Donation After Circulatory Death Lungs Research Articles

A multicenter analysis of lung transplantation outcomes comparing donation after circulatory death and donation after brain death

BackgroundDonor organ shortage is a barrier to lung transplantation. Donation after circulatory death (DCD) may offer a solution, although it is underutilized. The objective of this study was to compare survival and other postoperative outcomes between DCD and donation after brain death (DBD). MethodsWe performed a multi-center analysis of Multi-Institutional Extracorporeal Life Support (ECLS) Registry data from 11 lung transplant centers in the United States and Europe. Demographics and clinical parameters were compared using Chi-square test and Fisher's exact test. Survival was assessed by Kaplan-Meier curves and compared by log-rank test with propensity score matching. ResultsOf 1585 patients included in the study, 135 (8.5%) received DCD lungs and 1450 (91.5%) received DBD lungs. DCD recipients had higher rates of obstructive lung disease (p=0.042), longer total ischemic time (p<0.0001), and higher rates of primary graft dysfunction (PGD) at t0h (p<0.0001) and t24h (p=0.0005). PGD at t48h and t72h was not significantly different between DCD and DBD recipients. 90-day survival was lower among DCD recipients (91.2%) compared to DBD recipients (97.4%, p=0.038). Survival was higher without ECLS (p=0.014), whereas EVLP (p=0.47) did not affect survival. ConclusionOverall, our data showed excellent 90-day survival for DCD and DBD recipients, although DCD recipients had relatively lower survival. EVLP was not associated with survival, which may guide future strategies to optimize DCD utilization.

Ex vivo MFG-E8 treatment improves the function of lungs procured from cardiac death donors in preclinical porcine model

Ex vivo lung perfusion (EVLP) is a promising technology that allows the re-evaluation of donor lungs and has the potential to improve marginal lung reconditioning. The present study focused on the effects of milk fat globule epidermal growth factor 8 (MFG‐E8) on the function of donation after circulatory death (DCD) lungs during EVLP and transplant reperfusion. Domestic swine were assigned to 4 groups. In the control group, the donor lungs lacking warm ischemia were preserved in Perfadex for 4 h. The swine in the other three groups underwent hypoxic arrest, followed by 1 h of warm ischemia. The DCD lungs were procured and randomly divided into three groups: cold static preservation (DCD-CSP) group, DCD-EVLP group, and DCD-MFG-E8 group. The left lung of all groups was transplanted and reperfused. During EVLP and reperfusion, lung functions and pathological evaluations were performed. Treatment with MFG-E8 resulted in significantly improved blood oxygenation. The mean pulmonary artery pressure, peak airway pressure, and expression of IL-1β, IL-6, and IL-12 were significantly lower but IL-10 was higher in the DCD -MFG-E8 group. Furthermore, the lung injury severity score, pulmonary edema, and wet-to-dry weight ratio were also reduced in MFG-E8-treated lungs. However, the pulmonary vascular resistance and expression of TNF-α did not differ from the DCD -EVLP group but were significantly lower than in the DCD -CSP group. Adding MFG-E8 into the perfusate during EVLP obtains optimal graft function of lungs from DCD. This finding, if confirmed clinically, can be applied to recondition grafts and expanded use of DCD lungs.

Characteristics and outcomes of lung transplants performed with ex-situ lung perfusion

Ex-situ lung perfusion (ESLP) can be used to assess and rehabilitate donor lungs, potentially expanding the donor pool. We examined the characteristics and outcomes of lung transplants performed with ESLP in the United States. Retrospective review of the United Network for Organ Sharing registry of primary adult lung transplant recipients from February 28, 2018, to June 30, 2021, was performed, comparing baseline characteristics, in-hospital outcomes, and 1-year survival of ESLP vs no ESLP lung transplants. Of 8204 lung transplants, 426 (5.2%) were performed with ESLP. ESLP donors were older, more donation after circulatory death (DCD), and had lower PaO2:FiO2 (P:F) ratios. Recipients had lower lung allocation scores. ESLP lungs traveled further, had longer preservation times, and were more likely double lung transplants. Reintubation rates, extracorporeal membrane oxygenation at 72hours, and hospital length of stay were greater in the ESLP group. On multivariable analysis, ESLP was not an independent predictor of 1-year survival. However, further analysis showed that DCD lungs managed on ESLP had worse 1-year survival compared to DCD lungs preserved with standard cold storage or with donation after brain death donor lungs. ESLP is used in a small percentage of lung transplants in the US and is not independently associated with 1-year survival. ESLP combined with DCD lungs, however, is associated with worse 1-year survival and warrants further investigation.

Donation after circulatory death donors in high-risk recipients undergoing bilateral lung transplantation: An ISHLT database registry analysis.

Lung transplantation (LTx) using donation after circulatory death (DCD) donors has demonstrated equivalent outcomes compared to donation after brain dead (DBD) donors. However, data from the use of DCDs for high-risk (HR) recipients is limited. We performed a propensity match study to evaluate the impact of DCD transplantation on HR recipients. In addition, we assessed the effect of recipient profile (HR vs. non-HR) in DCDs and DBDs LTx. From 2009-2018, 1829 double lung transplants (DLTx) for HR recipients were identified. Of these, 131 were performed using DCD donors. There was no difference in survival between DCDs and DBDs among HR-DLTx recipients (p=0.16). However, HR recipients had worse survival compared to non-HR recipients in DBD (p < 0.001) but not in DCD transplantation (p=0.95). Our findings support that DCD lungs are appropriate for HR recipients and should not be considered inferior or higher-risk donors. Its use should be further stimulated rather than restricted.

Machine Perfusion of Donation After Circulatory Death Liver and Lungs Before Combined Liver-lung Transplantation.

Shortage of deceased donor organs for transplantation has led to the increased use of organs from donation after circulatory death (DCD) donors. There are currently no reports describing outcomes after multiorgan transplantation with DCD livers. The use of DCD organs for multiorgan transplantation can be enhanced if the detrimental effects of prolonged cold ischemia and subsequent ischemia-reperfusion injury are overcome. We present a case in which the liver and lungs of a DCD donor were preserved using ex situ machine perfusion for combined liver-lung transplantation. The recipient was a 19-year-old male patient requiring bilateral lung transplantation for severe progressive pleural parenchymal fibroelastosis and portal hypertension with portal vein thrombosis. The donor liver was preserved with dual hypothermic oxygenated machine perfusion, whereas the lungs were perfused using ex vivo lung perfusion. With ex vivo lung perfusion, total preservation time of right and left lung reached 17 and 21 h, respectively. Now, 2 y after transplantation, liver function is normal and lung function is improving. To conclude, we suggest that combined transplantation of DCD liver and lungs is feasible when cold ischemia is reduced with ex situ machine perfusion preservation.

Alterations in Perfusate Leukocyte Populations are Associated with Donor Mode of Death and the Outcome of Ex Vivo Lung Perfusion

<h3>Purpose</h3> Lung transplantation (LTx) is limited by the scarcity of suitable donor lungs. One option to expand the donor pool is the use of donation after circulatory death (DCD) lungs. Additionally, ex vivo lung perfusion (EVLP) allows for evaluation and treatment of donor lungs prior to LTx. There are limited data describing the cellular, specifically leukocyte populations in EVLP perfusate, and their link to donor mode of death. We hypothesized that EVLP perfusate leukocytes differ between DCD and neurological determination of death (NDD) lungs, and between lungs accepted and declined for transplant. <h3>Methods</h3> EVLP perfusates were sampled hourly from clinical EVLP cases until termination. Perfusate cells were separated and cryopreserved. The first and last available perfusate from lungs accepted (n = 10 NDD and n = 10 DCD) and declined (n = 10 NDD and n = 10 DCD) for LTx were selected and stained with flow cytometry panels to characterize major leukocyte populations. <h3>Results</h3> Lymphoid cells form the majority of perfusate cells (Fig A). B cells were significantly higher in declined lungs regardless of mode of donor death (Fig B). CD4+ memory T cells (CD3+ CD4+ CD45RO+) and activated CD8+ T cells (CD3+ CD8+ CD25+) were elevated in the DCD lung perfusates (Fig C). In all groups, CD163hi, HLA-DR+ monocytes were observed at first available perfusate and diminished at the end of EVLP, while neutrophils were low in the first perfusate sample but increased significantly by the end of EVLP (Fig D). <h3>Conclusion</h3> Interestingly, leukocyte populations in EVLP perfusate differ between mode of donor death, with lower levels of B cells associated with lungs accepted for transplant, and certain T cell subsets over-represented in DCD lungs. While no significant changes were observed in myeloid cells, their kinetics over time vary based on cell type. Future studies will be required to determine the sources of these cell populations and whether they are involved in the pathogenesis of lung injury prior to transplant.

Transcriptomic investigation reveals donor-specific gene signatures in human lung transplants.

Transplantation of lungs from donation after circulatory death (DCD) in addition to donation after brain death (DBD) became routine worldwide to address the global organ shortage. The development of ex vivo lung perfusion (EVLP) for donor lung assessment and repair contributed to the increased use of DCD lungs. We hypothesise that a better understanding of the differences between lungs from DBD and DCD donors, and between EVLP and directly transplanted (non-EVLP) lungs, will lead to the discovery of the injury-specific targets for donor lung repair and reconditioning. Tissue biopsies from human DBD (n=177) and DCD (n=65) donor lungs, assessed with or without EVLP, were collected at the end of cold ischaemic time. All samples were processed with microarray assays. Gene expression, network and pathway analyses were performed using R, Ingenuity Pathway Analysis and STRING. Results were validated with protein assays, multiple logistic regression and 10-fold cross-validation. Our analyses showed that lungs from DBD donors have upregulation of inflammatory cytokines and pathways. In contrast, DCD lungs display a transcriptome signature of pathways associated with cell death, apoptosis and necrosis. Network centrality revealed specific drug targets to rehabilitate DBD lungs. Moreover, in DBD lungs, tumour necrosis factor receptor-1/2 signalling pathways and macrophage migration inhibitory factor-associated pathways were activated in the EVLP group. A panel of genes that differentiate the EVLP from the non-EVLP group in DBD lungs was identified. The examination of gene expression profiling indicates that DBD and DCD lungs have distinguishable biological transcriptome signatures.

Ex Vivo Lung Perfusion for Circulatory Death Donors in Lung Transplantation

There is marked variability in the behavior of different transplant centers regarding utilization of ex vivo lung perfusion (EVLP) for donation after circulatory death (DCD) lung donors. While interest in utilization of DCD lungs is growing as a means to expand the lung donor pool, the utility and indications for EVLP of DCD lungs is not well defined. Our objectives were to determine the baseline differences between DCD lungs that received EVLP and those that did not as well as the effect of EVLP on survival following DCD LTx. Using the United Network for Organ Sharing (UNOS) database, we retrospectively reviewed all adult patients undergoing first-time isolated LTx between 2015 and 2017. Chi-squared tests and Wilcoxon-Mann-Whitney tests were used to investigate the differences in baseline characteristics between DCD and EVLP-DCD donors. Survival of DCD and EVLP-DCD transplants was analyzed using Kaplan Meier curves with a log rank test and a Cox proportional hazards model. A total of 5,866 patients met inclusion criteria and 218 (3.7%) LTx recipients received a DCD LTx. Of those receiving DCD lungs, 30 (13.7%) underwent EVLP prior to transplantation. Centers performing DCD LTx utilized EVLP-DCD with great variability; EVLP-DCD rates ranged from 0%-53.8% by center. Compared to DCD donors without EVLP, EVLP-DCD donors did not differ significantly by cause of death, age, gender, history of cigarette use, or PaO2/FiO2 ratio (Figure A). Recipients of EVLP-DCD lungs had equivalent survival to those who received DCD lungs as well as non-DCD lungs (Figure B). DCD donation alone should not be an indication for EVLP. DCD and EVLP-DCD lungs were nearly identical in terms of donor lung characteristics including PaO2/FiO2 ratio. DCD donor lungs, which provide equivalent survival to conventional LTx, should undergo EVLP selectively.

Expanding the Donor Pool by Extended DCD Lung Donation

Almost half of the lung transplantations (LTx) in the Netherlands are performed with donation after circulatory death (DCD) donors. However, over 25% of DCD procedures are cancelled because excessive length of the agonal phase: >120 minutes. Indeed, in 2017 4/20 and in 2018 4/19 suitable DCD lung procedures in our center were cancelled due to a prolonged agonal phase. Pig models have shown that a prolonged agonal phase does not compromise lung quality. Due to the possibility to test lungs by EVLP the length of the agonal phase might be even less important in DCD LTx. We therefore composed a protocol of DCD LTx irrespective of length of the agonal phase and present the first LTx using this protocol (fig 1). Informed consent is obtained from patients on the LTx waiting list from our center to receive extended DCD (eDCD) lungs. All suitable DCD lung donors from our center are included. When a donor exceeds the 2 hour agonal phase limit for regular DCD donation, the eDCD protocol starts and donation is limited to the lungs. When a donor passes away, after five minutes 'no touch', the donor is transported to the operating theater for intubation. Lungs are ventilated and procured <3 hours. Ventilation is done according to Dutch DCD guidelines. All eDCD lungs are evaluated with EVLP. If suitable, according to the EVLP protocol, the lungs are transplanted. Using our eDCD protocol, on the deadline date of abstract submission, we performed our first extended DCD LTx. The agonal phase was almost 3 hours. We propose to present the results of this and future eDCD LTx and discuss the benefits, difficulties and logistics of eDCD at the ISHLT at Montreal 2020.

Perfusate Metabolite Profiles in Ex Vivo Lung Perfusion Predict Graft Quality of Lungs Donated after Circulatory Death

The use of donation after circulatory death (DCD) lungs may expand the donor pool for lung transplantation. However, due to the variable quality of DCD lungs, many undergo ex vivo lung perfusion (EVLP) for evaluation. DCD lung assessment is challenging but can be greatly aided by biomarker readouts that predict transplant outcome. In this study, we performed a metabolomics analysis of human DCD lungs to identify predictive metabolites that may be clinically useful during EVLP assessment. EVLP perfusate was collected from 20 DCD lungs and evaluated on EVLP. Lungs were divided into 2 groups: 1) Good outcome (n = 11), with no primary graft dysfunction grade 3 (PGD3); 2) Poor outcome (n = 9), including PGD3 (n = 5) and declined lungs due to poor performance on EVLP (n = 4). Metabolomics profiling of perfusate samples taken at 1 h and 4 h of EVLP were processed by liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Bioinformatics and pathway analysis were performed with MetaboAnalyst webserver. In total, 275 metabolites were detected. Five metabolites at 1 h and 16 metabolites at 4 h of EVLP were significantly different between good and poor outcome groups (FDR < 0.05, fold change (FC) ≥1.5). Multiple amino acid levels were significantly higher and lipid levels were significantly lower in poor outcome lungs at 1 h and 4 h of EVLP. Metabolomic pathway analysis revealed that aminoacyl-tRNA biosynthesis, and glycine, serine and threonine pathways were affected. While several metabolites achieved statistical significance, it was notable that lysine and ornithine levels separated good vs. bad outcome groups at 1 h and 4 h with minimal overlap (Fig 1). We identified significantly altered metabolites in DCD lungs that distinguish between good and poor recipient outcomes. Future biomarker validation via a larger sample size is necessary prior to their use to optimally select post-EVLP DCD donor lungs for transplantation.

Alterations in Perfusate Leukocyte Populations are Associated with Donor Mode of Death and the Outcome of Ex Vivo Lung Perfusion

Lung transplantation (LTx) is limited by the scarcity of suitable donor lungs. One option to expand the donor pool is the use of donation after circulatory death (DCD) lungs. Additionally, ex vivo lung perfusion (EVLP) allows for evaluation and treatment of donor lungs prior to LTx. There are limited data describing the cellular, specifically leukocyte populations in EVLP perfusate, and their link to donor mode of death. We hypothesized that EVLP perfusate leukocytes differ between DCD and neurological determination of death (NDD) lungs, and between lungs accepted and declined for transplant. EVLP perfusates were sampled hourly from clinical EVLP cases until termination. Perfusate cells were separated and cryopreserved. The first and last available perfusate from lungs accepted (n = 10 NDD and n = 10 DCD) and declined (n = 10 NDD and n = 10 DCD) for LTx were selected and stained with flow cytometry panels to characterize major leukocyte populations. Lymphoid cells form the majority of perfusate cells (Fig A). B cells were significantly higher in declined lungs regardless of mode of donor death (Fig B). CD4+ memory T cells (CD3+ CD4+ CD45RO+) and activated CD8+ T cells (CD3+ CD8+ CD25+) were elevated in the DCD lung perfusates (Fig C). In all groups, CD163hi, HLA-DR+ monocytes were observed at first available perfusate and diminished at the end of EVLP, while neutrophils were low in the first perfusate sample but increased significantly by the end of EVLP (Fig D). Interestingly, leukocyte populations in EVLP perfusate differ between mode of donor death, with lower levels of B cells associated with lungs accepted for transplant, and certain T cell subsets over-represented in DCD lungs. While no significant changes were observed in myeloid cells, their kinetics over time vary based on cell type. Future studies will be required to determine the sources of these cell populations and whether they are involved in the pathogenesis of lung injury prior to transplant.

Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death

Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs. A porcine DCD and EVLP model was utilized. Two groups (n = 4 per group) of DCD lungs were randomized to target EVLP flows of 40% (high-flow) or 20% (low-flow) predicted cardiac output based on 100 ml/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion. After transplant, left lung-specific pulmonary vein partial pressure of oxygen was significantly higher in the low-flow group at 3 and 4 hours of reperfusion (3-hour: 496.0 ± 87.7 mm Hg vs. 252.7 ± 166.0 mm Hg, p = 0.017; 4-hour: 429.7 ± 93.6 mm Hg vs. 231.5 ± 178 mm Hg, p = 0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8 ± 9.4 ml/cm H2O vs. 10.2 ± 3.5 ml/cm H2O, p = 0.022) and throughout all subsequent time points in the low-flow group. After reperfusion, lung wet-to-dry weight ratio (7.1 ± 0.7 vs. 8.8 ± 1.1, p = 0.040) and interleukin-1β expression (927 ± 300 pg/ng protein vs. 2,070 ± 874 pg/ng protein, p = 0.048) were significantly reduced in the low-flow group. EVLP of DCD lungs with low-flow targets of 20% predicted cardiac output improves lung function, reduces edema, and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.

Donor Lung Referrals for Lung Transplantation: A ‘Behind The Scenes’ View

Australia's increasing organ donor rate has translated to increased lung donor referrals and subsequent lung transplantation (LTx). The LTx sector attempts to utilise as many organs as possible-but in reality, not all are used. This analysis aims to assess the utility and efficiency of donor lung referrals to the Alfred Hospital. All Donatelife Australia donor lung referrals for the year 2017 were analysed retrospectively. From a total of 440 lung referrals, 220 were local from the state of Victoria (population 6.4 million) and 220 from the Rest-of-Australia (ROA). Sixty-eight per cent (68%) of Victorian and 48% of the ROA were via the donation after circulatory death (DCD) pathway. One hundred and two (102) LTx were performed: 32 represent 21% of 149 Victorian and 8% of 106 ROA DCD donors, 70 represent 54% of the Victorian and 24% of the ROA donation after brain death (DBD) donors. Eighty per cent (80%) of all donors aged <35 and 30% >35 years were used or potentially useable. Thirteen per cent (13%) of DCD and 44% of DBD donors aged >65 years were used. Logistical and resource considerations, around the retrieval of older DCD lungs, are a significant issue. At 11.1 LTx per-million-population the Alfred has one of the highest lung donor conversion and LTx activity rates in the world. The Australian donor lung pool could still be further extended by focussing effort and logistics on optimising DBD referrals. Additional resources (staff and transport), tighter referral criteria, and the use of extended warm ischaemic time donors could increase particularly DCD recovery rates.

Unfavorable Donor after Cardiac Death Characteristics in Lung Transplantation: An Analysis of the UNOS Registry

Purpose Despite growing evidence that donation after circulatory death (DCD) lung transplants have comparable survival outcomes and primary graft dysfunction rates to donation after brain death (DBD), DCD continues to be underutilized in the US. We examined DCD donor characteristics associated with non-utilization. Methods In this retrospective study, all adult (age ≥ 18) DCD donors who donated at least one organ for transplant between 1993 and 2017 were analyzed from the UNOS registry. DBD donors and DCD donors who did not successfully donate any organ were excluded. Organ disposition per lung and reasons for non-use of donor lungs were identified. The primary outcome of interest was donor characteristics that correlated with lower transplant rates. Results A total of 12,627 DCD donors met inclusion criteria. Of 25,254 lungs available for analysis, 2.8% were transplanted and 68% were discarded primarily due to poor organ function and ischemic time constraints. Notably, consent was not requested in 15.3% of DCD offers with non-heart beating donor being the leading reason for consent not requested (77.7%). DCD lungs were less likely to be transplanted if the donor had a higher BMI (mean 26.6 vs. 25.4, p=0.008), smoking history (23.7% vs. 7.5%, p Conclusion The underutilization of DCD lungs in the US remains consistent with prior studies, in contrast with 30-40% utilization in several other countries. The most common reasons for non-transplantation of DCD lungs include modifiable pre-donor factors, such as lack of consent request, as well as donor factors, including hypoxemia. Interventions to increase consent and optimize DCD donor conditions, such as selective use of ex vivo lung perfusion, may increase utilization of DCD organs and expand the donor pool.

Lung Transplantation from Donation after Circulatory Death Donors Following Portable Ex-Vivo Lung Perfusion: Post-Hoc Analysis of OCS Lung EXPAND Trial

Purpose Donation after circulatory death (DCD) donors and ex-vivo lung perfusion (EVLP) both share the potential to attenuate lung shortage. We report the experience of the OCS Lung EXPAND trial on lung transplantation following EVLP for DCD pulmonary grafts. Methods OCS Lung EXPAND is an international multi-center clinical trial aiming to evaluate the safety and effectiveness of the OCS™ Lung to recruit, preserve and assess donor lungs that may not meet current standard donor lung acceptance criteria for transplantation. We performed a post-hoc analysis of the DCD donors. Data are reported as mean±standard deviation. Results Out of 93 OCS perfused donor lungs, 32 (34%) were DCD grafts of which 26 (81% utilization rate) were transplanted. Recipient age was 55±11 years; 18 male/ 8 female; indications were emphysema (n=11), fibrosis (n=5), cystic fibrosis (n=4), other (n=6); donor age was 40±14 years; 17 male/ 9 female. EVLP time was 389±127 min, final PO2/FiO2 was 403±84 mmHg. Pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and peak airway pressure (PAWP) remained stable during EVLP (Figure 1). Intensive care unit and hospital stay was 12±8 and 31±25 days, respectively. Time until first extubation was 5±8 days. Ratio of primary graft dysfunction grade 3 at 24, 48 and 72 hours was 15%, 8% and 8%, respectively. With a follow-up of 1 year, no acute rejections occurred and 1 patient developed chronic lung allograft dysfunction. Two patients died at 73 and 139 days post-transplant due to hyperkalemia and esophageal perforation; 24 patients were alive, resulting in a 1-year patient survival of 92%. Conclusion Portable EVLP is a safe and effective modality to assess functional performance of DCD lungs prior to transplantation, resulting in a high utilization rate and good clinical outcome.

Ex Vivo Assessment of Porcine Donation After Circulatory Death Lungs That Undergo Increasing Warm Ischemia Times.

BackgroundIncreased utilization of donation after circulatory death (DCD) lungs may help alleviate the supply/demand mismatch between available donor organs and lung transplant candidates. Using an established porcine DCD model, we sought to determine the effect of increasing warm ischemia time (WIT) after circulatory arrest on lung function during ex vivo lung perfusion (EVLP).MethodsPorcine donors (n = 15) underwent hypoxic cardiac arrest, followed by 60, 90, or 120 minutes of WIT before procurement and 4 hours of normothermic EVLP. Oxygenation, pulmonary artery pressure, airway pressure, and compliance were measured hourly. Lung injury scores were assessed histologically after 4 hours of EVLP.ResultsAfter EVLP, all 3 groups met all the criteria for transplantation, except for 90-minute WIT lungs, which had a mean pulmonary artery pressure increase greater than 15%. There were no significant differences between groups as assessed by final oxygenation capacity, as well as changes in pulmonary artery pressure, airway pressure, or lung compliance. Histologic lung injury scores as well as lung wet-to-dry weight ratios did not significantly differ between groups.ConclusionsThese results suggest that longer WIT alone (up to 120 minutes) does not predict worse lung function at the conclusion of EVLP. Expanding acceptable WIT after circulatory death may eventually allow for increased utilization of DCD lungs in procurement protocols.

Donation after Brain Death versus Donation after Circulatory Death: Lung Donor Management Issues.

Lung transplantation (LTx) has traditionally been limited by a lack of suitable donor lungs. With the recognition that lungs are more robust than initially thought, the size of the donor pool of available lungs has increased dramatically in the past decade. Donation after brain death (DBD) and donation after circulatory death (DCD) lungs, both ideal and extended are now routinely utilized. DBD lungs can be damaged. There are important differences in the public's understanding, legal and consent processes, intensive care unit strategies, lung pathophysiology, logistics, and potential-to-actual donor conversion rates between DBD and DCD. Notwithstanding, the short- and long-term outcomes of LTx from any of these DBD versus DCD donor scenarios are now similar, robust, and continue to improve. Large audits suggest there remains a large untapped pool of DCD (but not DBD) lungs that may yet further dramatically increase lung transplant numbers. Donor scoring systems that might predict the donor conversion rates and lung quality, the role of ex vivo lung perfusion as an assessment and lung resuscitation tool, as well as the potential of donor lung quality biomarkers all have immense promise for the clinical field.

Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death

BackgroundLung ischemia-reperfusion (IR) injury after transplantation as well as acute shortage of suitable donor lungs are two critical issues impacting lung transplant patients. This study investigates the anti-inflammatory and immunomodulatory role of human mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) to attenuate lung IR injury and improve of ex-vivo lung perfusion (EVLP)-mediated rehabilitation in donation after circulatory death (DCD) lungs.MethodsC57BL/6 wild-type (WT) mice underwent sham surgery or lung IR using an in vivo hilar-ligation model with or without MSCs or EVs. In vitro studies used primary iNKT cells and macrophages (MH-S cells) were exposed to hypoxia/reoxygenation with/without co-cultures with MSCs or EVs. Also, separate groups of WT mice underwent euthanasia and 1 h of warm ischemia and stored at 4 °C for 1 h followed by 1 h of normothermic EVLP using Steen solution or Steen solution containing MSCs or EVs.ResultsLungs from MSCs or EV-treated mice had significant attenuation of lung dysfunction and injury (decreased edema, neutrophil infiltration and myeloperoxidase levels) compared to IR alone. A significant decrease in proinflammatory cytokines (IL-17, TNF-α, CXCL1 and HMGB1) and upregulation of keratinocyte growth factor, prostaglandin E2 and IL-10 occurred in the BAL fluid from MSC or EV-treated mice after IR compared to IR alone. Furthermore, MSCs or EVs significantly downregulated iNKT cell-produced IL-17 and macrophage-produced HMGB1 and TNF-α after hypoxia/reoxygenation. Finally, EVLP of DCD lungs with Steen solution including MSCs or EVs provided significantly enhanced protection versus Steen solution alone. Co-cultures of MSCs or EVs with lung endothelial cells prevents neutrophil transendothelial migration after exposure to hypoxia/reoxygenation and TNF-α/HMGB1 cytomix.ConclusionsThese results suggest that MSC-derived EVs can attenuate lung inflammation and injury after IR as well as enhance EVLP-mediated reconditioning of donor lungs. The therapeutic benefits of EVs are in part mediated through anti-inflammatory promoting mechanisms via attenuation of immune cell activation as well as prevention of endothelial barrier integrity to prevent lung edema. Therefore, MSC-derived EVs offer a potential therapeutic strategy to treat post-transplant IR injury as well as rehabilitation of DCD lungs.

Expanding the donor lung pool: how many donation after circulatory death organs are we missing?

BackgroundThe number of patients with end-stage pulmonary disease awaiting lung transplantation is at an all-time high, while the supply of available organs remains stagnant. Utilizing donation after circulatory death (DCD) donors may help to address the supply-demand mismatch. The objective of this study is to determine the potential donor pool expansion with increased procurement of DCD organs from patients who die at hospitals. Material and methodsThe charts of all patients who died at a single, rural, quaternary-care institution between August 2014 and June 2015 were reviewed for lung transplant candidacy. Inclusion criteria were age <65 y, absence of cancer and lung pathology, and cause of death other than respiratory or sepsis. ResultsA total of 857 patients died within a 1-year period and were stratified by age: pediatric <15 y (n = 32, 4%), young 15-64 y (n = 328, 38%), and old >65 y (n = 497, 58%). Those without cancer totaled 778 (90.8%) and 512 (59%) did not have lung pathology. This leaves 85 patients qualifying for DCD lung donation (pediatric n = 10, young n = 75, and old n = 0). Potential donors were significantly more likely to have clear chest X-rays (24.3% versus 10.0%, P < 0.0001) and higher mean PaO2/FiO2 (342.1 versus 197.9, P < 0.0001) compared with ineligible patients. ConclusionsA significant number of DCD lungs are available every year from patients who die within hospitals. We estimate the use of suitable DCD lungs could potentially result in a significant increase in the number of lungs available for transplantation.

An experimental study of the recovery of injured porcine lungs with prolonged normothermic cellular exvivo lung perfusion following donation after circulatory death.

Donation after circulatory death (DCD) is an underused source of donor lungs. Normothermic cellular exvivo lung perfusion (EVLP) is effective in preserving standard donor lungs but may also be useful in the preservation and assessment of DCD lungs. Using a model of DCD and prolonged EVLP, the effects of donor warm ischemia and postmortem ventilation on graft recovery were evaluated. Adult male swine underwent general anesthesia and heparinization. In the control group (n=4), cardioplegic arrest was induced and the lungs were procured immediately. In the four treatment groups, a period of agonal hypoxia was followed by either 1h of warm ischemia with (n=4) or without (n=4) ventilation or 2h of warm ischemia with (n=4) or without (n=4) ventilation. All lungs were studied on an EVLP platform for 24h. Hemodynamic measures, compliance, and oxygenation on EVLP were worse in all DCD lungs compared with controls. Hemodynamics and compliance normalized in all lungs after 24h of EVLP, but DCD lungs demonstrated impaired oxygenation. Normothermic cellular EVLP is effective in preserving and monitoring of DCD lungs. Early donor postmortem ventilation and timely procurement lead to improved graft function.