Ex vivo rehabilitation of non–heart-beating donor lungs in preclinical porcine model: Delayed perfusion results in superior lung function

Abstract

Objectives Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and potential for rehabilitation of donor lungs with extended warm-ischemic times is unknown. This study compares the efficacy of different treatment strategies for uncontrolled non-heart-beating donor lungs. Methods Mature swine underwent hypoxic arrest followed by 60 minutes of no-touch warm-ischemia. Lungs were harvested and flushed with 4°C Perfadex®. Three groups (n=5/group) were stratified according to preservation method: cold-static preservation (CSP: 4 hrs 4°C storage), immediate EVLP (I-EVLP: 4 hrs EVLP at 37°C), and delayed EVLP (D-EVLP: 4 hrs cold storage followed by 4 hrs EVLP). EVLP groups were perfused with Steen solution™ supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. Lungs then underwent allotransplantation and four hours of recipient reperfusion prior to allograft assessment for resultant ischemia-reperfusion injury. Results Donor blood oxygenation (PO2:FiO2) prior to euthanasia was not different between groups. Oxygenation after transplantation was significantly higher in the D-EVLP group compared to the I-EVLP or CSP groups. Mean airway pressure, pulmonary artery pressure, and expression of IL-8, IL-1β, and TNF-α were all significantly reduced in the D-EVLP group. Importantly, post-transplant oxygenation exceeded acceptable clinical levels only in D-EVLP lungs. Conclusions Uncontrolled non-heart-beating donor lungs with extended warm-ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP present in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of non-heart-beating donor lungs.

Lung Transplantation With Donation After Circulatory Determination of Death Donors and the Impact of Ex Vivo Lung Perfusion

“…Firstly, the refinement of donor selection was illustrated by the study of Sanchez et al, which showed that, despite similar clinical characteristics and alveolocapillary barrier properties after the period of cardiac arrest and warm ischemia, donor lungs that did not receive prearrest heparinization had significantly worse physiological performance on EVLP compared to lungs from donors that received pre-arrest heparin (32). Secondly, the normothermic and metabolically active environment restored by EVLP provides an ideal platform for therapeutic manipulation of the DCDD organ (33)(34)(35)(36). EVLP-treated lungs showed better posttransplant lung function and less microthrombi formation compared to no-EVLP lungs in a DCDD experimental study (37).…”

Users’ guide to the surgical literature: how to assess a noninferiority trial

“…4 You follow the PICOT format, which serves as the starting point for identification of important key words used in the search process: 5 • Population: heart transplant patients • Intervention: heart transplantation with ex-vivo perfusion • Comparison: heart transplantation with cold storage • Outcome: patient survival and graft survival • Time horizon: 30 days after transplant You then conduct a literature search in PubMed Clinical Queries using the search terms "heart transplantation" AND "ex-vivo perfusion" AND "cold storage," using the "Therapy" and "Broad" filters. You identify 10 articles: 7 ex-vivo human/animal studies, [6][7][8][9][10][11][12] 1 nonrandomized clinical study, 13 1 review 14 and 1 RCT. 15 The RCT addresses your research question and has the benefit of being level-I evidence.…”

Mechanisms of Lung Ischemia-Reperfusion Injury and Donor Lung Rehabilitation by Ex Vivo Lung Perfusion

“…Our group and others have demonstrated in preclinical models that DCD lungs with extended warm ischemic times (up to 60 minutes) may be rehabilitated by EVLP to an acceptable state for transplantation [106,120]. These results have been furthered by clinical studies in which initially rejected human donor lungs have been rehabilitated to acceptable standards for transplantation [121,122].…”

“…Steen solution within the circuit was gradually warmed from 4°C to 37°C through the circuit water bath, and EVLP continued for 60 minutes. Steen solution perfusate was supplemented with 10,000 IU heparin, 500mg cefazolin and 500mg methylprednisolone per 1500mL, modeling preclinical and clinical EVLP protocols [103,105]. Steen solution was also supplemented with vehicle (DMSO) for the EVLP group or with ATL1223 (30nM) for the ATL1223-treated group.…”

“…shown that EVLP-mediated delivery of A2AR agonist is a potentially effective strategy for the rehabilitation of Maastricht category I DCD lungs [105]. Thus, the purpose of the current study was twofold: 1) to utilize a novel murine EVLP model to test the hypothesis that administration of a selective A2AR agonist during EVLP provides a superior strategy to EVLP with Steen solution alone for the rehabilitation of DCD lungs and 2) to assess the gene expression profile in NHBD lungs after EVLP.…”