is only a model legislation, designed to help states create legislation that is equivalent among all states. Because states may create whatever legislation they choose, there is some state-by-state variation. Outside of articles on organ donation for DCD, the cardio-respiratory criteria for death are rarely mentioned in the literature. In most institutions without DCD programs, process and procedures for cardiac death remain poorly defined and are largely at the discretion of individual physicians. The criteria may include the absence of heart beat (contraction), pulse (palpable circulation), blood pressure, heart electrical activity, and may include pulseless electrical activity as well as being unresponsive with absent breathing. To our knowledge, there are no recent studies that evaluate the reliability of the various methods to determine the gold standard for absence of circulation. As a result, even though there are a number of expert opinions, consensus conferences, and society recommendations, the criteria remain inconsistent on a worldwide level. As organ donation follows death, the definition of death requires clarity and consistency in the definition, medical criteria and confounding conditions. While there are persisting variabilities in the process and procedures for brain death globally (6) and within nations (7, 8), the clinical criteria for the evaluation of absent brainstem function are relatively consistent. These variabilities have not created the same amount 9 10 LEGAL, MORAL, AND ETHICAL ISSUES of controversy as the inconsistency of cardiopulmonary criteria. The immediacy of procurement procedures in DCD amplifies these concerns. In the meantime, expert consensus has provided the foundation for the majority of work for cardiac determinations of death and this has been driven by the progress of DCD. Table 2.1 provides an example of criteria for death after cardiac arrest recommended for DCD. Most international jurisdictions support a number of sound principles for the determination of death. These often include provisions that the determination should be made by one or more physicians who must not have direct care responsibility for the proposed transplant recipient and who cannot participate in the transplant proceedings. Irreversibility of death and time of confirmation Until recently there was little need for the medical community to concern itself with the timing of a patient’s death and the literature pertaining to this issue is scarce. The vast majority of deaths in society occur in circumstances where organ donation is not a consideration (9). Criteria to determine these deaths remain largely unarticulated and untaught. However, when contemplating DCD, the duration of circulatory arrest becomes relevant as the organs will deteriorate rapidly following cessation of oxygenation and perfusion. The so-called ‘Dead Donor Rule’ (10) requires that organ procurement neither cause nor precede the patient’s death. In a number of countries (e.g., United States, Denmark, The Netherlands), the use of DCD is made possible because the legislation has dual statutory standards of death (brain death as well as cardiac arrest). On the other hand, countries with legislation that recognises only the brain-death criterion (e.g., Germany, Romania) may experience problems when introducing DCD. Until recently, other countries such as Japan did not recognise brain death and so only performed DCD. Table 2.1 Representative example of national criteria for the determination of death for DCD (1) Determination of cardiocirculatory death This forum defined accepted medical practice for the determination of death for the purposes of organ donation in the context of DCD. For the purposes of DCD, we recommend that the following criteria be met before organ procurement: 1. Beginning with the onset of circulatory arrest, there must be a 5-minute period during which the absence of palpable pulses, blood pressure, and respiration are continuously observed by at least 1 physician. 2. Death is determined by 2 physicians by documenting the absence of palpable pulses, blood pressure, and respiration on completion of this 5-minute period. 3. The physician present during the 5-minute period of continuous observation and who makes one of the determinations of death must be a staff physician with the requisite skill and training. 4. Monitoring to establish the fact of death is the priority during this period of observation. There must be no interventions to facilitate donation during this period. IRREVERSIBILITY OF DEATH AND TIME OF CONFIRMATION International perspectives on the time interval required to confirm death after cardiac arrest generally vary from 2–10 minutes (1). The historical influences on these time frames include the International Maastricht NHBD Workshop (10 minute interval) (11), the 1997 US Institute of Medicine report on NHBD (no less than a 5-minute interval) (12), the Pittsburgh protocol (2 minutes of absence of circulation proven by objective methods including either echocardiogram or central arterial catheter tracing as well as absent respiration and responsiveness) and the 2 to 5 minutes for Society for Critical Care Medicine (SCCM) recommendations for non-heart-beating organ donation (see below (14)). None of these recommendations have been prospectively validated. One major concern is the meaning of ‘irreversible’, particularly when a decision to withhold/discontinue CPR has been made. Death statutes require irreversible stoppage of circulation, respiration, and responsiveness, yet it is unclear whether that means the heart could not be started or merely would not be (15). The difference is volitional: Could not implies that the heart would not start even after attempts to do so, and would not implies that circulation could be restored if an intervention were made (although it will not be). The 1997 IOM report (12) argues that irreversibility is defined by the absence of spontaneous recovery of cardio-respiratory function. There have been case reports of spontaneous resumption of heart function after cardiac arrest (auto-resuscitation), ranging from seconds to minutes and longer. The true incidence and conditions that increase the potential for such an event are unclear and many reports are hampered by inadequate monitoring (16, 17). Some cases are related to misdiagnosis in the setting of dynamic hyperinflation and elevations of intrathoracic pressure (18, 19, 20). There is a clear distinction between those cases who have received CPR, where the reports of auto-resuscitation range from seconds to 20 minutes (21). No auto-resuscitation after WLST (withdrawal of life sustaining therapy) has been described beyond 2 minutes in the absence of CPR (22), suggesting that the provision of CPR is a confounding condition. This may occur due to a buildup of pressure in the thorax as a cause of absent circulation even as the heart is beating (16, 23). The incidence of auto-resuscitation after even a minute, although cited as a common concern and criticism (24, 25), is extremely rare. Regardless, there have been no prospective studies to substantiate or negate these concerns. The true incidence, risk factors, temporal characteristics and outcomes after auto-resuscitation are unknown. It has been estimated that a study of over 10,000 patients would be required to have sufficient power to exclude the possibility of auto-resuscitation after more than 2 minutes. At a minimum, future discussion of auto-resuscitation must distinguish the confounding attempts at CPR and are clinically irrelevant in controlled DCD as no patient electively withdrawn from life-sustaining treatment will receive CPR. The irreversibility of cardiac arrest is related to the context in which it occurs. For example, ability to restore the circulation depends on the location of the arrest, a predetermined ethical decision regarding level of medical intervention, the types of interventions available (cardio-pulmonary resuscitation, extracorporeal membrane oxygenation, or ventricular assist devices) and the types of interventions actually used (for example, CPR may be available, but not used). Although access to technology 11 12 LEGAL, MORAL, AND ETHICAL ISSUES varies from country to country, and even hospital to hospital, medicine has advanced to the point that it is possible to support all vital organs (heart, lung, liver, kidney) using machines, or replace them through transplantation. Irreversible arrest of the heart is not death, if oxygenated circulation to the body can be provided mechanically using extracorporeal support like ECMO or ventricular assist devices. The event may be the cardiac arrest, but death only occurs if there is simultaneous loss of circulation, respiration, and responsiveness and if these remain permanent. From a conceptual standpoint, it is important to note that one accepted standard for brain death is the absence of brain blood flow. Absence of whole body circulation invariably is accompanied by absent brain blood flow, thus conceptually fulfilling criteria for brain death. Accepting this concept, any donor interventions after death that re-establishes brain blood flow as part of extracorporeal organ support after death, as discussed later in this chapter, becomes a major ethical concern. Addressing the ambiguity surrounding the term ‘irreversible’ in its position paper on DCD, the ethics committee of the American College of Critical Care Medicine (ACCCM) distinguishes between stronger and weaker interpretations of ‘irreversible’ (14). On the stronger interpretation, the heart cannot be restarted no matter what intervention is done, including CPR. On the weaker interpretation, circulation cannot be restored because CPR will not be applied. The ACCCM group has recommended the weaker interpretation, with a reasonable observation time of at least 2 minutes from cessation of cardio-pulmonary and neurologic functions with no spontaneous restoration of circulation, but no longer than 5 minutes. The ACCCM argues that no less than 2 minutes is acceptable and no more than 5 minutes is necessary when determining death for potential NHBD. Menikoff (26) argues that irreversibility of cardiopulmonary functioning may not be guaranteed following a five-minute period of arrest and that portions of the dying person’s brain may not have ceased functioning totally at this point. In case reports of monitored human cardiac arrest (27, 28) and animal studies (29), the electroencephalogram becomes isoelectric within 20 seconds after arrest of cerebral blood flow in a normothermic individual, eliminating the concern that cortical brain function may be occurring in patients without circulation for more than 20 seconds. Bernat (30) has argued that the concept of permanence is more relevant and definable than irreversibility. A major criticism of DCD protocols has been the concern regarding the time of observation to determine death and the possibility that death is not irreversible within the time limits proposed (24, 25). Concerns are expressed about violating the dead donor rule, ethical compromise, and the theoretical medico-legal risks for practitioners of being accused of causing the death of a potential donor. The impact these questions have on professional concerns and the uptake of DCD in different jurisdictions is unclear. There have been numerous attempts to resolve this debate by a series of national and international committee reports, but there have been no attempts to collect data that can help answer these fundamental and imperative questions. One might argue that even if it could be shown that auto-resuscitation never occurs after a given time frame, it does not overcome the criticism of the ‘strong’ irreversibility advocates who would require no brain function and circulation even if resuscitation were attempted. There is ample data (22) that hearts can be restarted after hours END-OF-LIFE CARE PRACTICE of absent function, and now using cooling techniques, normal brain function can occur after 10 minutes of absent circulation. As a result of this ‘strong’ irreversibility criticism, it is unlikely that this controversy will abate. End-of-Life care practice Withholding and withdrawal of life sustaining therapy Mortality rates in ICU patients vary according to case mix and acuity, but are approximately 10–20 per cent in adults and 3–5 per cent in children. Death in the ICU will usually occur in the following ways. 1. Patients are receiving full treatment, suffer a cardiac arrest, and an attempt at CPR is made but is unsuccessful. 2. Patients are receiving full treatment, suffer a cardiac arrest, and no attempt at CPR is made (DNR orders in place). 3. Some or all of full treatment is withheld or withdrawn, the patient suffers a cardiac arrest, and no attempt at CPR is initiated. 4. Death is determined based on neurologic criteria (neurological determination of death/brain death). The majority of deaths in neonatal, pediatric, and adult intensive care are related to irrecoverable illness and are preceded by withdrawal or withholding of life-sustaining treatment (WLST). This is accepted ICU practice in most countries throughout the world, although there is considerable practice variation. Where the burden of continued treatment far exceeds benefit, WLST takes place after discussion and consent/assent by the patient or the patient’s surrogate. Reported WLST rates in single center ICUs range from 65 per cent (31) to 79 per cent (32), but there is substantial international and geographic variability. In controlled DCD, a competent patient or their surrogate has consented to the withdrawal of ventilation or other life-sustaining therapy. Consent implies that the patient or substitute decision-maker has been informed of the nature and purpose of the treatment withdrawal and understands what this action entails. Consent to organ procurement is given by a patient or surrogate independently of the decision to withdraw life-support and requires that procurement will take place only after death has been declared. Lifesupport can justifiably be withdrawn and organ procurement commenced after a clinical declaration of death (33). One of the principle obstacles to DCD development has been a concern about real and perceived conflicts of interests between providing care for a dying patient and facilitating donation before death has been established (24, 25). It is widely agreed that patient care issues must be differentiated from those related to organ procurement. The decision to WLST must be made independently of any decision to donate organs for transplantation (34). Initially, it was advocated that discussions regarding organ donation and procurement should not to be held until the decision to withdraw medical therapy had been made (35). However, recent legislation in the US regarding requirements to notify OPOs (organ procurement organizations) of impending death, as well as the rapidly increasing number of people who have 13 14 LEGAL, MORAL, AND ETHICAL ISSUES decided before critical illness occurs to sign organ donor consents has changed perspectives on this issue. Nonetheless many organisations now prefer to require that the organ donation discussions be made separate and independent from decisions regarding life-sustaining treatment. Decisions regarding life-sustaining treatment should be made on their own merit, and not in consideration of organ donation. Physicians involved in the ICU patient care and WLST should not be involved also in the care of potential recipients. Transplant physicians must not be involved in the decision to WLST or in death determination. This minimises both real and perceived conflicts of interest for ICU staff between their therapeutic duty to the critically ill patient and their non-therapeutic relationship to potential organ transplant recipients (14, 36). Under the circumstances where the ICU may concurrently care for end-stage organ failure patients who are potential transplant recipients, physicians and caregivers who may be in conflict should voluntarily withdraw from the care of a potential donor or the potential recipient. Once a decision to WLST has been made between the treating team and the family, approaching families about donation is ethically appropriate and consistent with a process that would enable patients or their substitute decision-makers to realise the patient’s desire and intent to donate organs after death. Some families might perceive the request for donation to imply that the principal concern of the medical team is with the patient’s organs rather than with the patient. It may be appropriate to delegate these discussions to representatives from an organ procurement organisation or a program representative from the health care organisation itself. Over concern regarding caregiver conflict of interest can paralyze efforts toward organ donation. It should be recognised that clinicians have a duty to patients who want to donate their organs. This duty is to make donation occur if feasible and ethically appropriate. Many caregivers and organisations are so concerned about perceived conflict of interest that they fail to address their duty to fulfill patients’ wishes. If the perceived conflict of interest does preclude caregiver participation, efforts should be made to identify caregivers without the same barriers so that patient wishes may be ethically fulfilled. Variability in end-of-life care Survival Predictions ICU physicians tend to overestimate mortality risk and this influences decision making at the end-of-life (37). Physician predictions of a <10 per cent survival for mechanically ventilated adults compared to an actual 29 per cent survival and are associated with the provision of less intensive care, and significantly higher odds of withholding or withdrawal of various life support modalities. Physician estimates of a low probability of ICU survival may be more strongly associated with ICU mortality than baseline illness severity, evolving or resolving organ dysfunction, and use of inotropic agents or vasopressors (37). Families should be made aware of the possibility that patients may not die after WLST. In addition, practitioners should be mindful of the influence of flawed survival predictions, where WLST in brain injured patients may lead to a self-fulfilling prophecy (38). Prognostication and outcome predictions have known limitations and when present, these uncertainties should be transparent in family discussions. VARIABILITY IN END-OF-LIFE CARE Clinical determinants of WLST Numerous studies have documented practice variation related to the clinical determinants of WLST. Patient age, disease acuity and cognitive function are the most commonly cited clinical variables impacting on the decision to withdraw or withhold treatments. Advance directives and ethno-cultural attitudes also play a large role. In European ICU’s, limitation of therapy is associated with patient age, acute and chronic diagnoses, and number of days in ICU (39). Factors associated with WLST may be highly weighted to physician perceptions. Rather than age, severity of the illness or organ dysfunction, the strongest determinants of the withdrawal of ventilation in critically ill adults are physician perceptions that the patient preferred not to use life support, the physician’s predictions of a low likelihood of survival in the intensive care unit and a high likelihood of poor cognitive function (40). Variation with geography and physician characteristics The wide variation in the limitation of ICU life support throughout the world applies between and within countries. American studies have shown geographic variation ranging from 0 to 79 per cent (41). Similar widespread geographic variation has been more recently demonstrated in the United Kingdom, ranging from 1.7 to 96.1 per cent (42) (Figure 2.2). There was considerable variation by unit within the same country, even after accounting for patient factors and differences in size and type of ICU. 100 90 80 % of deaths 70 60 50 40 30 20 10 0 Individual ICU (n=127) Fig. 2.2 Variability in WLST practices. By individual ICU, the percentage of ICU deaths in the United Kingdom that occurred following the decision to withdraw active treatment (42) 15 LEGAL, MORAL, AND ETHICAL ISSUES Surveys of European ICU physicians reveal that the countries of southern Europe were less likely than those in the north to apply do-not-resuscitate orders and withhold treatment (43). With international surveys, most participants from Japan, Turkey, the United States, Southern Europe, and Brazil would aggressively treat clinical scenarios, whereas in Northern Europe, Central Europe, Canada, and Australia, terminal withdrawal of mechanical ventilation and extubation were the more commonly chosen responses (44). The large prospective European Ethicus study (39) reveals significant differences associated with religious affiliation and culture observed in European ICU practice for the type of end-of-life decision, the times to therapy limitation and death, and discussion of decisions with patient families (39, 45). Substantial inter-country variability was found in the limitations and the manner of dying, with variability associated with religious background of physicians and geography (Figures 2.3 and 2.4). As patient age and ICU stay increases, withholding and withdrawing treatments are more common than CPR use in northern and central European countries (39). Withholding occurred more often than withdrawing if the physician was Jewish, Greek Orthodox, or Moslem. Withdrawing occurred more often for physicians who were Catholic, Protestant, or who had no religious affiliation. Also relevant to DCD was that median times from limitations to death and discussions with families also varied widely relating to the physician’s religious affiliation. Variance can also be explained by other physician factors such as age and experience, subspecialty, or place of work (academic vs. community centre or open vs. closed ICU) (46, 47, 48). 80 Catholic 70 Protestant Greek Orthodox 60 Jewish Islam 50 Percent 16 None 40 30 20 10 0 Unsuccessful CPR Withholding LST Withdrawing LST Active Shortening of the Dying Process Fig. 2.3 End-of-life practices in European ICU’s influenced by the religious background of the attending physician (adapted from 39) VARIABILITY IN END-OF-LIFE CARE 50 Northern Europe 45 Central Europe 40 Percent 35 30 Southern Europe 25 Total 20 15 10 5 0 Unsuccessful CPR Brain Death Withholding Withdrawing Active Life-Sustaining Life-Sustaining Shortening of Treatment Treatment the Dying Process Fig. 2.4 Frequencies of patient end-of-life categories by region in Europe (n = 4248) (39) Variation in methods of WLST Methods of WLST are influenced by patient condition but may vary between individual physicians and ICU centers. Different approaches to withdrawal of mechanical ventilation have been cited (49). WLST methods may include, but are not limited to, terminal extubation (removal of mechanical ventilation and the artificial airway), rapid discontinuation of mechanical ventilatory support, terminal weaning (gradual decrease in mechanical ventilatory support with or without removal of the artificial airway), rapid discontinuation, or gradual weaning of hemodynamic supports There are no standardised procedures for WLST nor is there any intrinsically ‘correct’ way to proceed or optimal duration of the process. Patient care during this phase must be directed to maintaining patient comfort and alleviation of suffering. The principle of double-effect (50) supports the administration of treatments consistent with this intent, even if there is a risk (foreseen but not intended) of hastening death. The use of comfort medications may vary in type (analgesics, sedatives), dosage, and strategy (proactive prevention of pain vs. reactive treatment of pain) (49, 51). Regardless of underlying disease, variation in methods of WLST and the use of comfort medication may consequently result in variability of the time from WLST to death (Figure 2.5). It is interesting that although there are concerns that sedating drugs hasten death, in practice, their use is associated with a longer time to death (52, 53). The use of comfort medications for palliation and symptom relief is recommended and common practice before and after WLST in the ICU (49, 54). However, surveys of European Intensivists show that 40 per cent will deliberately administer large doses of sedation or analgesia drugs until death ensues (43). Shortening of the dying process 17 LEGAL, MORAL, AND ETHICAL ISSUES Shortening of the Dying Process (SDP) 1.0 Cumaulative Probability of Death 18 Withdraw 0.8 0.6 Withhold 0.4 0.2 0 0 3 6 9 12 15 Days since Most Severe Limitation to Death Fig. 2.5 Probability of death over time for withholding, withdrawing, or active shortening of the dying process (sdp) in European intensive care units. The predicted probability of death over time for the different limitations, adjusted for age, sex, diagnosis, practice, turnover, and region (39) has been reported in seven European countries (39). Clarity between therapies intended to relieve pain and suffering and those intended to shorten the dying process may be lacking (55). It is especially important in the process of DCD that there should be no ambiguity in the clinical intention to relieve any suffering of the dying individual in order to maintain public and professional trust. Variability in End-of-Life care and implications for DCD practice Surveys of seriously ill hospitalised patients demonstrate that important elements in EOL care are the following: trust and confidence in the treating physician, avoidance of unwanted life support, effective and honest communication, to bring end-of-life responsibilities to a closure and to ‘prepare for the end’ (56). The meaning of trust and confidence in the treating physician may vary according to culture, ranging from collaborative decisions in support of patient autonomy to paternalistic decisions based on physician autonomy and beneficence. Regardless of the ethical foundation, decisions should be made in the best interests of the patient in care. The existence of practice variations in EOL care, both between and within countries, remains a challenge. This may present a barrier to the establishment of DCD programs or has the capacity to subversively influence DCD practices. Given the known variability in practice, practitioners need to be cognizant about the potential impact of the existence of a DCD program on the practice patterns of WLST and vice versa. Decisions should best be influenced by patient and disease-dependent factors rather than physician/hospital characteristics. Although this may vary with cultural VARIABILITY IN END-OF-LIFE CARE norms and values, ideal EOL decisions should be based on the most accurate prognostication available, and consideration of the wishes and values of the patient. If programs articulate best practices in regards to WLST for any patient, it makes it easier to require adherence to ‘standard’ practices in the conduct of DCD. Predicting death The WLST does not necessarily lead to death within a time frame during which organ donation is possible. ICU practitioners are cognizant of the difficulty to reliably predict if and when a patient will die after WLST. Although no formal testing generally occurs (outside of DCD), possible variables of influence include 1. Patient conditions (e.g., level of consciousness, degree of airway obstruction, ventilatory drive, oxygenation impairment, hemodynamic instability). 2. Methods of WLST—procedures and comfort medications delivered and the types of therapies discontinued. After the family consents to controlled DCD, there are steps in the process that may preclude donation; for example, the duration of the dying process might exceed the upper limits of organ viability in the context of transplantation. During the interval of time from WLST to death, patients who experience a slow progressive demise (hypotension and hypoxemia) may become unsuitable candidates as organs will be irreparably damaged by warm ischemic injury during the dying process (35). In addition, there are time constraints related to logistical preparations that include the surgical procurement team and anesthetist/operating room staff who must be alerted and on hold until death and minimum criteria to donate are established. A clinical tool developed by the University of Wisconsin program has predicted, with 90 per cent accuracy, those patients who will expire within 2 hours following WLST (57) (follow-up data from 2003–2006 reveals 82 per cent accuracy (58)). The testing protocol collected information that includes patient age, airway status, vasopressor and inotrope therapy, and the respiratory status following 10 minutes of disconnect from the ventilator (respiratory rate, tidal volume, negative inspiratory force, blood pressure, pulse, and oxygen saturation). Selection of candidates for organ donation is predicated on the respiratory drive assessment and the use of this predictive tool prior to WLST. The Wisconsin experience would suggest that about 10 per cent of potential DCD donors were returned to the unit or hospital floor for palliative care (59). The United Network for Organ Sharing (UNOS) DCD consensus committee (60) developed criteria to predict death within 60 minutes. These criteria have now been validated, and they obviate the need for special evaluation as they are based on patient and life support characteristics at the time of WLST (61). They are largely based on degree of oxygenation failure, hemodynamic supports, the use of extracorporeal life support technologies and the method of WLST on how rapidly a patient dies. The authors found that the two most powerful predictors of death in under 60 minutes were peak inspiratory pressure greater than 30 and a Glasgow Coma Score of 3. Interestingly, dose of sedating medications was proportional to latency to death after WLST: the more medication the patient received in the first 60 minutes, the less likely they were to expire in under 30 or 60 minutes. 19 20 LEGAL, MORAL, AND ETHICAL ISSUES The role of the operating room WLST commonly occurs within the ICU environment, and rarely occurs in the operating room. As a result, one should expect a ‘culture shock’ among operating room staff who rarely care for dying patients, and even more rarely assist with the dying process by electively withdrawing life-sustaining treatment. Access to a surgical suite is typically required for organ procurement in controlled DCD, often necessitating transfer of the patient to the operating room prior to WLST. While this allows rapid surgical intervention for organ preservation and procurement after death, it can raise concerns among surgical staff. Concerns have also been cited about involvement of third party anesthesiologists during withdrawal of life-sustaining measures, particularly if they have not been previously involved with the care and WLST discussions specific to that patient (62). In most cases, it will be in the best interests of the patient, the family and the surgical suite staff for the ICU treating team to continue to assume responsibility for the dying process regardless of the location of WLST. Donor-based interventions relative to phases of care In many DCD programs, it is permissible to perform interventions on the patient to preserve the option of donation for the family, maximise the potential for useable organs, or improve the function of organs once transplanted. The timing and type of interventions may vary by region and also with the introduction of new therapies over time. From the bioethical and legal perspective, the relevant intervals of care are before death and after death, and the potential for restoration of cerebral function. Pre-mortem interventions may include the following: 1. Blood testing for donor eligibility (tissue typing, cross match, virology screen and organ function testing). 2. Staged preparation for in situ preservation or extracorporeal oxygenated perfusion, which may include sterile preparation and draping of the surgical field, isolation of femoral vessels by surgical cutdown and cannulation of vessels. 3. Pharmacological: administration of anticoagulants (e.g., heparin), arterial vasodilators (e.g., phentolamine) and thrombolytics. To be effective, intact circulation (prior to death) is required for systemic distribution, although some centers administer them after death in the preservation solution. Post-mortem interventions may include 1. Vessel cannulation, 2. In situ perfusion with preservation solution, 3. Re-institution of chest compressions and mechanical ventilation, and 4. Extracorporeal oxygenation and perfusion. Donor interventions prior to death in controlled DCD Interventions to facilitate donation prior to death should require the specific and informed consent of the patient/family for each intervention. Their purpose should be understood in terms of how they might improve successful donation after death. POST-MORTEM CARE INTERVENTIONS: UNCONTROLLED DCD These interventions should be undertaken with consideration of risks and benefits, not be intended to hasten death or otherwise harm the patient, and should pose no more than minimal risk. If the intention is not to hasten the death of the donor and still enables one to preserve the organs to provide benefit to the recipient, then it seems that the ethical balance favors the intervention (63). Although they do not provide any therapeutic benefit to the patient, benefit may be broadly defined to include the actualisation of the donor’s interests and wishes based on the patient’s desire and intent to donate. Ethical concerns are related to therapies that have no direct benefit to the patient, and where there is a theoretical but small risk. Practice is not uniform and no trials have been done to evaluate dosage, timing of administration (pre-mortem vs. postmortem), or impact on transplantable organ function. For example, giving heparin has been questioned. While heparin is not required for the care of the dying patient, it is highly unlikely to cause or hasten death, yet it may to promote the organ donation, consistent with the desire of the dying patient. Although not proven, pre-mortem heparin administration may lower the primary non-function and delayed graft function rates. Many reports recommend full disclosure in consent discussions (1, 64). Timing of administration of the drugs may diminish ethical concerns as the later the drug is given, the less likely it is to harm the patient. As a result, some DCD programs administer heparin with the onset of hypotension rather than before initiation of the withdrawal process. Other medications that have raised concerns are pre-mortem administration of phentolamine (whose use is less common) and streptokinase, which should only be given post-mortem. The risks of using these agents are not well described due to their use in such close proximity to death. In a sense, the discussion is more philosophic than empiric as a result. Many, but not all, European countries have followed the Maastricht policy, precluding the use of medication that is not beneficial to the patient until after death (65, 66). Post-mortem care interventions: uncontrolled DCD For uncontrolled DCD, the deceased has had a cardiac arrest prior to preparation or planned removal of LST. In most instances, there should be an established decision to terminate or not to initiate CPR. Management is difficult in that death is unanticipated and medical teams may be unprepared for commencement of in situ preservation. When death is sudden or unexpected, the deceased often do not have their relatives/surrogate decision makers with them and advanced directives may not be immediately available. Ideally, informed consent prior to donation-based interventions should be sought. However, the wishes of the deceased may or may not be known and next of kin may be absent. In some uncontrolled DCD programs, it is permissible to perform interventions on the deceased to preserve the option of donation for the family, to maximise the potential for useable organs or improve the function of organs once transplanted. To achieve these goals, the interventions may need to be started prior to the availability of family consent. When discussing whether these interventions are permissible, it is important to consider the ethical justifications for intervening on a dead body to 21 22 LEGAL, MORAL, AND ETHICAL ISSUES preserve options of the family for donation, respect for the body, principles of consent, and the legal implications. Some jurisdictions, including some American states, have adopted laws that allow for in situ preservation prior to consent (District of Columbia DC ST, 2002; Florida Statutes, 2002; Virginia State Code, 2002), but organ procurement is not allowed without consent. There are time constraints on how long these interventions can be applied, and it is possible that consent may not be available in a time frame that allows organ procurement. Under the new Human Tissue Act in the United Kingdom, invasive organ-preservation techniques in the event of sudden death and in the absence of consent are now deemed lawful (67). In cases where the deceased have not made a decision themselves, and the family is not available to exercise its right to consent, Dutch legislation allows that ‘the necessary measures to maintain the organ in a suitable condition for transplantation may be taken after death, so long as the procedure for obtaining the necessary consent in accordance with this law has not been completed’ (68). Dutch law requires that these measures do not conflict with the treatment of the patient, do not harm or mutilate the body, and cannot be postponed. Uncontrolled DCD in Spain may reinstitute CPR and initiate extracorporeal perfusion while efforts to gain consent are ongoing (69). Despite legalisation of these interventions, serious ethical and moral questions arise regarding the appropriate conduct of physicians at the time of death and the initiation of invasive organ preservation techniques without consent (70). There are two schools of thought on the issue of in situ preservation without prior consent. Minimisation of warm ischemic time preserves organ post-transplant function and provides the family with an opportunity to consider the merits of organ donation in a less hurried and somewhat less stressful environment. Given more time to consider the option, family support for DCD has been shown to dramatically increase if cannula insertion occurs before, rather than after, family consent (71). Those in favor of the pre-consent intervention point to the improved ability to fulfill family and patient wishes to donate. Nonetheless, ethical questions arise when medical interventions are performed in the absence of informed consent. In many countries, medical interventions are grounded in the principle of fully informed consent in line with societal expectations. US public surveys have shown that 74 per cent of respondents opposed allowing physicians to proceed with intravascular cannulation without prior consent (72). Many authors do not support these interventions, arguing that dignity for the dead is undermined by the unilateral decision of medical caregivers to proceed with these interventions (1, 25, 70). However, the socio-cultural conditions in those countries with presumed consent legislation influence these practices, in that the default procedure in the absence of consent is donor maintenance rather than non-intervention. Re-establishment of circulation following death Following the declaration of death, some centers may also choose to re-introduce cardiopulmonary support in an effort to provide some degree of oxygenated perfusion of targeted organs, thus effectively minimizing ischemic organ injury. These measures INTERNATIONAL CONSENT MODELS AND IMPLICATIONS FOR DCD PRACTICE may include re-intubation and cardiac compressions (manual or machine) (69, 73) or extracorporeal membrane oxygenation. Although primarily applied to uncontrolled DCD, some centers are in the early phase of using extracorporeal membrane oxygenation in controlled DCD (74, 75). Initial studies have reported balloon occlusion of the thoracic aorta to prevent coronary and cerebral blood flow (75). This practice has been abandoned in some centers for technical reasons but not in Spain where it was originally introduced for thoracic trauma to restrict perfusate loss but kept to prevent cardiac recovery. It is not unexpected that the reinstitution of coronary blood flow with extracorporeal organ support may lead to a resumption of myocardial function that has anecdotally required pharmacologic arrest of heart function. More concerning, however, are the ethical issues related to re-establishing cerebral blood flow after death has been determined. It is unclear to us if these individuals can still be considered to be dead. For this reason, some jurisdictions have explicitly precluded any interventions that may re-institute cerebral perfusion and oxygenation after the fact of death (1), and we concur. International consent models and implications for DCD practice In most countries, DCD has not been directly addressed by existing law. Practices are shaped instead by reports, protocols, and guidelines. Legal interpretations must be extrapolated from existing organ donation and transplant legislation. Countries have different consent models, generally ranging from requirements for explicit consent or ‘opting in’ (US, UK, Canada, Australia, Austria, Italy, Switzerland) to presumed consent ‘opting out’ (Belgium, Sweden, Netherlands, Spain). These models may or may not influence the acceptability of donor-based interventions prior to consent being known or available. The consent regime as it applies to DCD, especially related to premortem interventions, needs to be examined on a jurisdiction-by-jurisdiction basis to identify gaps or ambiguities. Where the medical team seeks consent for pre- or post-mortem interventions, the team must ensure that the proxy has appropriate (legal) authority to grant such consent. From a legal perspective, most jurisdictions have not directly addressed the issue of surrogate consent to treatment versus surrogate consent to non-therapeutic interventions that preserve the donation opportunity. Consideration should be given to the legal authority granted by consent to treatment legislation, tissue/organ donation legislation and case law. When the patient is capable, informed patient consent is to be obtained. In most jurisdictions requiring explicit consent, there is no legal or ethical reason for the family/proxy to be asked for consent when there is a valid consent from the donor with the possible exception of a falsified document, or patient withdrawal of consent (undocumented) prior to death that is not documented. Physicians may be unaware that the law gives them the authority to act on a documented intent to donate and this is sufficient legal authority to retrieve organs after death. This applies in the absence of available family consent and in the face of family opposition. The surrogate decision maker has no legal or ethical authority to give or refuse consent in the face of valid donor consent. 23 24 LEGAL, MORAL, AND ETHICAL ISSUES In jurisdictions requiring explicit consent, there are theoretical legal consequences of donation-based interventions after death in uncontrolled DCD in the absence of preceding patient or family consent. Under certain criminal codes, there is a potential for criminal liability when there is an offence of interference with a dead body. In nations with presumed consent, every deceased person is considered a possible donor unless there is an expressed desire against donation. Dutch (68), British (67), and Spanish practices (69) and law supports the commencement of preservation measures while the family are being localised, providing that these measures do not conflict with the treatment of the patient, do not harm or mutilate the body and cannot be postponed. Core values, ethics and temptations of transplant virtue Practitioners and those involved with DCD program development should be cognizant of risks that may lead to erosions of ethical practice. While the adoption of practice guidelines is standardizing many aspects of patient care, ethical dilemmas are occurring because the forgoing of life-sustaining therapies in intensive care is dealt with in diverse ways between different countries and cultures. The aforementioned variabilities in WLST practice, based on physician characteristics independent of patient conditions, calls for improved guidelines in order to facilitate uniform decision making. While the honorable goal of the individual’s wish to provide transplantable organs should be realised, the ethical conduct of practice needs to be protected and guarded from pressures arising from the scarcity of organs and donor performance targets linked to funding. These can lead to a policy or practice decisions based on what are best for organs, rather than what is best for dying patients. Risks include violations of the dead donor rule, transgressions of patient autonomy, coercive rather than factual consent discussions or the involvement of transplant professionals in the pre-mortem phase of care. Recent media reports with allegations of transplant professionals directing pre-mortem management and expediting death of potential DCD donors highlights these concerns (76). To minimise ‘out of bounds’ behaviours, we recommend a detailed policy and procedure. Some institutions utilise a pre-donation record sheet as well as a clinical record sheet to make sure that all the details are recorded (Figure 2.6). This practice not only assists the caregivers but also provides an opportunity to audit performance for unethical practices. It is important to emphasise core values and ethics that can serve to guide deliberations and ethical practices for DCD (1). End-of-life care should routinely include the opportunity to donate organs and tissues. The duty of care towards dying patients and their families remains the dominant priority of health care teams. The medical and ethical framework for WLST in the ICU falls within the domain of critical care practice, and decisions to WLST should not be influenced by donation potential. The management of the dying process, including procedures for WLST, sedation/analgesia/ comfort care should proceed according to existing ICU practice in the best zinterests of the dying patient. It is the responsibility of the critical care and neuro-critical care communities to ensure optimal and safe practice in this field. The complexity and profound implications of death are recognised and should be respected, along with differing personal, ethno-cultural, and religious perspectives CORE VALUES, ETHICS AND TEMPTATIONS OF TRANSPLANT VIRTUE on death and donation. Decisions around withdrawal of life-sustaining therapies, management of the dying process, and the determination of death should be separate from and independent of donation/transplant processes. Respect for the life and dignity of all individuals should remain paramount. The care of the dying patient should not be compromised by the desire to protect organs for donation or expedite death for the benefit of timely organ retrieval. Respect should be established or maintained for informed consent and patient autonomy and decisions about care at the end of life should be based on the known values and beliefs of the patient. Fig. 2.6 Pre-donation and clinical record sheet (University of Pittsburgh Medical Center). 25 26 LEGAL, MORAL, AND ETHICAL ISSUES Fig. 2.6 Cont’d. 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Rocker, G., Cook, D., Sjokvist, P., Weaver, B., Finfer, S., McDonald, M.E., et al.; for the Level of Care Study Investigators; the Canadian Critical Care Trials Group. ‘Clinician predictions of intensive care unit mortality’. CCM 2004 May;32(5):1149–54. 38. Becker, K.J., Baxter, A.B., Cohen, W.A., Bybee, H.M., Tirschwell, D.L., Newell, D.W., et al. ‘Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies’. Neurology 2001;56(6):766–72. 39. Sprung, C.L., Cohen, S.L., Sjokvist, P., Baras, M., Bulow, H.H., Hovilehto, S., et al.; for the Ethicus Study Group. ‘End-of-life practices in European intensive care units. The Ethicus Study’. JAMA 2003;290:790–7. 40. Cook, D., Rocker, G., Marshall, J., Sjokvist, P., Dodek, P., Griffith, L., et al.; Level of Care Study Investigators and the Canadian Critical Care Trials Group. ‘Withdrawal of mechanical ventilation in anticipation of death in the intensive care unit’. N Engl J Med 2003 Sep;349(12):1123–32. REFERENCES 41. Prendergast, T.J., Claessens, M.T., & Luce, J.M. ‘A national survey of end-of-life care for critically ill patients’. Am J Respir Crit Care Med 1998 Oct;158(4):1163–7. 42. Wunsch, H., Harrison, D.A., Harvey, S., & Rowan, K. ‘End-of-life decisions: a cohort study of the withdrawal of all active treatment in intensive care units in the United Kingdom’. Intensive Care Med 2005 Jun;31(6):823–31. Epub 2005 Apr 27. 43. Vincent, J.L. ‘Forgoing life support in western European intensive care units: the results of an ethical questionnaire’. Crit Care Med 1999 Aug;27(8):1626–33. 44. Yaguchi, A., Truog, R.D., Curtis, J.R., Luce, J.M., Levy, M.M., Melot, C., et al. ‘International differences in end-of-life attitudes in the intensive care unit: results of a survey’. Arch Intern Med 2005 Sep;165(17):1970–5. 45. Sprung, C.L., Maia, P., Bulow, H.H., Ricou, B., Armaganidis, A., Baras, M., et al.; the Ethicus Study Group. ‘The importance of religious affiliation and culture on end-of-life decisions in European intensive care units’. Intensive Care Med 2007 Jun 1. Epub. ahead of print. 46. Asch, D.A., Faber-Langendoen, K., Shea, J.A., & Christakis, N.A. ‘The sequence of withdrawing life-sustaining treatment from patients’. Am J Med 1999;107(2):153–6. 47. Cook, D.J., Giacomini, M., Johnson, N., & Willms, D; for the Canadian Critical Care Trials Group. ‘Life support in the intensive care unit: a qualitative investigation of technological purposes’. CMAJ 1999;161(9):1109–13. 48. Keenan, S.P., Busche, K.D., Chen, L.M., Esmail, R., Inman, K.J., & Sibbald, W.J. ‘Withdrawal and withholding of life support in the intensive care unit: a comparison of teaching and community hospitals. The Southwestern Ontario Critical Care Research Network’. Crit Care Med 1998;26(2):245–51. 49. Rocker, G.M., Heyland, D.K., Cook, D.J., Dodek, P.M., Kutsogiannis, D.J., & O’Callaghan, C.J. ‘Most critically ill patients are perceived to die in comfort during withdrawal of life support: a Canadian multicentre study’. Can J Anaesth 2004 Jun–Jul;51(6):623–30. 50. Robertson, J.A. ‘The dead donor rule’. Hasting Cent Rep 1999;29(6):6–14. 51. Hall, R.I., Rocker, G.M., & Murray, D. ‘Simple changes can improve conduct of end-of-life care in the intensive care unit’. Can J Anaesth 2004 Jun–Jul;51(6):631–6. 52. Edwards, M.J. ‘Opioids and benzodiazepines appear paradoxically to delay inevitable death after ventilator withdrawal’. J Pall Care 2005;21(4):299–303. 53. Good, P.D., Ravenscroft, P.J., & Cavenaugh, J. ‘Effects of opioids and sedatives on survival in an Australian inpatient palliative care population’. Intern Med J 2005;35:512–17. 54. Truog, R.D., Cist, A.F.M, Brackett, S.E., Burns, J.P., Curley, M.A., Danis, M., et al. ‘Recommendations for end of life care in the intensive care unit: The Ethics Committee of the Society of Critical Care Medicine’. Crit Care Med 2001;29:2332–2348. 55. Quill, T.E. ‘The ambiguity of clinical intentions’. N Engl J Med 1993;329:1039–40. 56. Heyland, D.K., Dodek, P., Rocker, G., Groll, D., Gafni, A., Pichora, D., et al. ‘What matters most in end-of-life care: perceptions of seriously ill patients and their family members’. CMAJ 2006 Feb;174(5):627–33. 57. Lewis, J., Peltier, J., Nelson, H., Snyder, W., Schneider, K., Steinberger, D., et al. ‘Development of the University of Wisconsin donation after cardiac death evaluation tool’. Prog Transplant 2003;13(4):265–73. 58. de Vita, M.A., Brooks, M.M., Zawistowski, C., Rudich, S., Daly, B., & Chaitin, E. ‘Donors after cardiac death: validation of identification criteria (DVIC) study for predictors of rapid death’. Am J Transplant 2008;8(2):432–41. 29 30 LEGAL, MORAL, AND ETHICAL ISSUES 59. Cooper, J.T., Chin, L.T., Krieger, N.R., Fernandez, L.A., Foley, D.P., Becker, Y.T., et al. ‘Donation after cardiac death: the University of Wisconsin experience with renal transplantation’. Am J Transplant 2004;4(9):1490–4. 60. Bernat, J.L., D’Alessandro, A.M., Port, F.K., Belck, T.P., Heard, S.O., Medina, J., et al. ‘Report of a national conference on donation after cardiac death’. Am J Transplant 2006;6:281–91. 61. DeVita, M.A., Brooks, M.M., Zawistowski, C., Rudich, S., Daly, B., & Chaitin, E. ‘Donors after cardiac death: validation of identification criteria (DVIC) study for predictors of rapid death’. Am J Transplant 2008;8:432–41. 62. Van Norman, G.A. ‘Ethical issues and the role of anesthesiologists in non-heart-beating organ donation’. Curr Opin Anaesthesiol 2003 Apr;16(2):215–9. 63. Veatch, R. Transplantation Ethics. Washington: Georgetown University Press, 2000. 64. Institute of Medicine. Non-Heart-Beating Organ Transplantation: Practice and Protocols. Washington: National Academy Press, 2000. 65. Sudhindran, S., Pettigrew, G.J., Drain, A., Shrotri, M., Watson, C.J., Jamieson, N.V., et al. ‘Outcome of transplantation using kidneys from controlled (Maastricht category 3) non-heart-beating donors’. Clin Transplant 2003;17(2):93–100. 66. Koffman, G. & Gambaro, G. ‘Renal transplantation from non-heart-beating donors: a review of the European experience’. J Nephrol 2003;16(3):334–41. 67. United Kingdom Human Tissue Act 2004. http://www.legislation.hmso.gov.uk/acts/ acts2004/20040030.html. 68. Bos, M.A. ‘Legal issues concerning the use of non-heart-beating donors’. Transpl Proc 1995;27:2929. 69. Nunez, J.R., Del Rio, F., Lopez, E., Moreno, M.A., Soria, A., & Parra, D. ‘Non-heart-beating donors: an excellent choice to increase the donor pool’. Transplant Proc 2005 Nov;37(9):3651–4. 70. Bell, M.D. ‘Emergency medicine, organ donation and the Human Tissue’. Act Emerg Med J 2006 Nov;23(11):824–7. 71. DeVita, M., Snyder, J., & Grenvik, A. ‘History of organ donation by patients with cardiac death’. Kennedy Inst Ethics J 1993;3:113–29. 72. Seltzer, D., Arnold, R., & Siminoff, L.A. ‘Are non-heart-beating cadaver donors acceptable to the public?’. J Clin Ethics 2000,11:347–56. ~¡nuez, C., Aguirrezabalaga, J., Otero, A., et al. 73. Quintela, J., Gala, B., Baamonde, I., Fern A ‘Long-term results for liver transplantation from non-heart-beating donors maintained with chest and abdominal compression-decompression’. Transplant Proc 2005 Nov;37(9):3857–8. 74. Gravel, M.T., Arenas, J.D., Chenault, R., Magee, J.C., Rudich, S., Maraschio, M., et al. ‘Kidney transplantation from organ donors following cardiopulmonary death using extracorporeal membrane oxygenation support’. Ann Transplant 2004;9(1):57–8. 75. Magliocca, J.F., Magee, J.C., Rowe, S.A., Gravel, M.T., Chenault, R.H., Merion, R.M., et al. ‘Extracorporeal support for organ donation after cardiac death effectively expands the donor pool’. J Trauma 2005 Jun;58(6):1095–101 discussion 1101–2. 76. http://www.venturacountystar.com/news/2007/jul/06/lawsuit-filed-in-mans-death/. Chapter 3 History of organ perfusion in organ transplantation Diethard Monbaliu, Qiang Liu, Katrien Vekemans, and Jacques Pirenne Introduction In solid organ transplantation, preservation has always been of critical importance to maintain organ viability after donation until transplant. Until recently, cold storage has been the most widely used preservation method. However, the growing use of ‘expanded criteria’ donors has led to a revival of interest in the use of machine perfusion to improve preservation of organs from these donors. Interestingly, organ preservation using machine perfusion technology is not new, and in fact is as old as solid organ transplantation itself. Machine perfusion was introduced clinically almost simultaneously with organ transplantation, and its basic principles have not really changed since then. Nevertheless, machine perfusion preservation became widely replaced by cold storage when Geoffrey Collins introduced a static preservation solution (1). The good results of cold storage, associated with its simplicity and easy logistics, led to the worldwide adoption of this technique as a standard preservation method. However, due to its perceived superiority over simple cold storage as proposed by some transplant centres—especially for ‘expanded criteria’ organs— machine perfusion of kidneys was not completely abandoned (2). Machine perfusion offers the possibility of thoroughly removing all blood, especially in the microcirculation, allowing an optimal equilibration of the preservation solution within the tissues, thereby continuously supporting metabolism whilst removing waste products (3). In addition, machine perfusion offers the possibility of assessing viability of organs prior to transplantation. Pioneers in organ perfusion and preservation The concept of organ preservation by perfusion was first proposed in 1813 by Julien-Jean-Cesar le Gallois (1770–1840). This French physician, scientist and philosopher stated that If one could replace for the heart some kind of injection of artificial blood, either natural or artificially made...one could succeed easily in maintaining alive indefinitely any part of the body... (4, 5). 32 HISTORY OF ORGAN PERFUSION IN ORGAN TRANSPLANTATION Despite his idea, Gallois never attempted to create such a substitute for the heart. Today, le Gallois’ words still sound visionary since machine perfusion of organs is—except for the kidney—not commonly applied in clinical practice. One of the true founders of the modern era of organ transplantation is Alexis Carrel (1873–1944). Besides his landmark publications on blood vessel surgery, vascular anastomosis, and experimental transplantation, he also studied tissue and organ preservation by both cold storage and machine perfusion (6). He observed that hypothermia (1–2°C) slowed down the destructive processes in tissues, in contrast to normothermic conditions (30–40°C). At that time this observation led to the cold storage of cadavers, used in an experimental setting as donors for grafts and tissues. The transplantation of blood vessels preserved for several days in Locke’s solution was shown possible. Soon thereafter, other tissues such as skin, cornea, and omentum were successfully transplanted after cold storage (7). Despite the successful short-term preservation of a variety of tissues, Carrel was soon confronted with the limitations of cold storage: limited and imperfect preservation. Therefore, organ perfusion—a technique that would allow extracorporeal survival of organs for longer periods of time—became a new focus of research. Alexis Carrel cooperated with Charles Lindbergh, an engineer and pilot, who designed the first organ perfusion device. Lindbergh’s interest in extracorporeal perfusion started in 1929 when his sister-in-law was diagnosed with a rheumatic heart disease. Lindbergh could not comprehend why a mechanical pump capable of maintaining blood circulation would not allow cardiac surgery. He could not have imagined that it would be 25 years before open heart surgery would become possible with the development of cardiopulmonary bypass. The design of a perfusion pump system was a logical extension of Carrel’s cell and tissue culture experiments. I wished to find a method by which tissues extirpated from a living animal or a fresh cadaver could be stored during the period which elapses between the extirpation and their transplantation on the patient...to maintain tissues in a condition of uninterrupted growth in a medium that does not deteriorate spontaneously...the problem consists of giving the cells the necessary food material and removing the catabolic substances from the medium without disturbing the tissues and without introducing bacterial contamination... Today, almost 100 years later, these goals and needs to preserve organs by machine perfusion are still valid. In 1935, Carrel and Lindbergh described ‘an apparatus for the culture of whole organs’ in the Journal of Experimental Medicine (8). Herein, an apparatus was designed capable of maintaining a sterile, pulsating circulation of fluid through living organs. Although it was the first perfusion pump of its kind, it already met—at that time—most of the vital criteria for optimal isolated organ perfusion (e.g.,