Metabolic Considerations in Direct Procurement and Perfusion Protocols with DCD Heart Transplantation.

Heart transplantation with donation after circulatory death (DCD) provides excellent patient outcomes and increases donor heart availability. However, unlike conventional grafts obtained through donation after brain death, DCD cardiac grafts are not only exposed to warm, unprotected ischemia, but also to a potentially damaging pre-ischemic phase after withdrawal of life-sustaining therapy (WLST). In this review, we aim to bring together knowledge about changes in cardiac energy metabolism and its regulation that occur in DCD donors during WLST, circulatory arrest, and following the onset of warm ischemia. Acute metabolic, hemodynamic, and biochemical changes in the DCD donor expose hearts to high circulating catecholamines, hypoxia, and warm ischemia, all of which can negatively impact the heart. Further metabolic changes and cellular damage occur with reperfusion. The altered energy substrate availability prior to organ procurement likely plays an important role in graft quality and post-ischemic cardiac recovery. These aspects should, therefore, be considered in clinical protocols, as well as in pre-clinical DCD models. Notably, interventions prior to graft procurement are limited for ethical reasons in DCD donors; thus, it is important to understand these mechanisms to optimize conditions during initial reperfusion in concert with graft evaluation and re-evaluation for the purpose of tailoring and adjusting therapies and ensuring optimal graft quality for transplantation.

Lactate during ex-situ heart perfusion does not predict the requirement for mechanical circulatory support following donation after circulatory death (DCD) heart transplants.

BACKGROUND: Ex-situ heart perfusion (ESHP) is commonly used for the reanimation and preservation of hearts following donation after circulatory determined death (DCD). The only commercially available existing ESHP device promotes perfusate lactate levels for assessment of heart viability. The reliability of this marker is yet to be confirmed for DCD heart transplantation. METHODS: This is a single center, retrospective study examining DCD heart transplants from March 1, 2015 to June 30, 2020. Recipients were divided into 2 groups dependent upon their requirement for or absence of mechanical circulatory support post-transplant. Lactate profiles obtained during ESHP were analyzed. Hearts were procured using the direct procurement and perfusion (DPP) method. RESULTS: Fifty-one DCD heart transplant recipients were studied, of which 20 (39%) were dependent on mechanical circulatory support (MCS) following transplantation, (2% Ventricular Assist Device (VAD), 16% Extra Corporeal Membrane Oxygenation (ECMO) and 21% Intra-aortic balloon pumps (IABP). There was no difference in arterial lactate profiles on ESHP at any time point for those dependent upon MCS support (MCS) and those that were not (no MCS) post-transplant. After 3 hours of ESHP, the arterial lactate was >5mmol/L in 80% upon MCS vs 62% no MCS, p = .30. There was also no difference in ESHP rising arterial lactate concentrations, (15% MCS vs 13% non MCS, p = 1.00). CONCLUSION: For DCD hearts transplants retrieved using the DPP technique, lactate profiles do not seem to be a reliable predictor of mechanical circulatory support requirement post-transplant.

Pediatric heart transplantation following donation after circulatory death, distant procurement, and ex-situ perfusion.

BACKGROUND: Limited availability of suitable donor hearts remains a challenge to pediatric heart transplantation, contributing to waitlist mortality. Controlled donation after circulatory death (DCD) has demonstrated success in adults. Early series of pediatric DCD heart transplantation using cold storage alone reported significant early mortality. We report a collaboration between 2 centers in the United Kingdom, combining expertise in adult DCD organ retrieval and pediatric transplantation. METHODS: This retrospective series comprises 6 children (4 male, all >20 kg) undergoing DCD heart transplantation at Great Ormond Street Hospital between 1 February and 30 September 2020, following retrieval with direct procurement and perfusion using portable normothermic machine perfusion by the Royal Papworth Hospital service. Baseline characteristics and 1-year follow-up were compared to 9 children who underwent donation after brain death (DBD) transplants contemporaneously. RESULTS: Mean DCD donor age was 24.67 years and mean DCD recipient age was 13.83 years. Mean functional warm ischemic time was 28.5 minutes and ex-situ heart perfusion time was 280 minutes. Median ICU and hospital stay were 9 and 17 days, respectively. All children survived to 1-year post-transplant. Survival and ICU and hospital stay were similar between the DCD and DBD cohorts. Performing DCD transplants resulted in a 66.7% increase in transplants for children >20 kg at GOSH during the study. CONCLUSIONS: This series demonstrates that DCD heart transplant can be performed safely with excellent short-term survival in children. Although the cohort is small, there was no significant difference in major outcomes compared to a DBD cohort.

Emergency medical staffs' knowledge and attitude about organ donation after circulatory determined death (DCD) and its related factors.

BACKGROUND: Adverse attitudes and insufficient knowledge about organ donation after Circulatory Determined Death (DCD) among emergency staff can have important consequences for the proper identification of potential DCD donors. This is aided by the constant application of donation after Circulatory Determined Death policies, and the relative strength of support for this type of donation. Therefore, this study was conducted to investigate the awareness and attitude of emergency personnel about organ donation after Circulatory Determined Death. METHODS: This descriptive study was carried out with the participation of 49 physicians and 145 nurses working in the emergency departments of educational and medical centers of Tabriz University of Medical Sciences. Nurses were selected by simple random sampling, and all physicians working in the emergency departments were included in the study. The questionnaire of Knowledge and Attitude regarding Organ Donation after Circulatory Determined Death designed by Rodrigue et al. was used. Data were analyzed using descriptive statistics and independent samples t-test, one-way ANOVA, and chi-square test. RESULTS: Most of the nurses (62.8%) and physicians (66.7%) had a high level of knowledge about organ donation after circulatory determined death. The mean attitude score was 101.84 (SD: 9.88) out of 170 for nurses and 106.53 (SD: 11.77) for physicians. Physicians who carried organ donation cards had a more positive attitude toward organ donation after circulatory determined death. CONCLUSION: According to this study findings, knowledge and attitude of the emergency staff about organ donation was both high and positive. It is recommended to devise necessary guidelines for organ donation in Iranian emergency departments to assist in the training of colleagues in organ donation ensuring no necessary measures are missed. The results of this study would support the development of guidelines for the successful introduction of DCD in Iran.

A 5-year single-center early experience of heart transplantation from donation after circulatory-determined death donors.

BACKGROUND: In an effort to address the increasing demand for heart transplantation within the United Kingdom (UK), we established a clinical program of heart transplantation from donation after circulatory-determined death (DCD) donors in 2015. After 5 years, we report the clinical early outcomes and impact of the program. METHODS: This is a single-center, retrospective, matched, observational cohort study comparing outcomes of hearts transplanted from DCD donors from March 1, 2015 to February 29, 2020 with those from matched donation after brain death (DBD) donors at Royal Papworth Hospital (RPH) (Cambridge, UK). DCD hearts were either retrieved using thoracoabdominal normothermic regional perfusion or the direct procurement and perfusion technique. All DBD hearts were procured using standard cold static storage. The primary outcomes were recipient 30-day and 1-year survival. RESULTS: During the 5-year study, DCD heart donation increased overall heart transplant activity by 48% (79 for DCD and 164 for DBD). There was no difference in survival at 30 days (97% for DCD vs 99% for DBD, p = 1.00) or 1 year (91% for DCD vs 89% for DBD, p = 0.72). There was no difference in the length of stay in the intensive care unit (7 for DCD vs 6 for DBD days, p = 0.24) or in the hospital (24 for DCD vs 25 for DBD days, p = 0.84). CONCLUSIONS: DCD heart donation increased overall heart transplant activity at RPH by 48%, with no difference in 30-day or 1-year survival in comparison with conventional DBD heart transplantations. DCD heart donation is set to make a dramatic difference in the number of patients who can benefit from heart transplantation.

Impact of stroke on outcomes following cardiac surgery: Propensity matched analysis.

BACKGROUND: Stroke remains a devastating complication of cardiac surgery. The aim of this study was to characterize the incidence of stroke and analyze the impact of stroke on patient outcomes and survival. METHODS: A retrospective analysis was performed of patients with a computed tomography-confirmed stroke diagnosis between 1 January 2015 and 31 March 2019 at a single center. 2:1 propensity matching was performed to identify a control population. RESULTS: Over the period 165 patients suffered a stroke (1.99%), with an incidence ranging from 0.85% for coronary artery bypass grafting to 8.14% for aortic surgery. The mean age was 70.3 years and 58.8% were male. 18% had experienced a previous stroke or transient ischemic attack. Compared to the comparison group, patients experiencing postoperative stroke had a significantly prolonged period of intensive care unit admission (8.0 vs 1.1 days P < .001) and hospital length of stay (12.94 vs 8.0 days P < .001). Patient survival was also inferior. In-hospital mortality was almost three times as high (17.0% vs 5.9%; P < .001). Longer-term survival was also inferior to Kaplan-Meier estimation (P < .001). The 1-year and 3-year survival were 61.5% and 53.8% respectively compared to 89.4% and 86.1% for the comparison group. CONCLUSION: Perioperative stroke is a devastating complication following cardiac surgery. Perioperative stroke is associated with significantly inferior outcomes in terms of both morbidity and mortality. Notably a 28% reduction in 1-year survival. Efforts should focus on identifying strategies aimed at reducing the incidence, morbidity, and mortality of perioperative stroke following cardiac surgery.

Combined heart-lung transplantation from a donation after circulatory death donor.

Combined heart-lung transplantation is the optimal treatment option for many patients with end-stage heart failure and fixed severe pulmonary hypertension. It offers the only possibility of long-term survival and a return to a normal quality of life. Unfortunately, it is rarely performed because of donor organ allocation policies. We present the case of a critically ill 24-year-old man, who after waiting for >100 days in-hospital on the urgent transplant list, deteriorated further and underwent the first successful heart-lung transplant with organs from a donation after circulatory death.

Heart Transplantation With Donation After Circulatory Death.

Heart transplantation remains the preferred option for improving quality of life and survival for patients suffering from end-stage heart failure. Unfortunately, insufficient supply of cardiac grafts has become an obstacle. Increasing organ availability with donation after circulatory death (DCD) may be a promising option to overcome the organ shortage. Unlike conventional donation after brain death, DCD organs undergo a period of warm, global ischemia between circulatory arrest and graft procurement, which raises concerns for graft quality. Nonetheless, the potential of DCD heart transplantation is being reconsidered, after reports of more than 70 cases in Australia and the United Kingdom over the past 3 years. Ensuring optimal patient outcomes and generalized adoption of DCD in heart transplantation, however, requires further development of clinical protocols, which in turn require a better understanding of cardiac ischemia-reperfusion injury and the various possibilities to limit its adverse effects. Thus, we aim to provide an overview of the knowledge obtained with preclinical studies in animal models of DCD heart transplantation, to facilitate and promote the most effective and efficient advancement in preclinical research. A literature search of the PubMed database was performed to identify all relevant preclinical studies in DCD heart transplantation. Specific aspects relevant for DCD heart transplantation were analyzed, including animal models, graft procurement and storage conditions, cardioprotective approaches, and graft evaluation strategies. Several potential therapeutic strategies for optimizing graft quality are identified, and recommendations for further preclinical research are provided.

Heart transplantation from donation after circulatory determined death.

Fifty years since the first successful human heart transplant from a non-heart beating donor, this concept of heart transplantation from donation after circulatory determined death (DCD) promises to be one of the most exciting developments in heart transplantation. Heart transplantation has established itself as the best therapeutic option for patients with end-stage heart failure, with the opportunity to provide these patients with a near-normal quality of life. However, this treatment is severely limited by the availability of suitable donor hearts. In recent times, heart transplantation has been limited to using donor hearts from donors following brain stem death. The use of donor hearts from DCD had been thought to be associated with high risk and poor outcomes until recent developments in organ perfusion and retrieval techniques have shown that this valuable resource may provide an answer to the global shortage of suitable donor hearts. With established DCD heart transplant programmes reporting encouraging results, this technique has been shown to be comparable to the current gold standard of donation after brain death (DBD) heart transplantation.

Transplantation of Hearts Donated after Circulatory Death.

Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.

Outcome after heart transplantation from donation after circulatory-determined death donors.

BACKGROUND: The requirement for heart transplantation is increasing, vastly outgrowing the supply of hearts available from donation after brain death (DBD) donors. Transplanting hearts after donation after circulatory-determined death (DCD) may be a viable additive alternative to DBD donors. This study compared outcomes from the largest single-center experience of DCD heart transplantation against matched DBD heart transplants. METHODS: DCD hearts were retrieved using normothermic regional perfusion (NRP) or direct procurement and perfusion (DPP). During NRP, perfusion was restored to the arrested heart within the donor with the exclusion of the cerebral circulation, whereas DPP hearts were removed directly. All hearts were maintained on machine perfusion during transportation. A retrospective cohort of DBD heart transplants, matched for donor and recipient characteristics, was used as a comparison group. The primary outcome measure of this study (set by the United Kingdom regulatory body) was 90-day survival. RESULTS: There were 28 DCD heart transplants performed during the 25-month study period. Survival at 90 days was not significantly different between DCD and matched DBD transplant recipients (DCD, 92%; DBD, 96%; p = 1.0). Hospital length of stay, treated rejection episodes, allograft function, and 1-year survival (DCD, 86%; DBD, 88%; p = 0.98) were comparable between groups. The method of retrieval (NRP or DPP) was not associated with a difference in outcome. CONCLUSIONS: These results suggest that heart transplantation from DCD heart donation provides comparable short-term outcomes to traditional DBD heart transplants and can serve to increase heart transplant activity in well-selected patients.

Ventriculo-arterial coupling detects occult RV dysfunction in chronic thromboembolic pulmonary vascular disease.

Chronic thromboembolic disease (CTED) is suboptimally defined by a mean pulmonary artery pressure (mPAP) <25 mmHg at rest in patients that remain symptomatic from chronic pulmonary artery thrombi. To improve identification of right ventricular (RV) pathology in patients with thromboembolic obstruction, we hypothesized that the RV ventriculo-arterial (Ees/Ea) coupling ratio at maximal stroke work (Ees/Eamax sw) derived from an animal model of pulmonary obstruction may be used to identify occult RV dysfunction (low Ees/Ea) or residual RV energetic reserve (high Ees/Ea). Eighteen open chested pigs had conductance catheter RV pressure-volume (PV)-loops recorded during PA snare to determine Ees/Eamax sw This was then applied to 10 patients with chronic thromboembolic pulmonary hypertension (CTEPH) and ten patients with CTED, also assessed by RV conductance catheter and cardiopulmonary exercise testing. All patients were then restratified by Ees/Ea. The animal model determined an Ees/Eamax sw = 0.68 ± 0.23 threshold, either side of which cardiac output and RV stroke work fell. Two patients with CTED were identified with an Ees/Ea well below 0.68 suggesting occult RV dysfunction whilst three patients with CTEPH demonstrated Ees/Ea ≥ 0.68 suggesting residual RV energetic reserve. Ees/Ea > 0.68 and Ees/Ea < 0.68 subgroups demonstrated constant RV stroke work but lower stroke volume (87.7 ± 22.1 vs. 60.1 ± 16.3 mL respectively, P = 0.006) and higher end-systolic pressure (36.7 ± 11.6 vs. 68.1 ± 16.7 mmHg respectively, P < 0.001). Lower Ees/Ea in CTED also correlated with reduced exercise ventilatory efficiency. Low Ees/Ea aligns with features of RV maladaptation in CTED both at rest and on exercise. Characterization of Ees/Ea in CTED may allow for better identification of occult RV dysfunction.

Functional assessment and transplantation of the donor heart after circulatory death.

BACKGROUND: After a severe shortage of brain-dead donors, the demand for heart transplantation has never been greater. In an attempt to increase organ supply, abdominal and lung transplant programs have turned to the donation after circulatory-determined death (DCD) donor. However, because heart function cannot be assessed after circulatory death, DCD heart transplantation was deemed high risk and never adopted routinely. We report a novel method of functional assessment of the DCD heart resulting in a successful clinical program. METHODS: Normothermic regional perfusion (NRP) was used to restore function to the arrested DCD heart within the donor after exclusion of the cerebral circulation. After weaning from support, DCD hearts underwent functional assessment with cardiac-output studies, echocardiography, and pressure-volume loops. In the feasibility phase, hearts were transported perfused before evaluation of function in modified working mode extracorporeally. After the establishment of a reliable assessment technique, hearts with demonstrable good function were then selected for clinical transplantation. RESULTS: NRP was instituted in 13 adult DCD donors, median age of 33 years (interquartile range [IQR], 28-38 years), after a median ischemic time from withdrawal to perfusion of 24 minutes (IQR, 21-29; range, 17-146 minutes). Two of 4 hearts in the feasibility phase were unsuitable for transplantation after functional assessment. Nine DCD hearts were transplanted in the clinical phase, with 100% survival. The median intensive care duration was 5 days (IQR, 4-5 days), with 2 patients requiring mechanical support. There were no episodes of rejection (total, 1,436 patient-days; range, 48-297). During the same period, we performed 20 standard heart transplants using brain-dead donors. CONCLUSIONS: NRP allows rapid reperfusion and functional assessment of the DCD donor heart, ensuring only viable hearts are selected for transplantation. This technique minimizes the risk of primary graft dysfunction and maximizes confidence in DCD heart transplantation, realizing a 45% increase in our heart transplant activity.

The ETTAA study protocol: a UK-wide observational study of 'Effective Treatments for Thoracic Aortic Aneurysm'.

INTRODUCTION: Chronic thoracic aortic aneurysm (CTAA) affecting the arch or descending aorta is an indolent but life-threatening condition with a rising prevalence as the UK population ages. Treatment may be in the form of open surgical repair (OSR) surgery, endovascular stent grafting (ESG) or best medical therapy (BMT). Currently, there is no consensus on the best management strategy, and no UK-specific economic studies that assess outcomes beyond the chosen procedure, but this is required in the context of greater demand for treatment and limited National Health Service (NHS) resources. METHODS AND ANALYSIS: This is a prospective, multicentre observational study with statistical and economic modelling of patients with CTAA affecting the arch or descending aorta. We aim to gain an understanding of how treatments are currently chosen, and to determine the clinical effectiveness and cost-effectiveness of the three available treatment strategies (BMT, ESG and OSR). This will be achieved by: (1) following consecutive patients who are referred to the teams collaborating in this proposal and collecting data regarding quality of life (QoL), medical events and hospital stays over a maximum of 5 years; (2) statistical analysis of the comparative effectiveness of the three treatments; and (3) economic modelling of the comparative cost-effectiveness of the three treatments. Primary study outcomes are: aneurysm growth, QoL, freedom from reintervention, freedom from death or permanent neurological injury, incremental cost per quality-adjusted life year gained. ETHICS AND DISSEMINATION: The study will generate an evidence base to guide patients and clinicians to determine the indications and timing of treatment, as well as informing healthcare decision-makers about which treatments the NHS should provide. The study has achieved ethical approval and will be disseminated primarily in the form of a Health Technology Assessment monograph at its completion. TRIAL REGISTRATION NUMBER: ISRCTN04044627.

Rat model of veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: We aim to develop a rat model of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: VA-ECMO was established in twelve Male Sprague-Dawley rats (250-350 g) through cannulation of the right jugular vein for venous drainage and the right femoral artery for arterial reinfusion. Arterial blood pressure was measured using a conductance catheter through cannulation of the left carotid artery. Heart rate was monitored by electrocardiography and arterial blood gas parameters with a blood gas analyzer. The VA-ECMO circuit was tested by subjecting the rats to hypoxic cardiac arrest with resuscitation using VA-ECMO. Both load-dependent and load-independent measures of myocardial contractility were measured using pressure-volume loop analysis to confirm restoration of myocardial function post-resuscitation. RESULTS: Following hypoxic cardiac arrest VA-ECMO provided sufficient oxygenation to support the circulation. The haemodynamic and blood gas parameters were maintained at transition and during ECMO. All animals were resuscitated, regained cardiac function and were able to be weaned off ECMO post-resuscitation. CONCLUSION: We have established a safe, high-throughput, economical, functioning rat model of VA-ECMO.

Surgical treatment of atrial fibrillation in the heart failure population.

Surgery to correct a structural heart valve problem can restore sinus rhythm in approximately one-fifth of patients with atrial fibrillation (AF), and the addition of a maze procedure will increase this proportion. Evidence shows that the maze procedure may restore atrial function in some patients and may have beneficial effects on functional symptoms and prognosis. The role of the maze procedure as an isolated treatment for lone AF in the context of heart failure with no structurally correctable cause is unknown. Future progress will determine the appropriate indications for treatment and the risks and benefits of any intervention.

The influence of endoscopic vein harvesting on outcomes after coronary bypass grafting: a meta-analysis of 267,525 patients.

In recent times, practice in cardiac surgery has shifted towards using endoscopic techniques to harvest the saphenous vein from the leg for use as a bypass graft. A paper published in the New England Journal of Medicine (NEJM) in 2009 raised concerns over increased graft occlusion rates in veins harvested endoscopically. This NEJM paper has been criticized, but has nonetheless been influential in guiding practice. We have undertaken this meta-analysis to provide evidence on the clinical outcomes of endoscopic vein harvesting (EVH), so that clinicians can make an informed judgement about whether this technique, popular as it is with patients, should still be offered. We systematically reviewed the global literature and performed a meta-analysis of clinical outcomes after endoscopic and open vein harvesting. In all outcomes, endoscopic harvesting appears to be equal, if not superior, to open harvesting. The suspicion of higher rates of vein graft occlusion was not borne out by randomized studies. When considering evidence from only randomized studies, there is no statistical difference in vein graft stenosis or occlusion between open and endoscopically harvested veins. In conclusion, EVH reduces pain and leg wound complications. At a median follow-up of 2.6 years, we found no significant difference in mortality, myocardial infarction, repeat revascularization, angina recurrence, vein graft stenosis or occlusion. Therefore, the authors support the ongoing use of endoscopic harvesting techniques.

Primitive neuroectodermal tumor of the heart.

We present a case of primitive neuroectodermal tumor of the left atrium with involvement of the coronary sinus. The initial presentation was of cardiac tamponade resulting from the size of the tumor. There was no evidence of tumor elsewhere, and after complete resection and without adjuvant chemotherapy the patient is well at 2-year follow-up. There has been no evidence of tumor recurrence. This is a rare reported case of resection of a cardiac primitive neuroectodermal tumor without adjuvant chemotherapy. Other cases in the literature have been treated by orthoptic transplantation and resection with chemotherapy.