Donation After Circulatory Death: A New Frontier

Heart failure represents a significant disease burden on healthcare systems worldwide—patients with end-stage heart failure (ESHF), refractory to maximal medical therapy, face frequent hospitalisation, and high morbidity and mortality [1]. In this patient population, heart transplantation remains the optimal treatment but remains limited by donor organ availability [2, 3]. Annually, it is estimated that 6000 heart transplants are being performed globally, with the number of heart transplants performed demonstrating an overall increasing trend over time [3‐5]. However, recipient listings and waitlists have also grown, creating an increasing gap between demand and supply of donor hearts [6]. Arguably contributing to this growing waitlist is an expanding population of patients with advanced heart failure, an increasing acceptance of older and more medically complex recipients, and improvements in and increased utilisation of mechanical support therapies allowing for more patients to be bridged to transplantation [3‐5].

Given these trends, increasing the number of donor hearts sourced is of great interest and importance in order for supply to meet demand. With the majority of heart transplants traditionally being performed from donors after brain death (DBD), donors from a donation after circulatory death (DCD) pathway are emerging as a key alternative source of donor hearts [7••, 8••].

With heart transplantation from DCD donors still in its relative infancy, in this review, we aim to explore the evolution of preservation strategies that have allowed an increasing uptake of DCD donors as a source of donor hearts, examine early global clinical outcomes, and highlight the growing role and use of DCD donors as a new frontier in heart transplantation.

Inspired by surgical and preservation techniques pioneered by Dr. Norman Shumway and his team [9], the first clinical orthotopic heart transplant performed by Dr. Christian Bernard in 1967 was in fact from a 25-year-old DCD donor [10]. In this landmark operation, the donor heart was retrieved following a 5-min stand-down after cessation of electrocardiographic activity; cardiopulmonary bypass was then established and the heart ultimately selectively perfused and cooled to 16 °C after which point the donor heart was excised, placed in 10 °C Ringer’s lactate, and transported to the adjacent theatre where it was immediately reperfused and subsequently implanted [10].

Although the recipient ultimately succumbed to pneumonia and acute rejection after 18 days, the foundation had been laid for future heart transplants to follow [11]. Subsequent to this, the number of heart transplantations began to increase globally, aided in particular by the 1968 Harvard Medical School Committee statement defining brain death [12]. This led to a global adoption of BD donors in whom, as death had been declared based on neurological, rather than circulatory criteria, an assessment of the beating heart was possible after death and prior to organ procurement [4, 11].

Despite the world’s first heart transplant being derived from a DCD donor, over the next four decades, donor hearts were almost entirely retrieved from BD donors and were preserved in cold-static storage (CSS) [11]. The reluctance in using DCD donors can be attributed to the donation pathway necessitating a cessation of circulation involving variable periods of warm ischaemia prior to organ procurement [13]. The heart is sensitive to warm ischaemia, and in a DCD donor is also subjected to a period of severe pulmonary vasoconstriction during withdrawal of life support (WLS) resulting in an additional insult to the right ventricle [14, 15]. Consequently, at the time of procurement, the DCD heart is in a distended, non-beating state. In contrast to BD donors where the beating heart can be assessed in situ prior to organ procurement, concerns surrounding the potential impact of WLS on the myocardial viability prevented the use of DCD donor hearts, particularly as there was an inability at the time to assess cardiac viability following cessation of circulation [13, 16].

Over time however, uptake of DCD donation for other organs increased with acceptable post-transplant outcomes. Transplantation of kidneys retrieved from DCD donors showed no difference in survival compared to those retrieved from BD donors [17] and gradually acceptance of other organs from DCD donors such as the liver, pancreas, and lungs followed suit [13]. Heart transplantation from DCD donors re-emerged in the paediatric setting. Boucek et al. from Denver Children’s Hospital reported the first three successful cases of paediatric heart transplants from DCD donors [18•]. Noteworthy (and controversial) features of these transplants were the measures taken to minimise the warm ischaemic insult to the donor heart during WLS and subsequent procurement [16]. These included co-location of donor and recipient in adjacent operating theatres, antemortem cannulation of the donor to allow rapid administration of preservation solution after death, and a shortened “stand-off” time of 75 s in the 2nd and 3rd cases. In all 3 cases, CSS was used to preserve the heart while it was transferred to the adjacent operating room. Subsequently, the International Society of Heart and Lung Transplantation (ISHLT) reported a total of 21 paediatric DCD heart transplants (HT) between 2005 and 2014 [19]. The ISHLT reported paediatric DCD-HT recipients to have a significantly higher requirement for post-operative mechanical support and 1-year mortality compared to DBD-HT recipients (though it should be noted that a higher proportion of the DCD-HT recipient cohort were on pre-operative mechanical circulatory support suggesting higher pre-operative risk) [19]. Location of donor and recipient and the mode of preservation of the DCD hearts were not reported but it is likely that in the majority if not all cases a similar protocol to that reported by Boucek et al was utilised [18•]. While this paediatric experience provided “proof of principle” that DCD hearts could be recovered and successfully transplanted, in order for DCD heart transplantation to significantly address the worldwide organ shortage in adult heart transplantation, it was clear that there was a need to develop procurement and preservation strategies that allowed for not only an assessment of the viability of the DCD donor heart following procurement and prior to implantation, but also a means to allow DCD donor hearts to be distantly procured [18•, 19].

With growing global interest into DCD donors as a means to increase the donor pool, pre-clinical research conducted by our unit at the Victor Chang Cardiac Research institute in Sydney laid the groundwork for our unit to commence a clinical DCD heart transplant program at St. Vincent’s Hospital in 2014. In a porcine DCD model, hearts subjected to 30 min of total warm ischaemia from the time of withdrawal of life support (WLS) followed by administration of a supplemented Celsior cardioplegic solution were able to demonstrate functional recovery during normothermic perfusion on an ex situ working heart apparatus (after 1 h of Langendorff perfusion) [20]. This study prompted consideration into the role of ex situ perfusion in the setting of DCD heart preservation.

The introduction of the TransMedics (Andover, MA, USA) Organ Care System (OCS) Heart normothermic machine perfusion (NMP) device as a means of reperfusing donor hearts with normothermic, oxygenated blood in a resting (or Langendorff) fashion played a vital role in the translation of our pre-clinical findings into a clinical DCD heart transplant program [21]. The Proceed II [22] trial had demonstrated that NMP with the OCS Heart was non-inferior to cold-static storage in the setting of BDD-HT recipients.

The use of NMP allowed, for the first time, an assessment of donor heart viability ex situ—the lack of which had previously inhibited the uptake of DCD donor hearts. Pre-clinical work by our unit demonstrated NMP with the OCS Heart to be superior to CSS in a porcine DCD transplant model [21]. On the basis of these findings, in 2014, our unit performed the world’s first series of distantly procured DCD donor heart transplants [23]; we have since performed 77 DCD heart transplants in Australia to date [24].

Following our initial experience, the uptake of DCD donor hearts began to occur globally. In addition to using the OCS Heart, the Royal Papworth Hospital in the UK also began to retrieve DCD hearts using thoraco-abdominal machine perfusion (TA-NRP) [8••, 25]. TA-NRP emerged as an alternative to NMP for assessing DCD donor heart viability, and its uptake has seen DCD programs appear more recently in Belgium [26••], Spain [27••], and the USA [28••, 29••, 30••].

DCD donation processes involve the withdrawal of life support (WLS). In DCD donors where the heart is being retrieved, WLS has generally occurred in a controlled environment such as in an intensive care unit or anaesthetic bay (Maastricht Category III donors). Occasionally (usually at the request of the donor family), retrieval of the donor heart and other organs has occurred after controlled WLS in brain-dead donors (Maastricht Category IV donors) [7••, 31]. Once WLS has occurred, retrieval teams then await donor progression to circulatory arrest—this usually must occur within a certain time frame or the organ is rejected. The maximum times that teams are willing to wait following the withdrawal of life support varies between countries, as does the designated stand-off period and definitions of functional warm ischaemic times. Table 1 illustrates known published thresholds for retrieval teams following the withdrawal of life supports.

In Australia, death determined by circulatory criteria is defined as irreversible cessation of the circulation. Based on this definition, re-establishment of the circulation by normothermic regional perfusion is not permitted after death has been determined by DCD pathway. For this reason, we developed a direct procurement protocol (DPP) for retrieving hearts from DCD donors. Our retrieval team waits up to 90 min following the WLS for the donor systolic blood pressure (SBP) to fall below 90 mmHg [7••]. Once SBP is < 90 mmHg, asystole must then occur within 30 min or the heart is declined. Should the donor progress to asystole, a further 5-min “stand-off” time is observed in order to ensure there has been no auto-resuscitation of the heart [7••]. In Australia, the process of WLS mainly occurs in ICU, with family often present. In some hospitals, WLS occurs in the anaesthetic bay of the operating theatre. After the “stand-off” period, which has recently been standardised to 5 min in all states and territories, the donor is taken to the operating room and is prepped and draped for the organ procurement procedure to rapidly begin as described by Chew et al. [7••].

Total warm ischaemic time (WIT) is the duration between WLS and administration of cardioplegia at the time of organ procurement. Different units have varying definitions for the functional warm ischaemic time (fWIT). In our unit, this is duration between SBP < 90 mmHg and cardioplegia. We refer to the period of time from asystole to the administration of cardioplegia as the asystolic warm ischaemic time (aWIT). Several measures have been adopted to minimise the fWIT. One measure that has been implemented in Spain, Belgium, and certain USA units has been to undertake WLS with the donor prepped and draped in the operating room prior to WLS negating the accumulation of WIT during transport [27••, 30••]. Another more controversial measure has been to shorten the “stand-off” time. During the first reported series of paediatric DCD donors, the “stand-off” time was controversially lowered from 3 to 1.25 min [18•]; currently, “stand-off” times range from 2 to 20 min in different countries with 5 min being the “stand-off” time most commonly used (see Table 1).

Two main strategies currently assist in assessing viability of DCD donor hearts: normothermic machine perfusion (utilising the OCS Heart) and normothermic thoraco-abdominal regional perfusion.

In the St. Vincent’s initial experience with DCD heart transplantation, we noted an ECMO rate of 35% for PGD in the first 23 patients who were transplanted with DCD hearts following OCS Heart NMP [7••]. During this initial experience, it was evident to us that the aWIT played a key role in determining DCD donor heart graft function as DCD-HT recipients who required ECMO had a significantly higher aWIT (15 ± 3 min compared to 12 ± 2 min in recipients not requiring ECMO, p = 0.002). For the purposes of our protocol, we define “cold ischaemic time” as the time taken from the delivery of cardioplegia during donor heart procurement until the time of reperfusion on the OCS Heart. Cold ischaemic time was not associated with an increased risk of ECMO.

Since that initial series, our program has grown and we have been able to learn from our experiences along the way. The addition of tirofiban to our blood collection protocol during the DPP in response to module filter clotting issues has resulted in the subsequent absence of module filter clotting and is an example of one of the tweaks successfully made during our close to 9-year experience with DCD heart retrieval [42]. Furthermore, as aforementioned, experiences with potential high-risk donors have allowed for the development of novel techniques to allow for ex vivo coronary angiography to contribute to donor heart assessment when required [32].

Whilst our initial ECMO rate was high, our ongoing use of the OCS Heart has enabled ongoing familiarisation with DPP techniques and an appreciation of the need to minimise aWIT. The ECMO rate in the subsequent 54 DCD heart transplants that have occurred since the initial series is now at 7% [24]. Despite our cold ischaemic time being significantly higher in this more contemporary cohort, this did not significantly impact ECMO rates and neither did significantly longer fWIT times. Different countries have different definitions of fWIT times; however in considering the importance of ischaemic times in DCD donor hearts, our experience lead us to believe that the aWIT arguably plays the most important role in predicting graft dysfunction [24, 39••]. Recent findings in serial endomyocardial biopsies of human hearts not destined for transplant support this notion in demonstrating that markers of cardiac cell dysfunction are intimately associated with periods of prolonged (> 10 min) circulatory arrest [43].

The future approach to DCD hearts should be to consider ways to minimise aWIT in particular, or to develop strategies of allograft preservation aimed at mitigating potential cellular damage that may occur during aWIT.

The implementation of a DCD heart transplantation program has been shown to have a tangible impact on heart transplant wait lists. Messer et al. [8••] report an overall increase in heart transplant activity by 48%. In Australia, our 9-year experience with DCD heart transplantation has resulted in a 26% increase in heart transplantation; furthermore, since 2020, 30% of all heart transplants have been from DCD donors [24, 39••]. More than half of our DCD-HT recipients required a redo sternotomy at the time of transplant (due to previous cardiac surgery, including durable ventricular assist device implantation) reflecting the complexity of patients that DCD-HTs have been able to relieve from the transplant wait list [24, 39••].

Starting a DCD clinical heart transplantation program requires significant resources, coordination, and training. Utilising normothermic machine perfusion involves logistical and financial consideration into the transportation and constant monitoring of the OCS Heart. In contrast, TA-NRP requires the initiation of cardiopulmonary bypass and the management of a heart–lung bypass machine and oxygenator.

Adopting either TA-NRP or NMP is a decision made based on the specific needs of the transplant unit, local laws, and the geographical areas serviced. In Australia for example, due to the size of the country, a DPP followed by NMP with the OCS Heart is advantageous in facilitating distant procurement to interstate and rural retrieval locations [7••, 23].

The administration of antemortem heparin in DCD donors is an ethically challenging subject, with no clear international consensus [25, 44]. There is currently variable clinical practice with regard to the use of antemortem heparin in DCD organ retrieval. Certain countries practising TA-NRP allow for pre-withdrawal peripheral cannulation and administration of heparin [27••]. In Australia, the permissibility of antemortem heparin varies between ICUs and states. This variability is due in part to the complex ethics surrounding DCD transplantation and to the dearth of scientific evidence to support a practice of antemortem heparin administration [25, 44]. The role of antemortem heparin needs to be better understood. Pre-clinical studies performed by our unit on a rodent DCD model have shown antemortem heparin to be associated with improved recovery of donor hearts following a DCD protocol [45].

Following withdrawal of life support, the physiological milieu is one of profound acidosis; data from our DCD retrieval experience demonstrates mean pre-withdrawal pH to be 7.41 (± 0.06), and this drops to a mean pH of 7.10 (± 0.23) following asystole [46••]. This acidosis is likely a result of reduced oxygenation leading to lactic acidosis generated from anaerobic metabolism, which contributes to both intracellular and extracellular acidosis [46••].

Acid Sensing Ion Channel 1a (ASIC1a) plays key roles in mediating cellular injury in response to acidosis [46••, 47, 48]. A proton-gated cation channel, acidosis triggers the recruitment of serine/threonine kinase receptor interaction protein 1 (RIP1) to ASIC1a, where the phosphorylation of RIP1 results in downstream signaling resulting in necroptosis. Inhibition of ASIC1a has also been shown to protect rodent heats from ischaemic reperfusion injury following an ischaemic insult [46••]. Pre-clinical studies in our laboratory have shown an improvement in cardiac function and recovery in a rodent DCD model when Hi1a, an inhibitor of ASIC1a derived from funnel-web spider venom, is used as a supplement to cardioplegia [46••, 48]. These results warrant further exploration into the cardioprotective role Hi1a may play in clinical DCD heart transplants.

Data from two of the longest and largest DCD heart transplantation programs in Australia and the UK have demonstrated that survival from DCD heart transplantation is equivalent to traditional DBD donors. DCD programs are now emerging across Europe and the USA with early success. It is now established that the uptake of DCD donor hearts has the impact of improving overall heart transplantation numbers and can legitimately contribute to the reduction of global transplant wait lists. The decision to choose between NMP and TA-NRP retrieval strategies is multifactorial and location dependent. Ongoing research and clinical experience into pushing the boundaries of preservation strategies will provide the impetus for the ongoing evolution of DCD heart transplantation.