The impact of ex vivo lung perfusion location on lung transplant outcomes.

BACKGROUND: Ex vivo lung perfusion (EVLP) conducted outside of the transplant center has increased in recent years to mitigate its limitation by resources and expertise. We sought to evaluate EVLP performed at transplant centers and externally. METHODS: Lung transplant recipients were identified from the United Network for Organ Sharing Database. Recipients were then stratified into two groups based where they were perfused: Transplant Program (TP) or External Perfusion Centers (EPC). The groups were assessed with comparative statistics and long-term survival was assessed by Kaplan-Meier method. The groups were then 1:1 propensity and this process was repeated. RESULTS: EPC use was generally restricted to the Southern United States. Following matching, there were no significant differences in post-operative outcomes to include post-operative stroke, dialysis, airway dehiscence, ECMO use, ventilator use or incidence of primary graft dysfunction Grade 3. Adjusted 3-year survival was 68.9% (95% Confidence Interval [CI]: 60.9%-77.9%) for the TP group and 67.6% (95% CI: 61.0%-74.9%) for the EPC group (p = 0.69). In allografts with extended ischemia (14+ h), those in the TP group had significantly longer length of stay, prolonged ventilation and treated rejection in the 1st year, though no significant difference in mid-term survival (p = 0.66). CONCLUSION: EVLP performed at an EPC can be carried out with results and survival similar to allografts undergoing EVLP at a TP. EPCs will extend the valuable resource of EVLP to lung transplant programs without the resources to perform EVLP.

Extended ischemic times during ex vivo lung perfusion is not associated with increased mortality.

BACKGROUND: The purpose of this study was to identify the association of increasing ischemic times in recipients who receive lungs evaluated by ex vivo lung perfusion (EVLP) and their association with outcomes following lung transplantation. METHODS: Lung transplant recipients who received an allograft evaluated by EVLP were identified from the United Network for Organ Sharing (UNOS) Database from 2016-2023. Recipients were stratified into three groups based on total ischemic time (TOT): short TOT (STOT, 0 to <7 h), medium TOT (MTOT, 7> to <14 h), and long TOT (LTOT, +14 h). The groups were assessed with comparative statistics and Kaplan-Meier methods. A Cox regression was created to determine the association of ischemic time in EVLP donors and long-term mortality. RESULTS: Recipients in the LTOT group had significantly longer length of stay and post-operative extracorporeal membrane use at 72 h (p < 0.05 for both). Additionally, they had nonsignificant increases in rate of stroke (4.7%, p = 0.05) and primary graft dysfunction grade 3 (PGD3, 27.5%, p = 0.082). However, there was no significant difference in hospital mortality or mid-term survival (p > 0.05 for both). On multivariable analysis, ischemic time was not associated with increased mortality whereas increasing recipient age, preoperative ECMO use and donation after circulatory death donors were (p < 0.05 for all). CONCLUSIONS: If EVLP technology is available, under certain circumstances, surgeons should not be dissuaded from using an allograft with extended ischemic time.

An Unexpected Partnership: Alexis Carrel, Charles Lindbergh, and Normothermic Machine Perfusion.

Organ transplantation is a triumph of modern medicine which represents a culmination of science and imagination, saving thousands of lives a year. However, transplantation is severely limited by suitable donor allografts. To expand the donor pool and make transplantation achievable for all, normothermic machine perfusion (NMP) is being employed more frequently. Normothermic machine perfusion involves the utilization of a device to approximate the physiology of the human body, preserve organs outside of the donor, and provide a dynamic assessment platform to determine organ suitability for transplantation. As NMP technology advances, it will soon be possible to genetically modify and actively repair these organs. Although its application to the field of transplantation is relatively new, the concept, foundation, and development of NMP can be traced back to the pioneering work of the surgeon-scientist, Alexis Carrel and the famous aviator, Charles Lindbergh in the 1930s. Their collaboration resulted in the Carrel-Lindbergh Perfusion device, an early perfusion device that was able to keep organs alive ex vivo for weeks and is most appropriately viewed as a precursor to modern machine perfusion technologies. As NMP technology becomes more advanced and refined, it is important to acknowledge the historical context in which these technologies emerged.

Is Time Scheduling Important? An Analysis of Donor Heart Cross-clamp Times During Heart Transplantation.

Background: Outcomes in heart transplantation are affected by a variety of variables and patient factors. However, the impact of circadian rhythms, gene expression, and transcription remain underexplored. We thus evaluated the potential role of donor heart cross-clamp times on short-term and long-term outcomes after heart transplantation. Methods: A total of 31 713 heart transplants were identified from the United Network for Organ Sharing Database. Patients were first stratified on the basis of time of donor procurement: 12 am to 12 pm or 12 pm to 12 am. To evaluate a possible effect of circadian rhythms, donor time was further divided into 5 groups based on preclinical data: 4 am to 8 am; 8 am to 11 am; 11 am to 5 pm; 5 pm to 10 pm; 10 pm to 4 am. Groups were assessed with comparative statistics. Long-term survival was evaluated using Kaplan-Meier methods and a multivariate Cox proportional hazard model. Results: Patients who received hearts recovered between 12 am and 12 pm had significantly higher survival than those who received hearts recovered between 12 pm and 12 am. This survival difference was observed in both unadjusted (P = 0.002) and adjusted analyses (hazard ratio [HR]: 0.93; 95% confidence interval [CI], 0.89-0.97; P < 0.001). On unadjusted analysis, the survival difference among the 5 groups was insignificant (P = 0.07). Following adjustment, the periods of 11 am to 5 pm (HR: 1.09, 95% CI, 1.02-1.17; P = 0.012), 5 pm to 10 pm (HR: 1.11; 95% CI, 1.04-1.19; P = 0.002), and 10 pm to 4 am (HR: 1.07; 95% CI, 1.01-1.15; P = 0.034), were all independently associated with increased long-term mortality. Notably, the time of 8 am to 11 am was not associated with a change in survival (HR: 1.04; 95% CI, 0.96-1.14; P = 0.3). Conclusions: Given the independent association of donor timing and survival after adjustment in a large national cohort, further investigation into the role of donor circadian rhythm and donor procurement time is warranted in preclinical and clinical studies. Understanding the underlying mechanisms of this observation could potentially lead to the development of effective treatments and donor procurement processes that prepare the organs for transplantation in a better condition.

Ex Vivo Lung Perfusion and Primary Graft Dysfunction Following Lung Transplantation: A Contemporary United Network for Organ Sharing Database Analysis.

Background: Primary graft dysfunction (PGD) has detrimental effects on recipients following lung transplantation. Here, we determined the contemporary trends of PGD in a national database, factors associated with the development of PGD grade 3 (PGD3) and ex vivo lung perfusion's (EVLP) effect on this harmful postoperative complication. Methods: The United Network for Organ Sharing database was queried from 2015 to 2023, and recipients were stratified into No-PGD, PGD1/2, or PGD3. The groups were analyzed with comparative statistics, and survival was determined with Kaplan-Meier methods. Multivariable Cox regression was used to determine factors associated with increased mortality. PGD3 recipients were then stratified based on EVLP use prior to transplantation, and a 3:1 propensity match was performed to determine outcomes following transplantation. Finally, logistic regression models based on select criteria were used to determine risk factors associated with the development of PGD3 and mortality within 1 year. Results: A total of 21.4% of patients were identified as having PGD3 following lung transplant. Those with PGD3 suffered significantly worse perioperative morbidity, mortality, and had worse long-term survival. PGD3 was also independently associated with increased mortality. Matched EVLP PGD3 recipients had significantly higher use of ECMO postoperatively; however, they did not suffer other significant morbidity or mortality as compared to PGD3 recipients without EVLP use. Importantly, EVLP use prior to transplantation was significantly associated with decreased likelihood of PGD3 development, while having no significant association with early mortality. Conclusions: EVLP is associated with decreased PGD3 development, and further optimization of this technology is necessary to expand the donor pool.

The role of CD38 in ischemia reperfusion injury in cardiopulmonary bypass and thoracic transplantation: a narrative review.

Background and Objective: Ischemia reperfusion injury (IRI) is often the underlying cause of endothelium breakdown and damage in cardiac or transplantation operations, which can lead to disastrous post-operative consequences. Recent studies of cluster of differentiation 38 (CD38) have identified its critical role in IRI. Our objective is to provide a comprehensive overview of CD38-mediated axis, pathways, and potential CD38 translational therapies for reducing inflammation associated with cardiopulmonary bypass (CPB) or thoracic transplantation and IRI. Methods: We conducted a review of the literature by performing a search of the PubMed database on 2 April 2023. To find relevant publications on CD38, we utilized the MeSH terms: "CD38" AND "Ischemia" OR "CD38" AND "Transplant" OR "CD38" AND "Heart" from 1990-2023. Additional papers were included if they were felt to be relevant but were not captured in the MeSH terms. We found 160 papers that met this criterion, and following screening, exclusion and consensus a total of 36 papers were included. Key Content and Findings: CD38 is most notably a nicotine adenine dinucleotide (NAD)+ glycohydrolase (NADase), and a generator of Ca2+ signaling secondary messengers. Ultimately, the release of these secondary messengers leads to the activation of important mediators of cellular death. In the heart and during thoracic transplantation, this pathway is intimately involved in a wide variety of injuries; namely the endothelium. In the heart, activation generally results in vasoconstriction, poor myocardial perfusion, and ultimately poor cardiac function. CD38 activation also prevents the accumulation of atherosclerotic disease. During transplantation, intracellular activation leads to infiltration of recipient innate immune cells, tissue edema, and ultimately primary graft dysfunction (PGD). Specifically, in heart transplantation, extracellular activation could be protective and improve allograft survival. Conclusions: The knowledge gap in understanding the molecular basis of IRI has prevented further development of novel therapies and treatments. The possible interaction of CD38 with CD39 in the endothelium, and the modulation of the CD38 axis may be a pathway to improve cardiovascular outcomes, heart and lung donor organ quality, and overall longevity.