Startseite Organ donation and transplantation after cardiac death

Organ donation and transplantation after cardiac death

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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.
Jahr: 2009
Edition: 1
Verlag: Oxford University Press
Sprache: english
Seiten: 322 / 335
ISBN 10: 0199217335
ISBN 13: 978-0-19-921733-5
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Organ Donation and
Transplantation after
Cardiac Death

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Organ Donation and
Transplantation
after Cardiac Death
Edited by

David Talbot
Anthony M. D’Alessandro
Assistant Editor

Paolo Muiesan

1

1

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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.

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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

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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

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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

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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

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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

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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.

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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

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LEGAL, MORAL, AND ETHICAL ISSUES

Fig. 2.6 Cont’d.

While it is important to recognise and minimise possibilities for conflicts of interest
that might occur in the setting of DCD, they should be differentiated from the dual
commitments that naturally arise when health care teams provide the opportunity to
donate for those who may wish to do so. The duty of care to the individual patient
includes what that patient would have wanted after death. The perception of professional conflict of interest may often be a caregiver-centric issue, and not a patient
issue. It is important to recognise the donors’ interest in organ donation, the positive
impact on grieving by family, and the provision of meaning in a context of tragedy.

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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).

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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.,