Hong Chee Chew

Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series

BACKGROUND Orthotopic heart transplantation is the gold-standard long-term treatment for medically refractive end-stage heart failure. However, suitable cardiac donors are scarce. Although donation after circulatory death has been used for kidney, liver, and lung transplantation, it is not used for heart transplantation. We report a case series of heart transplantations from donors after circulatory death. METHODS The recipients were patients at St Vincents Hospital, Sydney, Australia. They received Maastricht category III controlled hearts donated after circulatory death from people younger than 40 years and with a maximum warm ischaemic time of 30 min. We retrieved four hearts through initial myocardial protection with supplemented cardioplegia and transferred to an Organ Care System (Transmedics) for preservation, resuscitation, and transportation to the recipient hospital. FINDINGS Three recipients (two men, one woman; mean age 52 years) with low transpulmonary gradients (<8 mm Hg) and without previous cardiac surgery received the transplants. Donor heart warm ischaemic times were 28 min, 25 min, and 22 min, with ex-vivo Organ Care System perfusion times of 257 min, 260 min, and 245 min. Arteriovenous lactate values at the start of perfusion were 8·3-8·1 mmol/L for patient 1, 6·79-6·48 mmol/L for patient 2, and 7·6-7·4 mmol/L for patient 3. End of perfusion lactate values were 3·6-3·6 mmol/L, 2·8-2·3 mmol/L, and 2·69-2·54 mmol/L, respectively, showing favourable lactate uptake. Two patients needed temporary mechanical support. All three recipients had normal cardiac function within a week of transplantation and are making a good recovery at 176, 91, and 77 days after transplantation. INTERPRETATION Strict limitations on donor eligibility, optimised myocardial protection, and use of a portable ex-vivo organ perfusion platform can enable successful, distantly procured orthotopic transplantation of hearts donated after circulatory death. FUNDING NHMRC, John T Reid Charitable Trust, EVOS Trust Fund, Harry Windsor Trust Fund.

Extracorporeal heart perfusion before heart transplantation: the heart in a box.

Purpose of reviewCold static storage is a time-tested and simple method of preserving hearts retrieved from optimal donors after brain death (DBD). The increasing gap between supply and demand for donor organs together with changing donor and recipient characteristics have led to renewed interest in the use of machine perfusion to increase both the quality and quantity of donor hearts for transplantation. Recent findingsTwo major approaches to machine perfusion of donor hearts have been investigated – hypothermic (HMP) and normothermic machine perfusion (NMP). Recent preclinical studies with HMP confirm that it provides superior donor heart preservation to cold static storage. HMP systems have been developed for human heart preservation but have yet to be tested clinically. In contrast, NMP has undergone extensive clinical evaluation in human heart transplantation, including optimal and higher risk DBD donors. In addition, NMP has enabled distant procurement and successful transplantation of hearts retrieved from human donation after circulatory death donors. SummaryInitial clinical experience suggests that NMP of donor hearts retrieved from higher risk DBD and donation after circulatory death donors enables well tolerated ex-vivo reanimation, preservation, and assessment of these organs. In particular, this technology allows successful utilization of extended-criteria donor hearts that would otherwise be discarded.

Pathophysiological Trends During Withdrawal of Life Support: Implications for Organ Donation After Circulatory Death.

Background Donation after circulatory death (DCD) provides an alternative pathway to deceased organ transplantation. Although clinical DCD lung, liver, and kidney transplantation are well established, transplantation of hearts retrieved from DCD donors has reached clinical translation only recently. Progress has been limited by concern regarding the viability of DCD hearts. The aim of this study was to document the pathophysiological changes that occur in the heart and circulation during withdrawal of life (WLS) support. Methods In a porcine asphyxia model, we characterized the hemodynamic, volumetric, metabolic, biochemical, and endocrine changes after WLS for up to 40 minutes. Times to circulatory arrest and electrical asystole were recorded. Results After WLS, there was rapid onset of profound hypoxemia resulting in acute pulmonary hypertension and right ventricular distension. Concurrently, progressive systemic hypotension occurred with a fall in left atrial pressure and little change in left ventricular volume. Mean times to circulatory arrest and electrical asystole were 8 ± 1 and 16 ± 2 minutes, respectively. Hemodynamic changes were accompanied by a rapid fall in pH, and rise in blood lactate, troponin-T, and potassium. Plasma noradrenaline and adrenaline levels rose rapidly with dramatic increases in coronary sinus levels indicative of myocardial release. Conclusions These findings provide insight into the nature and tempo of the damaging events that occur in the heart and in particular the right ventricle during WLS, and give an indication of the limited timeframe for the implementation of potential postmortem interventions that could be applied to improve organ viability.

Donation After Circulatory Death for Liver Transplantation: A Meta-Analysis on the Location of Life Support Withdrawal Affecting Outcomes.

Background Liver transplantation using donation after circulatory death (DCD) donors is associated with inferior outcomes compared to donation after brain death (DBD). Prolonged donor warm ischemic time has been identified as the key factor responsible for this difference. Various aspects of the donor life support withdrawal procedure, including location of withdrawal and administration of antemortem heparin, are thought to play important roles in mitigating the effects of warm ischemia. However, a systematic exploration of these factors is important for more confident integration of these practices into a standard DCD protocol. Methods Medline, EMBASE, and Cochrane libraries were systematically searched and 23 relevant studies identified for analysis. Donation after circulatory death recipients were stratified according to location of life support withdrawal (intensive care unit or operating theater) and use of antemortem heparin. Results Donation after circulatory death recipients had comparable 1-year patient survival to DBD recipients if the location of withdrawal of life support was the operating theater, but not if the location was the intensive care unit. Likewise, the inferior 1-year graft survival and higher incidence of ischemic cholangiopathy of DCD compared with DBD recipients were improved by withdrawal in operating theater, although higher rates of ischemic cholangiopathy and worse graft survival were still observed in DCD recipients. Furthermore, administering heparin before withdrawal of life support reduced the incidence of primary nonfunction of the allograft. Conclusions Our evidence suggests that withdrawal in the operating theater and premortem heparin administration improve DCD liver transplant outcomes, thus allowing for the most effective usage of these valuable organs.

Improved heart function from older donors using pharmacologic conditioning strategies

BACKGROUND Hearts from older donors are increasingly being referred for transplantation. However, these hearts are more susceptible to ischemia-reperfusion injury (IRI), reflected in higher rates of primary graft dysfunction. We assessed a strategy of pharmacologic conditioning, supplementing Celsior (Genzyme, Naarden, The Netherlands) preservation solution with glyceryl trinitrate (GTN; Hospira Australia Pty, Ltd, Mulgrave, VIC, Australia), erythropoietin (EPO; Eprex; Janssen-Cilag, North Ryde, NSW, Australia), and zoniporide (ZON; Pfizer, Inc., Groton, CT), to protect older hearts against IRI and improve graft function. METHODS Wistar rats, aged 3, 12, and 18 months old, were used to represent adolescent, 30-year-old, and 45-year-old human donors, respectively. Animals were subjected to brain death (BD) and hearts stored for 6 hours at 2° to 3°C in Celsior or Celsior supplemented with GTN+EPO+ZON. Cardiac function and lactate dehydrogenase before and after storage were assessed during ex vivo perfusion. Western blots and histopathology were also analyzed. RESULTS After BD, 18-month hearts demonstrated impaired aortic flow, coronary flow, and cardiac output compared with 3-month hearts (p < 0.001 to p < 0.0001). After storage in Celsior, the recovery of aortic flow, coronary flow, and cardiac output in 18-month BD hearts was further impaired (p < 0.01 vs 3-month hearts). Percentage functional recovery of 18-month BD hearts stored in Celsior supplemented with GTN+EPO+ZON was equivalent to that of 3-month hearts and significantly improved compared with 18-month hearts stored in Celsior alone (p < 0.01 to p < 0.001), with reduced lactate dehydrogenase release (p < 0.01) and myocardial edema (p < 0.05) and elevated phosphorylated extracellular signal-related kinase 1/2 (p < 0.05) and phosphorylated Akt (p < 0.01). CONCLUSIONS Older hearts are more susceptible to IRI induced by BD and prolonged hypothermic storage. Supplemented Celsior activates cell survival signaling in older hearts, reduces IRI, and enhances donor heart preservation.

Size and Gender Matching in Heart Transplantation – Optimizing Donor Utilization in an Era of Changing Donor and Recipient Characteristics

Heart transplantation is limited by donor organ availability. Increased use of marginal donor organs, combined with increased recipient complexity, has increased the risk of primary graft failure. These changes in donor and recipient characteristics have led to a renewed focus on modifiable donor–recipient characteristics that have historically been shown to impact on post-transplant outcomes, namely size and gender matching. Recently published analyses of large registries have found that the use of body weight to size donor organs for transplantation fails to predict post-transplant outcomes, whereas newer methods such as predicted heart mass (utilizing height, age, and gender as well as weight) correlate well with a number of post-transplant outcomes, including survival. The well recognized risks of under-sizing in female donor:male recipient transplants and in recipients with increased pulmonary vascular resistance are reinforced by recent studies. Over-sizing is not associated with increased risk or survival benefit versus ideally matched adult donor hearts.

Ischaemic Tolerance and the Effect of Ageing Using a Rodent Donation after Circulatory Death (DCD) Model.

To investigate the effect of ageing on donor heart recovery after exposure to DCD withdrawal in a rodent model. Method Wistar rats (3, 12, 18 and 24 months) were anaesthetised and instrumented for invasive blood pressure and continuous heart rate/saturation monitoring using pulse oximetry. Circulatory death was induced by asphyxiation via tracheal ligation followed by injection of 500IU heparin via the renal vein. 3 month rats were exposed to 12 minutes warm ischaemia time (WIT). All other groups were exposed to 20 minutes WIT. At the end of the fixed WIT, hearts were flushed with 100mLs of celsior (C) or supplemented celsior(Cs) solution (containing erythropoietin, glyceryl trinitrate and zoniporide), followed by reperfusion on ex-vivo perfusion rig with oxygenated Krebs buffer at 37oc for 15 minutes followed by ‘working’ mode for 30mins. Aortic flow (AF), heart rate (HR) and pressure (MAP) were measured using PowerLab™; coronary flow (CF) was measured at 5 minute intervals. Results HR and MAP recovery were similar in all groups. CF and AF recovery are presented below: All results were corrected to heart weight[SVMHS1].CF was poorest in 3C group when compared to all other groups. AF recovery was superior in both 12mo groups when compared to other age groups (P<0.05); and all Cs groups show better AF recovery when compared to C only group. (P<0.05) Figure. No caption available. Conclusion These results suggest that myocardial tolerance to WIT increases through adolescence into adulthood then declines through the process of ageing. It is important to note, however, all age groups showed improved recovery after WIT with pharmacological supplementation.

ECMO use post DCD Heart Transplantation: A Retrospective Study

Method Between 2014 and 2017, 18 heart transplants were performed from DCD donors using machine perfusion (MP) for transport and resuscitation. Recipients were stratified into two groups based on early ECMO use. Donor data were collected using referral paperwork; retrieval data from local database and recipient data extracted from hospital medical records. Key donor and retrieval factors were identified and compared between the two groups (including. timing of withdrawal, MP duration), intraoperative details, and post-operative outcomes. Results 7 recipients required ECMO support post-operatively. Baseline demographics for donor and recipient between both groups were similar. The time interval between circulatory arrest (CA) and institution of cardioplegia was significantly longer in the ECMO group, due mainly to a longer delay between CA and knife to skin time when compared to non-ECMO group. Cold ischaemic time and time on MP were similar in both groups with poorer lactate recovery in the ECMO group when compared to the non ECMO group. Intraoperatively, ECMO group required longer bypass time and in the post-operative period require significantly longer stay in ICU. All recipients regained normal graft function and overall survival was 100% in both groups. Conclusion ECMO utility in our cohort appears to correlate with prolonged asystole to cardioplegia time, largely due to delays during transportation of donor to the operating table. This is associated with delayed graft recovery. However, all hearts were able to be recovered to normal cardiac function despite ECMO use, and there appears to be no impact on short term survival. Figure. No caption available.