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Lungs donated after circulatory death and prolonged warm ischemia are transplanted successfully after enhanced ex vivo lung perfusion using adenosine A2B receptor antagonism.

ABSTRACT: OBJECTIVE:The current supply of acceptable donor lungs is not sufficient for the number of patients awaiting transplantation. We hypothesized that ex vivo lung perfusion (EVLP) with targeted drug therapy would allow successful rehabilitation and transplantation of donation after circulatory death lungs exposed to 2 hours of warm ischemia. METHODS:Donor porcine lungs were procured after 2 hours of warm ischemia postcardiac arrest and subjected to 4 hours of cold preservation or EVLP. ATL802, an adenosine A2B receptor antagonist, was administered to select groups. Four groups (n = 4/group) were randomized: cold preservation (Cold), cold preservation with ATL802 during reperfusion (Cold + ATL802), EVLP (EVLP), and EVLP with ATL802 during ex vivo perfusion (EVLP + ATL802). Lungs subsequently were transplanted, reperfused, and assessed by measuring dynamic lung compliance and oxygenation capacity. RESULTS:EVLP + ATL802 significantly improved dynamic lung compliance compared with EVLP (25.0 ± 1.8 vs 17.0 ± 2.4 mL/cmH2O, P = .04), and compared with cold preservation (Cold: 12.2 ± 1.3, P = .004; Cold + ATL802: 10.6 ± 2.0 mL/cmH2O, P = .002). Oxygenation capacity was highest in EVLP (440.4 ± 37.0 vs Cold: 174.0 ± 61.3 mm Hg, P = .037). No differences in oxygenation or pulmonary edema were observed between EVLP and EVLP + ATL802. A significant decrease in interleukin-12 expression in tissue and bronchoalveolar lavage was identified between groups EVLP and EVLP + ATL802, along with less neutrophil infiltration. CONCLUSIONS:Severely injured donation after circulatory death lungs subjected to 2 hours of warm ischemia are transplanted successfully after enhanced EVLP with targeted drug therapy. Increased use of lungs after uncontrolled donor cardiac death and prolonged warm ischemia may be possible and may improve transplant wait list times and mortality.

SUBMITTER: Charles EJ

PROVIDER: S-EPMC6743073 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Lungs donated after circulatory death and prolonged warm ischemia are transplanted successfully after enhanced ex vivo lung perfusion using adenosine A2B receptor antagonism.

Charles Eric J EJ Mehaffey J Hunter JH Sharma Ashish K AK Zhao Yunge Y Stoler Mark H MH Isbell James M JM Lau Christine L CL Tribble Curtis G CG Laubach Victor E VE Kron Irving L IL

The Journal of thoracic and cardiovascular surgery 20170412 5

<h4>Objective</h4>The current supply of acceptable donor lungs is not sufficient for the number of patients awaiting transplantation. We hypothesized that ex vivo lung perfusion (EVLP) with targeted drug therapy would allow successful rehabilitation and transplantation of donation after circulatory death lungs exposed to 2 hours of warm ischemia.<h4>Methods</h4>Donor porcine lungs were procured after 2 hours of warm ischemia postcardiac arrest and subjected to 4 hours of cold preservation or EVL ...[more]

PMID: 28483262

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Project description:Experimental studies have suggested that end-ischaemic dual hypothermic oxygenated machine perfusion (DHOPE) may restore hepatocellular energy status and reduce reperfusion injury in donation after circulatory death (DCD) liver grafts. The aim of this prospective case-control study was to assess the safety and feasibility of DHOPE in DCD liver transplantation.In consecutive DCD liver transplantations, liver grafts were treated with end-ischaemic DHOPE. Outcome was compared with that in a control group of DCD liver transplantations without DHOPE, matched for donor age, donor warm ischaemia time, and recipient Model for End-stage Liver Disease (MELD) score. All patients were followed for 1 year.Ten transplantations involving liver grafts treated with DHOPE were compared with 20 control procedures. There were no technical problems. All 6-month and 1-year graft and patient survival rates were 100 per cent in the DHOPE group. Six-month graft survival and 1-year graft and patient survival rates in the control group were 80, 67 and 85 per cent respectively. During DHOPE, median (i.q.r.) hepatic adenosine 5'-triphosphate (ATP) content increased 11-fold, from 6 (3-10) to 66 (42-87) µmol per g protein (P = 0·005). All DHOPE-preserved livers showed excellent early function. At 1 week after transplantation peak serum alanine aminotransferase (ALT) and bilirubin levels were twofold lower in the DHOPE group than in the control group (ALT: median 966 versus 1858 units/l respectively, P = 0·006; bilirubin: median 1·0 (i.q.r. 0·7-1·4) versus 2·6 (0·9-5·1) mg/dl, P = 0·044). None of the ten DHOPE-preserved livers required retransplantation for non-anastomotic biliary stricture, compared with five of 20 in the control group (P = 0·140).This clinical study of end-ischaemic DHOPE in DCD liver transplantation suggests that the technique restores hepatic ATP, reduces reperfusion injury, and is safe and feasible. RCTs with larger numbers of patients are warranted to assess the efficacy in reducing post-transplant biliary complications.

Project description:Liver ischemia-reperfusion injury (IRI) is a known risk factor for the postoperative outcome of patients undergoing liver surgery/transplantation. Attempts to protect from organ damage require multidisciplinary strategies and are of emerging interest in view of patients with higher age and American Society of Anesthesiology status. Ischemic preconditioning has been successfully applied to prevent from IRI during liver resection/transplantation. Because even short periods of ischemia during preconditioning inevitably lead to hypoxia and formation of anti-inflammatory/cytoprotective acting adenosine, we reasoned that short nonischemic hypoxia also protects against hepatic IRI.Mice underwent hypoxic preconditioning (HPC) by breathing 10% oxygen for 10 min followed by 10 min of 21% oxygen before left liver lobe ischemia (45 min) and reperfusion (4 hr). The interactions of hypoxia?adenosine?adenosine receptors were tested by pharmacologic antagonism at adenosine receptor (AR) sites in wild-type mice and in mice with genetic deletions at the A1, A2A, A2B, and A3 ARs. Hepatocellular damage, inflammation, and metabolic effects were quantified by enzyme activities, cytokines, liver myeloperoxidase, blood adenosine, and tissue AMP, respectively.Hepatoprotection by HPC was significant in wild-type and A1, A2A, and A3 AR knockout mice as quantified by lower alanine aminotransferase serum activities, cytokine levels, histologic damage scores, tissue myeloperoxidase concentrations, and preserved AMP concentrations. Protection by HPC was blunted in mice pretreated with the A2B AR antagonist MRS1754 or in A2B AR knockout mice.Because liver protective effects of HPC are negated when the A2B receptor is nonfunctional, the hypoxia?adenosine?A2B receptor pathway plays a critical role in the prevention of warm IRI in vivo. Hypoxic activation of this pathway warrants use of selective A2B AR agonists or even intermittent hypoxia (e.g., in deceased organ donors) to protect from liver IRI.

Project description:BackgroundLivers derived from donation after circulatory death (DCD) are increasingly accepted for transplantation. However, DCD livers suffer additional donor warm ischemia, leading to biliary injury and more biliary complications after transplantation. It is unknown whether oxygenated machine perfusion results in better preservation of biliary epithelium and the peribiliary vasculature. We compared oxygenated hypothermic machine perfusion (HMP) with static cold storage (SCS) in a porcine DCD model.MethodsAfter 30 min of cardiac arrest, livers were perfused in situ with HTK solution (4°C) and preserved for 4 h by either SCS (n = 9) or oxygenated HMP (10°C; n = 9), using pressure-controlled arterial and portal venous perfusion. To simulate transplantation, livers were reperfused ex vivo at 37°C with oxygenated autologous blood. Bile duct injury and function were determined by biochemical and molecular markers, and a systematic histological scoring system.ResultsAfter reperfusion, arterial flow was higher in the HMP group, compared to SCS (251±28 vs 166±28 mL/min, respectively, after 1 hour of reperfusion; p = 0.003). Release of hepatocellular enzymes was significantly higher in the SCS group. Markers of biliary epithelial injury (biliary LDH, gamma-GT) and function (biliary pH and bicarbonate, and biliary transporter expression) were similar in the two groups. However, histology of bile ducts revealed significantly less arteriolonecrosis of the peribiliary vascular plexus in HMP preserved livers (>50% arteriolonecrosis was observed in 7 bile ducts of the SCS preserved livers versus only 1 bile duct of the HMP preserved livers; p = 0.024).ConclusionsOxygenated HMP prevents arteriolonecrosis of the peribiliary vascular plexus of the bile ducts of DCD pig livers and results in higher arterial flow after reperfusion. Together this may contribute to better perfusion of the bile ducts, providing a potential advantage in the post-ischemic recovery of bile ducts.

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Lungs donated after circulatory death and prolonged warm ischemia are transplanted successfully after enhanced ex vivo lung perfusion using adenosine A2B receptor antagonism.

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Lungs donated after circulatory death and prolonged warm ischemia are transplanted successfully after enhanced ex vivo lung perfusion using adenosine A2B receptor antagonism.

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