Journal of Hepatology
Volume 45, Issue 4 , Pages 499-503, October 2006

Can non-heart-beating donors replace cadaveric heart-beating liver donors?

Kings College London School of Medicine at Kings College Hospital, Institute of Liver Studies, Denmark Hill, Camberwell, London SE5 9RS, UK

published online 31 July 2006.

Article Outline

Abbreviations: NHBD, non-heart-beating donor, ICU, intensive care unit

 

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1. Introduction 

Recently non-heart-beating donation (or also called donation after cardiac death) has re-emerged as a major potential way of increasing the supply of organs for transplantation. The success of renal transplantation from non-heart-beating donors (NHBD) [1] has led to a renewed and wide interest in liver, pancreas and lung retrieval [2], [3].

In the early years of transplantation, before the definition and legal acceptance of brain death, NHBD was the principal source of grafts. Following introduction of the concept of irreversible coma [4] and brain death, cadaveric donation gradually replaced NHBD due to the superior results obtained. However, with subsequent improvements in immunosuppression, organ preservation and the standardisation of surgical techniques, liver grafts from NHBD appear to be a valuable new source of organs with significant potential for expansion of the donor pool.

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2. Non-heart-beating donation 

Non-heart-beating donors have been classified into four categories according to the Maastricht criteria (Table 1). The division into controlled and uncontrolled NHBD is helpful as it underlines differences in ethics, clinical practice, graft outcome and future potential between the two groups [5]. Controlled donation occurs in a hospital intensive care unit (ICU) setting in a controlled environment usually with a policy driven planned withdrawal of treatment. In uncontrolled donation, donor death occurs either outside the hospital or in the emergency room following unsuccessful attempts at resuscitation. Most of the current published literature relates to controlled NHBD. The ethics of controlled NHB donation are readily understood and accepted by doctors and the public. There is more time to assess the donors for co-morbidity; they tend to be haemodynamically stable, with normal liver and renal function. The donors are extubated after planned treatment withdrawal either in the ICU or in the operating room. These patients usually have brain injury incompatible with life with rapid cessation of cardiopulmonary function. Warm ischaemia can be accurately assessed and cold ischaemia minimised by prior preparation of a suitable recipient. There is adequate opportunity to counsel both the donor family and the recipient. In comparison to uncontrolled NHBD they tend to be older, have greater co-morbidity and have had organ support on the ICU. It has been estimated that controlled NHBD in its current form has the potential to increase the donor liver pool by at least 20% [6].

Table 1. First International Workshop on non-heart-beating donation, Maastricht, 1994
Categories of non-heart-beating donation
(categories 1 and 2, Uncontrolled; 3 and 4, Controlled)
1. Dead on arrival
2. Unsuccessful resuscitation
3. Awaiting cardiac arrest-ventilator switch off
4. Cardiac arrest while brain-dead

Uncontrolled NHBD are more likely to be younger and fitter without significant co-morbidity. However, death occurs in an uncontrolled setting, often after prolonged periods of resuscitation, which makes assessment of warm ischaemic time problematic. The legal, ethical and logistic issues that have to be overcome are considerable. However, an approximately twofold net increase in the donor pool has been successfully achieved by a Spanish group [7] and it has been speculated that there is the potential to increase the donor pool by up to 300%. The resources to be invested in such a programme are significant.

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3. Reported outcomes after liver transplantation from controlled NHBD (Table 2) 

All techniques used to procure organs from controlled NHBD aim to keep warm ischaemia to a minimum. A variety of techniques have been utilised including cardiopulmonary bypass with or without cooling, extracorporeal membrane oxygenation and super-rapid retrieval as a modification of the en bloc multiorgan harvest technique [3]. Our own technique involves rapid aortic and caval cannulation, topical cooling, aortic clamping and perfusion of the aorta with heparinised Marshall’s solution followed by cannulation of the superior mesenteric vein to perfuse the liver with University of Wisconsin solution [6]. The best outcome from controlled NHBD livers has been associated with less than 30min of warm ischaemia, cold ischaemic times of less than 8h and donor age of less than 50 years [6], [8], [9]. A variety of techniques, including pulsatile and non-pulsatile machine perfusion, have been utilised experimentally to try to prolong organ preservations to allow more detailed assessment of the graft. To date there are little clinical data in liver transplantation to identify, which techniques will prevail in the longer term [10].

Table 2. Outcome after liver transplantation from NHBD
AuthorYearNPat. survivalaGraft survivala
Controlled NHBD
Muiesan et al. [6]20053287%84%
Abt et al. [12]200414479.7%70.2%
Foley et al. [13]20053680%67%
Manzarbeitia et al. [14]20041989.5%

Uncontrolled NHBD
Otero et al. [19]20042080% (2 yr)55% (2 yr)
Quintela et al. [20]20051090% (57m)80% (57m)

N, number of patients.

aOne-year survival, unless otherwise stated.

Early experience of NHBD was associated with inferior patient and graft survival, particularly for the uncontrolled group [3]. Casavilla et al. reported the early experience of Pittsburgh with poor graft survival secondary to vascular complications and primary non-function. D’Alessandro et al. reported a significantly higher incidence of primary non-function (PNF) and worse graft and patient survival in recipients of controlled NHBD [11]. More recently, Abt et al. reported a higher incidence of PNF and retransplantation when compared to HBD [12]. A publication from our own centre reported a single case of PNF in a series of 32 consecutive liver transplants from controlled NHBD [6]. Current experience suggests that the results of controlled NHBD are now approaching those of heart-beating donation (HBD) [6]. Graft and patient survival at one year is 90% and 94%, respectively, in our own institution after 54 liver transplants from controlled NHBD.

There are continuing concerns regarding reports of vascular and biliary complications in recipients of controlled NHBD livers. Foley et al. reported a 16.6% incidence of hepatic artery stenosis, 13.8% incidence of biliary stricture and 16.7% incidence of biloma and abscess [13]. There was a high rate of graft loss secondary to these complications. The majority of centres with significant experience of NHBD livers have reported a higher incidence of non-anastomotic biliary strictures. Abt et al. proposed that the increased susceptibility towards ischaemic cholangiopathy was a consequence of longer warm or cold ischaemia times and microcirculatory injury [8]. Manzarbeitia et al. have also reported a higher incidence of vascular complications when compared to brain dead heart-beating donors [14].

Attempts have been made to identify donor and recipient characteristics associated with poor outcome [11]. Prolonged cold ischaemia is associated with graft function and biliary complications. Beyond 12h graft failure approaching 60% has been reported. Keeping the cold ischaemic time to less than 8h reduces the graft failure to 10% [11]. Warm ischaemic periods of greater than 30min have a high risk of graft non-function. Donor age greater than 40 years also appears to increase the risk of graft failure. The choice of recipient may also have a bearing on graft outcome with those on organ support pre-transplant doing less well [11]. It appears that NHBD livers have lower functioning hepatocyte mass and hepatocyte viability in experimental and clinical studies [6]. The development of clinical programmes and the recognition of ‘good’ controlled NHBD livers has led to the use of liver reduction techniques for successful transplantation of 10 children at our centre [15]. These results suggest that these ‘good’ donors should not be considered to be marginal.

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4. Outcomes after liver transplantation from uncontrolled NHBDs 

Early results of uncontrolled NHBD were not encouraging. There was a high incidence of PNF and graft loss due to vascular complications [3]. However, studies reported excellent graft and patient survival in kidney recipients [16] and long-term renal function was reported to be better in Maastricht types 1 and 2 as compared to types 3 and 4 [17]. Alvarez et al. using well-defined criteria for accepting uncontrolled NHBD reported good graft function in both transplanted kidneys and livers [18]. Otero et al. reported significantly higher rates of PNF, biliary complications and initial organ dysfunction in 20 liver recipients from uncontrolled NHBD [19]. More recently there have been several case reports of successful uncontrolled NHBD maintained on mechanical chest and abdominal compression, cardio-pulmonary bypass or on ECMO [20]. Wider application and evaluation of these techniques and subsequent graft function are required.

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5. The use of NHBD to expand the donor pool 

What is the potential for NHBD to expand the donor pool and how do we realise them? The results of controlled NHBD are now approaching those obtained with HBD provided that donor age is less than 50 years, warm ischaemia does not extend beyond 30min and cold ischaemia is kept to a minimum with a cut off of 10h being accepted as reasonable by the majority of centres. This may increase the donor pool by 20%, better than living donation (which may help 10%), but falling short of what is required.

How can graft quality and early function be improved? Warm ischaemia cannot be avoided, but has to be minimised by excellent surgical technique, the use of low viscosity perfusion fluids possibly under pressure (50mmHg) to clear the microcirculation and thorough flushing of the biliary tree. The use of heparin pre-donation (if allowed) and thrombolytic agents to maintain the microcirculation is considered to improve function and reduce vascular and possibly biliary complications. The need for cold preservation and the subsequent effects of ischaemia/reperfusion injury on the graft are important determinants of graft survival [21]. Experimental studies suggest that pre-treatment of NHBD prior to withdrawal of care may improve outcome by ameliorating ischaemia/reperfusion injuries [22]. A number of agents are being evaluated in experimental studies. The avoidance of cold ischaemia using techniques such as normothermic continuous organ perfusion could expand the safe use of more marginal donors and such models are being developed. Other techniques such as short term hypothermic oxygenated perfusion prior to implantation may also rescue NHBD grafts [23].

The choice of recipient should be restricted to avoid long difficult dissections and possibly those with severe portal hypertension or those on organ support. Techniques of implantation have not been formally evaluated in clinical trials, but clinical experience from small for size grafts and experimental studies suggest that alleviation of severe portal hypertension, blood flush and arterial reperfusion may be of value and may extend donor criteria for NHBD. With extended criteria for controlled NHBD it may be possible to expand the potential pool by 30–40% over the next 10 years.

To successfully exploit uncontrolled NHBD a number of important obstacles need to be overcome (Table 3). The most pressing is to establish a legal framework that is acceptable to the public. At present uncontrolled NHBD is contentious and considered illegal in many countries. The point when resuscitation becomes futile and organ donation should be considered is not always clear and there are no internationally agreed guidelines. Public acceptance and changes to the law, which allow the use of continuous mechanical chest and abdominal compression, cardiopulmonary bypass techniques or extracorporeal membrane oxygenation whilst family members are consulted, are required. Presumed consent (opt out) helps to provide the appropriate legal framework for this type of donation.

Table 3. Prerequisites for establishing a NHBD liver transplant program
Controlled NHBD
(1) Ensure appropriate legal framework
(2) Establish protocols for NHBD retrieval and train donor coordinators and other teams
(3) Identify Intensive Care Units and agree protocols for withdrawal of treatment
(4) Develop a successful NHBD kidney program followed by liver program, concentrating experience initially within a small team
(5) Address consent and allocation issues for NHBD liver transplantation
(6) Concentrate on busiest units first with extensive experience of use of marginal grafts and then expand the program

Uncontrolled NHBD
(1) Establish legal and ethical framework acceptable to the public
(2) Carry out public and political consultation with consideration towards ‘presumed consent’ (opt out) policy for organ donation
(3) Develop a regional strategy and funding for 24-h availability of dedicated resuscitation ambulances deployed within defined territories to identify and resuscitate potential donors
(4) Establish a robust protocol for cessation of resuscitation, consent issues, donor maintenance and subsequent retrieval
(5) Twenty-four-hour availability of a dedicated retrieval team of surgeons, nurses and donor coordinators trained for uncontrolled NHBD
(6) Develop cooperation and involvement of the hospital emergence department to establish the program (if possible, develop uncontrolled NHBD after a successful controlled NHBD program)

The logistics of establishing a programme of uncontrolled donation are also significant. To obtain organs from patients who have collapsed on the street or fail resuscitation in the emergency room requires a dedicated resuscitation ambulance team available 24h a day able to reach the scene within a very short time [18]. Alvarez et al. reported their experience of 111 potential category–1 uncontrolled NHBD [17]. Of these, 53 were accepted as donors and resulted in the retrieval of 72 kidneys and 12 livers. Of the 12 livers retrieved eight were transplanted with good function. Of note, the median time from cardiac arrest to arrival in hospital was 68min and to being placed on cardio-pulmonary bypass was 111min. The assessment of the warm ischaemic time, the effectiveness of resuscitation and the suitability of the donor under these conditions is much more difficult. The initial investment in the training and provision of emergency services is high and the early return relatively low. Effective resuscitation will buy time for assessment of the donor and the potential graft. Reliable tests predicting graft function are needed. Liver biopsy is of limited value and other markers that have been used, which include Glutathione S-transferase and xanthine oxidase, are not reliable indicators of subsequent function.

Could NHBD replace HBD? It has been suggested that the absence of brain stem death in NHBD categories 1–3 may be associated with less inflammatory infiltrate in the donor organs and that long-term graft survival may be better. The data are not yet available, but the incidence of acute rejection is currently about 25% (personal observation), certainly no higher than observed for HBD. Data are lacking for long-term outcome in liver recipients, but long-term graft survival in NHBD kidneys is excellent [1]. The early results of liver transplantation from controlled NHBD are approaching those obtained with HBD provided that conservative selection criteria are used. This will supplement the donor pool by 20%, but cannot replace HBD and should be viewed as complementary. Of concern, there may be a trend towards NHDB away from HBD to reduce donor hospital stay and to satisfy the wishes of donor family for cardio-pulmonary death, which may limit the overall increase in organ donation (i.e., a switch from HBD to NHBD as a mode of death). The greatest potential lies with uncontrolled NHBD, but changes are needed from Governments to provide a clear legal framework, funding and training for the infrastructure and acceptance by the public. The development of treatments to preserve, resuscitate and maintain these grafts in the medium term and tests which can accurately assess potential graft function will begin to tap this potential. If successful, NHBD could rival or surpass HBD and living donation as a source of organs for transplantation.

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References 

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PII: S0168-8278(06)00398-9

doi:10.1016/j.jhep.2006.07.018

Journal of Hepatology
Volume 45, Issue 4 , Pages 499-503, October 2006

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