Arjun Iyer

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.

Primary Graft Failure after Heart Transplantation

Primary graft failure (PGF) is a devastating complication that occurs in the immediate postoperative period following heart transplantation. It manifests as severe ventricular dysfunction of the donor graft and carries significant mortality and morbidity. In the last decade, advances in pharmacological treatment and mechanical circulatory support have improved the outlook for heart transplant recipients who develop this complication. Despite these advances in treatment, PGF is still the leading cause of death in the first 30 days after transplantation. In todays climate of significant organ shortages and growing waiting lists, transplant units worldwide have increasingly utilised “marginal donors” to try and bridge the gap between “supply and demand.” One of the costs of this strategy has been an increased incidence of PGF. As the threat of PGF increases, the challenges of predicting and preventing its occurrence, as well as the identification of more effective treatment modalities, are vital areas of active research and development.

Increasing the Tolerance of DCD Hearts to Warm Ischemia by Pharmacological Postconditioning

Donation after circulatory death (DCD) offers a potential additional source of cardiac allografts. We used a porcine asphyxia model to evaluate viability of DCD hearts subjected to warm ischemic times (WIT) of 20–40 min prior to flushing with Celsior (C) solution. We then assessed potential benefits of supplementing C with erythropoietin, glyceryl trinitrate and zoniporide (Cs), a combination that we have shown previously to activate ischemic postconditioning pathways. Hearts flushed with C/Cs were assessed for functional, biochemical and metabolic recovery on an ex vivo working heart apparatus. Hearts exposed to 20‐min WIT showed full recovery of functional and metabolic profiles compared with control hearts (no WIT). Hearts subjected to 30‐ or 40‐min WIT prior to C solution showed partial and no recovery, respectively. Hearts exposed to 30‐min WIT and Cs solution displayed complete recovery, while hearts exposed to 40‐min WIT and Cs solution demonstrated partial recovery. We conclude that DCD hearts flushed with C solution demonstrate complete recovery up to 20‐min WIT after which there is rapid loss of viability. Cs extends the limit of WIT tolerability to 30 min. DCD hearts with ≤30‐min WIT may be suitable for transplantation and warrant assessment in a transplant model.

Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors.

The shortage of donors in cardiac transplantation may be alleviated by the use of allografts from donation after circulatory death (DCD) donors. We have previously shown that hearts exposed to 30 min warm ischemic time and then flushed with Celsior supplemented with agents that activate ischemic postconditioning pathways, show complete recovery on a blood‐perfused ex vivo working heart apparatus. In this study, these findings were assessed in a porcine orthotopic heart transplant model. DCD hearts were preserved with either normothermic ex vivo perfusion (NEVP) using a clinically approved device, or with standard cold storage (CS) for 4 h. Orthotopic transplantation into recipient animals was subsequently undertaken. Five of six hearts preserved with NEVP demonstrated favorable lactate profiles during NEVP and all five could be weaned off cardiopulmonary bypass posttransplant, compared with 0 of 3 hearts preserved with CS (p < 0.05, Fishers exact test). In conclusion, DCD hearts flushed with supplemented Celsior solution and preserved with NEVP display viability before and after transplantation. Viability studies of human DCD hearts using NEVP are warranted.

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.

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.

Development of a Mock Extracorporeal Membrane Oxygenation Circuit to Assess Recirculation.

A limitation of veno-venous extracorporeal membrane oxygenation (VV-ECMO) is the recirculating of newly oxygenated blood back to the VV-ECMO circuit. We compared cannulation strategies for combating recirculation utilizing a mock circulation loop (MCL) with ultrasonic flow probes and pressure transducers ensuring that the MCL was run at physiological hemodynamic parameters. Mean recirculation percentages were lower (ANOVA, F = 14.25; p = 0.0001) with the Wang-Zwische dual lumen cannula (4.00 ± 1.77, n = 7) than both the femoro-jugular (15.23 ± 7.00, n = 8) and the femoro-femoral cannulation configurations (13.49 ± 1.44, n = 8).

56-year-old lady with transaortic gradient

Clinical introduction A 56-year-old lady with a background of hypertension was admitted to our institution with acute pulmonary oedema. She reported gradual and increasingly severe dyspnoea on exertion over the preceding 12 months and, prior to presentation, her exercise tolerance was restricted to one flight of stairs. On transthoracic echocardiography during the index admission, left ventricular size and systolic function were normal, and peak and mean transaortic gradients were 67 mm Hg and 33 mm Hg, respectively, with a peak velocity of 3.9 m/s. No aortic incompetence or other significant valvular abnormality was noted. A transoesophageal echocardiogram was performed. Figure 1 depicts the mid-oesophageal parasternal long-axis view. What is the explanation behind the significant transaortic gradient? Figure 1 Transoesophageal echocardiogram, mid-oesophageal long-axis view at 135 degrees. Question What is the explanation behind the significant transaortic gradient? Ventricular septal defect Supravalvular aortic stenosis Aortic valvular stenosis Subaortic membrane Hypertrophic obstructive cardiomyopathy

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.

Pharmacological Conditioning of Brain Dead Donor Hearts with Erythropoietin and Glyceryl Trinitrate: Clinical Experience

Background: With the increasing success of heart transplantation, older and higher-risk donors and recipients are being accepted for transplantation. The risk of primary graft dysfunction (PGD) is thus increased. We investigated a ‘pharmacological conditioning’ strategy, where Celsior preservation solution supplemented with glyceryl trinitrate (GTN) and erythropoietin (EPO) was used for cardioplegia and hypothermic storage, and determined graft recovery and patient survival after cardiac transplantation.