Treating the donor
Dr Dermot W McKeown (corresponding author)
Consultant Anaesthetist and Honorary Clinical Senior Lecturer
Scottish Liver Transplant Unit
Edinburgh Royal Infirmary
+44 (0)7980994293
Dr Jonathan Ball
Consultant and Honorary Senior Lecturer in General and Neuro Intensive Care
St George's Hospital and Medical School, London, UK
Abstract.
Purpose of Review:
Current pressures of organ supply and demand require maximisation of potential for organ
donation. The donor population is older and has more significant comorbidity than in the
past.
Optimal management of the donor after brain death (DBD) is essential to ensure that the
greatest number of organs can be transplanted per donor. Defining evidence-‐based drugs and
techniques to assist this has never been more important.
Recent findings:
Care of patients with catastrophic brain injury incorporating supportive therapy targeted at
specific goals and delivered by experienced specialists provides the best donation outcomes.
Such pathways represent best practice critical care applied to this population. In this context,
the value of some previously recommended therapies appears questionable and warrants
reassessment. Prolonged (>24 hours) in-‐corporeal organ conditioning may have significant
benefits.
Extra-‐corporeal support in the resuscitation arena is emerging and,in patients who fail to
respond, may yield a new source of donors.
Summary:
Early identification of potential DBD, best practice critical care, and achieving defined
treatment goals are associated with more transplantable organs.
Study of a complex intervention like donor management presents significant problems of
organisation, ethics and consent. This is recognised internationally and progress is being
made.
Keywords:
Organ donor, brain death, management, transplantation
Introduction
Increasing demand for transplants has mandated organisational change aimed at early
identification and active support of possible organ donors to maximise the potential for, and
function of, transplantable organs. Changes in public safety, management of critically ill
patients, medical and surgical advances have all contributed to a change in the demographics
of deceased donors with a trend towards older donors with more comorbidities[1**2**3**].
Donation from the heartbeating donor after brain death (DBD) provides more organs per
donor than donation after circulatory death (DCD). Meticulous organ donor management
(ODM) – essentially continued high quality critical care -‐ is needed to maximise this potential.
The shift of focus from treatment aimed at patient survival with best possible functional
outcome to ODM should be seamless.
ODM directed by specialists has shown that the principles of treatment of the critically ill are
entirely applicable to DBD, with resulting improvements in organ numbers and quality. Drug
and hormone treatments derived from animal studies and used specifically for donor pre-‐
treatment are being reassessed.
There is variation in the delivery of ODM, though senior staff commitment to achieving Donor
Management Goals (DMG) can increase the number of good quality transplantable organs.
New treatments developed in animal studies will need to be tested in donors. Organisational
and ethical challenges are likely. High quality audit and registries of donors, their
management and transplant outcomes will assist.
Early identification of donors
Early identification of patients who may become organ donors must involve co-‐operation with
colleagues in the intensive care unit (ICU) and emergency department (ED)[4**, 5**]. This is
of increasing importance with early application of advanced resuscitation techniques such as
extracorporeal support[6*, 7*] -‐ even pre-‐hospital[8*]. These can produce good results for
patients in previously unsurvivable circumstances, but many fail to respond to treatment,
suffer severe brain injury, or become brain dead. Appropriate techniques for diagnosis of
brain death are required. In one study of Extracorporeal Cardiopulmonary Resuscitation (E-‐
CPR) commenced in the pre-‐hospital phase, three of seven patients developed brain death in
the ICU after admission and two of those became organ donors[8*]. An ED study found two of
eight patients receiving E-‐CPR had absent brain perfusion later in the ICU[7*]. Maintaining the
potential for donation in end-‐of-‐life care is a major challenge, but could provide increased
numbers of transplantable organs.
Patients who have been resuscitated and whose trachea is intubated before neurological
deterioration have less time pressure for perhaps hurried decisions to be made on
termination of life support. It is also important not to rush identification of patients as donors
before a considered evaluation, perhaps including further observation in ICU.
Clinical guidelines for the early management of neurological disturbance are therefore
particularly important for patients and possible donors. Use of catastrophic brain injury
guidelines (CBIG) with organisational change seems consistently associated with more donors
and a higher chance of meeting early donor management goals (DMG)[5**, 9**, 10*].
(table 1)
Initial Support and Brain death testing
Best practice ICU methods for patients are also entirely applicable to donors[11] so there is no
ethical conflict or change of focus until brainstem death is confirmed. Full critical care is
necessary to ensure adequate conditions for brainstem death testing. A ‘ventilator bundle’ of
care is continued with optimised PEEP. Effective circulating volume is ensured and after
initial resuscitation fluid is limited to avoid organ oedema, especially in lung. Cardiovascular
support may include vasoconstrictors or inotropes and should be guided by both organ
specific and global markers of adequate perfusion. If diabetes insipidus has developed DDAVP
or vasopressin are indicated.
The preconditions for brain death testing must be met – drug metabolism is markedly altered
by induced hypothermia, and adequate time must be allowed for clearance of drug before
neurological assessment. Therapeutic hypothermia treatment following cardiac arrest
extends the duration of ICU care necessary before neurological examination is reliable[12].
15% of patients treated with TH who make a good recovery only wake after > 72 hours of ICU
care. During this time some patients may become brain dead.
(Figure 1)
Specific Donor treatment
Hormonal resuscitation (HR) comprising variably of insulin, thyroid supplementation,
vasopressin and corticosteroids has traditionally been advocated as part of ODM. Recent
reviews and meta analysis have shown that the treatment effects are less dramatic than
previously thought[11, 13*, 14*]. In early studies HR was often introduced at the same time
as guidelines for donor treatment, or specific DMGs, and results may therefore reflect more
consistent ODM rather than treatment effect.
Randomised Controlled Trials (RCT) of thyroid supplementation in addition to active ODM
have not demonstrated a treatment effect in the general population of DBD[14*, 15**]. While
there might be an effect in cardiovascularly unstable donors, the evidence for this is not
strong, and demonstrating benefit would require a large, appropriately powered RCT
concentrating on marginal donors.
Methylprednisolone is given for anti-‐inflammatory effects. Inflammatory processes triggered
by brain death are associated with immune changes and worse transplant outcomes in
comparison to live donation[16*-‐18]. This is an appropriate target for treatment, but multi-‐
organ procurement operations have been shown to be associated with marked rises in both
pro-‐inflammatory and anti-‐inflammatory cytokines and chemokines even when
methylprednisolone is given[19**]. The balance between these transmitters could be a target
for manipulation in the future. If the rationale for steroid administration is to improve
cardiovascular response, only small doses of a steroid with mineralocorticoid effect such as
hydrocortisone are required[20*]. Methylprednisolone has no mineralocorticoid effect.
Early arginine vasopressin use is advocated in many guidelines, particularly those aimed at
increasing lung procurement, and can allow cardiovascular goals to be more easily achieved
without excessive fluid loading or high doses of catecholamines. Of 12,332 donors from the
United Network for Organ Sharing (UNOS) database, 7686 received vasopressin (62%) and
had a significant increase (51% vs. 39%) in high organ yield (≥4) retrievals, mean number of
organs (3.75 vs. 3.33), and rate of lung recovery (26. % vs. 20%)[21*]. The vasopressin group
were however significantly younger and more likely to have died following traumatic brain
injury. The association is strong, but this is a retrospective analysis and indications and
application of HR and ODM may have varied. Vasopressin use may be a proxy marker of
commitment to ODM. Terlipressin, which is more widely available, is probably a non-‐inferior
alternative.
Good rates of thoracic organ retrieval can also be achieved without universal use of
vasopressin. One group quadrupled their numbers of transplantable lungs with the
introduction of an intensive ODM programme including experienced support, cardiac output
monitoring, methylprednisolone, l-‐thyroxine and cardiovascular support in >90% with
catecholamines[22**]. Vasopressin or desmopressin were not mandatory and their use was
not specified. Physiological goals were achieved with low CVP values and limited fluids, and
there was no apparent deleterious effect on abdominal organ retrieval or function. These
results may reflect that committed ODM including advanced cardiovascular monitoring based
on general ICU principles is more important than specific drugs or hormones.
Physiological targets for donor management are broadly similar across organisations and
countries. There is an increasing recognition where ODM occurs that these are guidelines,
and that some such as central venous pressure, (CVP) may be of limited value[23**]and
should be considered secondary to an overall management plan based on protective
ventilation, adequate intravascular volume to ensure effective cardiac output, and avoidance
of excessive lung water[11]. Older patients with more comorbidities may require
modification of goals.
(Table 2)
Implementation
Reliably implementing ODM with DMGs as quickly and effectively as possible presents the
same challenges for critical care as other complex interventions such as management of
sepsis[24**]. There is variation in application of evidence-‐based techniques-‐protective
ventilation for example is still underused in ICU[25*, 26]. Improvement science techniques
have been used to enhance compliance with guidelines, with improved outcomes[27**]. More
consistent delivery of the general critical care components of ODM will provide information
on the utility of treatments like methylprednisolone and HR from good quality large audits of
donor physiology, treatments given, goals achieved and outcomes of transplanted organs.
Goals
Suggested physiological goals of ODM have been derived from historic practices and expert
opinion. Eight Organ Procurement Organisations (OPO) in UNOS Region 5 created a checklist
of nine DMGs to be achieved as soon as possible after brain death and maintained until
retrieval procedure. Achieving DMG at the time of consent (after diagnosis of brain death)
may reflect either a stable donor, or active management of brain death related physiological
disturbance. Only 15% of 380 standard criteria donors had > 7 of 9 DMG met at the time of
consent, but this increased to 33% at 12-‐18 hours later, and 38% prior to organ
recovery[28**]. Donors with ≥4 organs transplanted had more DMG met at all the time points.
If >7 DMG were met at the time of consent there was an odds ratio of 2.03 for ≥4 organs
transplanted. Increase in achieved DMG from consent to 12-‐18 hours later gave increased
odds ratio for ≥4 organs transplanted of 1.13 per additional goal.
Practically this emphasises the need for early identification and support of the brain injured
using CBIG, and the value of active ODM in increasing numbers of transplantable organs. In
another study[9**] this group showed that meeting more (>7) DMG at the time of consent was
associated with less requirement for dialysis in the first week (17% vs. 30%, p=0.007)
following renal transplants.
It may take time to achieve DMG, and there is a debate on whether it is more advantageous to
remove organs as soon as possible from a hostile physiological environment triggered by
brain death, or if in-‐corporeal repair and recovery can occur. In a prospective study 58 of 100
donors had active ODM for more than 20 hours from diagnosis of brain death and provided
more transplanted organs per donor than those managed <20 hours[29**]. This was
particularly evident for heart donation(26 vs. 5, p<0.01) and lungs (40 vs. 6). There was no
significant difference between the groups in terms of DMG achieved.
Prolonged ODM may have particular advantages for the heart to allow recovery from stress
cardiomyopathy[30] resulting from the sympathetic storm at the time of brain death. As
proof of this concept a series of 15 brain dead donors who were haemodynamically unsuitable
for cardiac donation were treated with vasopressin, tri-‐iodothyronine, methylprednisolone
and insulin as well as an active ODM protocol[31**]. Serial cardiac evaluations were
performed over 48 hours of treatment. Norepinephrine infusions were either not required or
stopped within 12 hours. Ultimately 8 cardiac transplants were performed with no primary
graft failure and 100% 6 month survival. Although this is a single centre report it
demonstrates that prolonged treatment may be practical and effective.
Prolonged treatment may permit active treatment to reduce lung water and improve results
in recipients[32]. Lungs can however also now be treated after retrieval by ex vivo perfusion.
New donor sources
In addition to increased numbers of DBD following cerebrovascular disease, there has been
re-‐evaluation of DBD donation from cardiac arrest patients[33**]. In the United States organs
retrieved from donors who had undergone CPR comprised 5.5 % of the donor pool. Between
1999 and 2011 with appropriate selection at least 1000 organs per year were transplanted
and had graft survival not significantly different to non-‐CPR organs[34-‐36].
Organisational change
In one large hospital organisational changes over a 20-‐year period stabilised falling donor
numbers and improved organ recovery rates and transplant numbers despite increases in
donor age and comorbidity[5**]. Donor identification, conversion of potential to actual
donors, and protection of organs during the procurement phase were targeted for
intervention.
Specialist support by intensivists, dedicated retrieval teams, remote monitoring and advice,
and movement of donors to dedicated facilities have all been introduced or rediscovered in
order to provide high quality ODM[5**, 22**, 37*,38,39**].
Future research
Study of ODM in a heterogenous population of donors who have had variable aetiologies of
brain death and durations of treatment before diagnosis has many difficulties. There is
variable application of ODM and associated treatments, different timings of retrieval
operation, skills of surgeons and level of intraoperative support. Preservation, transport,
recipient selection, implantation and post-‐transplant management also affect outcomes.
These, and issues of consent for donor pre-‐treatment and recipients of subsequent organs are
complex[40**-‐42], but it is important that we find ways of dealing with the barriers to allow
interventions which have good evidence in animal models to be tested in the clinical
environment. Some more general critical care interventions have already been tested[43,
44**]. In the study of Beta Agonists for Oxygenation in Donors (BOLD) consent for
randomized donor management was obtained, but recipient consent was not deemed to be
required as the risks would be minimal[45]. The MOnIToR study of fluid therapy in donors
guided by stroke volume variation has completed recruitment but results of ensuing
transplant operations are not yet available[46]. Randomized studies of pre-‐retrieval induced
hypothermia, and remote ischaemic preconditioning in retrieval procedures are in progress,
and several other strategies are ready to be assessed clinically[16*].
We might learn from methods used in the study of cardiac arrest-‐another complex
intervention where use of standard reporting systems for both clinical details and linked
laboratory research (The ‘Utstein Style’) has facilitated promotion of guidelines and
assessment of effectiveness of clinical and organisational changes internationally.
Conclusion
If we are to maximise the potential for DBD organ donation, optimal treatment needs to be
delivered at an early stage to all critically ill patients, particularly those with neurological
injury. If these patients deteriorate and are suspected to be brain-‐dead, full support should be
continued under the close supervision of an experienced specialist until the diagnosis can be
confirmed and wishes with regard to organ donation ascertained.
When ODM based on best practice critical care techniques is properly applied, the additional
benefit of some previously recommended drugs and hormones may be marginal. The duration
of ODM should be determined by changes in organ performance. Data relating to the process
should be collected with a common international dataset.
Specific donor pre-‐treatments identified as effective in laboratory studies should be
introduced in ways which will allow their utility to be evaluated prospectively by RCT.
Key Points:
• Organisational change allows early identification of potential donors and prevents
donor loss.
• When patients become potential organ donors, high quality critical care must be
continued.
• Specialist involvement and standard critical care techniques are the most important
components of organ donor management.
• Standard donor and recipient datasets would aid study of new donor therapies aimed
at improved transplant outcomes
References
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hypothermia is highly variable. Implications for prolonged ICU care.
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physicians might produce best outcomes.
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inflammation in brain dead donors. Clin Transplant 2013 Jul-‐Aug; 27(4):613-‐8. Procurement
operations are associated with upregulation of inflammation. Relevance of this on outcomes
requires study. Balance of pro- and anti-inflammatory cytokines might be manipulated.
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regimens for organ donor management. J Crit Care 2013 Feb; 28(1): 111.e1-‐7.Case series with
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No apparent detriment to organs retrieved, improved glucose control in donors.
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procurement and lung function. J Surg Res 2013 Oct7. Doi: 10.1016/j.jss.2013.09.028. [Epub
ahead of print] OPTN database. AVP use was associated with more high yield donations, mean
number of organs retrieved, and lung recovery. Not randomised, strong association but AVP use
may be a proxy for more active ODM.
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Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Medicine 2013; 39:165-‐
228.Classic example of a complex intervention in ICU. Heterogenous patient group, multiple body
systems with time-sensitive physiological goals. Analagous to ODM.
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lung injury. J Crit Care 2012; 27:323.e321-‐329.Secondary analysis of ARDSNet trial. Simple
interventions could improve compliance with protective ventilator settings for patients (and
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on the number of organs transplanted per donor. Crit Care Med 2012; 40:2773-‐
2780.Prospective introduction of DMG. Meeting DMGs at consent and organ recovery are both
associated with more high yield organs transplanted per donor. Only 15% of donors met DMG at
consent but they had double the chance of high-yield donation. Catastrophic brain injury
guidelines may increase liklihood of meeting DMG at consent.
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allowed 8 of 15 hearts previously defined as untransplantable to be transplanted. Needs
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Cardiopulmonary Resuscitation. Crit Care Med 2013 Aug 14 [Epub ahead of print].
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management improved numbers retrieved.
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specialized donor management unit. Transplant 2012; 94:e6-‐8.
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[46] Kellum J. Personal communication. October 2013.
Table 1. Example of a catastrophic brain injury screening tool
Brainstem death should be suspected if:
The pupils are fixed and dilated
The Glasgow coma score is 3/15
There is no triggering / patient interaction with the mechanical ventilator
There are no potentially reversible cause for these clinical findings
No depressant drugs
Core temperature >34°C
No obvious reversible circulatory, metabolic or endocrine cause
No neuromuscular blocking agents or other reversible causes of apnoea
Blood levels
Sodium 115 -160mmol/L
Potassium >2mmol/L
Phosphate 0.5 - 3.0mmol/L
Magnesium 0.5 - 3.0mmol/L
Glucose 3.0 - 20.0mmol/L
Figure 1. A Suggested Timeline for Physiological Optimisation Following Catastrophic Brain Injury.
Modified version of figure published in: Ball J: Optimal management of the potential organ donor following catastrophic brain injury. ICU Management 2013, 13:10-13. http://healthmanagement.org/download/ICU_v13_i2_WEB.pdf
