Prolonged dual hypothermic oxygenated machine preservation (DHOPE-PRO) in liver transplantation: study protocol for a stage 2, prospective, dual-arm, safety and feasibility clinical trial

Abstract

IntroductionEnd-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally.Methods and analysisThis is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00–3:59 hour) or to the control arm (4:00–15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation.Ethics and disseminationThe protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation.Trial registration numberNL8740.

Prolonged preservation by hypothermic machine perfusion facilitates logistics in liver transplantation: A European observational cohort study

“…www.trial regis ter.nl). 37 We conclude that good outcomes can be achieved after trans- Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CVVH, continuous veno-venous hemofiltration; DBD, donation after brain death; DCD, donation after circulatory death; mpEAD, machine perfusion early allograft dysfunction. a Hemodynamic instability after reperfusion defined as post-reperfusion syndrome with a decrease in mean arterial pressure >30% below baseline, lasting for ≥1 min, within 5 min after reperfusion (Aggarwal criteria 6 ), or as vasoplegia with a fall in mean arterial pressure on reperfusion to <50 mmHg either sustained >30 min and/or requiring >0.15 µg/kg/min norepinephrine, >2 U/h vasopressin, or infusion of epinephrine (significant hypotension resistant to pressors).…”

“…To further investigate the safety and feasibility of prolonged DHOPE, we have initiated a prospective, pseudo‐randomized, clinical trial (IDEAL‐D stage 2) comparing prolonged DHOPE (≥4 h) to regular short‐term (1–2 h) DHOPE (DHOPE‐PRO trial, NTR NL8740; http://www.trialregister.nl). 37 …”

Impact of Machine Perfusion on the Immune Response After Liver Transplantation – A Primary Treatment or Just a Delivery Tool

“…Of note, prolonged HOPE of >4hrs was also shown after more than 10hrs of cold storage in extended criteria donor livers in Germany and in combination with high MELD recipients in Brasil (95). A prospective study on prolonged HOPE is currently ongoing in the Netherlands to confirm the safe prolongation to compensate logistical issues (96).…”

Association between Hepatocellular Carcinoma Recurrence and Graft Size in Living Donor Liver Transplantation: A Systematic Review

“…Interestingly, the HOPE approach delivering high-perfusate oxygen levels under cold conditions was found to reprogram mitochondria and to prevent later IRI-associated inflammation after liver implantation. Various mechanistic and clinical studies exist together with four randomized controlled trials [ 62 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. Based on the underlying mechanism of protection, this perfusion technique reduces posttransplant complications, improves graft survival and reduces re-transplantation rates [ 76 , 82 ].…”