Why a trial on cold OR warm end-ischemic perfusion ?

In 2019, approximately 1865 patients were listed for liver transplantation in Germany, however only 831 transplantations were performed due to organ shortage. Liver allografts that would have previously been deemed un-suitable for transplantation have nowadays become an essential part of the organ pool and are being transplanted routinely in extended criteria donors (ECD) programs.

The common practice of conventional cold storage (CCS) organ preservation has changed very little since the initial introduction in the late 1980s. CCS relies on hypothermia to decelerate metabolism and reduce the oxygen demand in order to prolong the time of ischemia without rapid functional graft impairment. While metabolism does not cease completely during CCS, a significant amount of anaerobic metabolism continues at a low rate, depleting cellular adenosine triphosphate (ATP) levels and thereby deregulating ionic homeostasis. ECD allografts poorly tolerate extended periods of cold storage. In recent years, the main research focus has therefore been the development of improved organ preservation techniques. Machine perfusion (MP) has been recognized as a promising strategy in the context of OLT using ECD allografts. While CCS only prolongs storage time and limits the damage sustained during the period of cold ischemia, MP even appears to be capable of reversing some of these effects. Currently, two main MP paradigms prevail: hypothermic oxygenated MP (HOPE) aims to combine the positive effects of hypothermia observed in classical cold storage (e.g. technical simplicity, relative safety, decreased metabolism) with the positive effects of dynamic oxygenated preservation (e.g. controlled sheer stress mediated gene activation, removal of metabolites, transport of oxygen and ATP recharging). Normothermic perfusion (NMP) aims at re-equilibration of cellular metabolism by preserving the organ at physiological temperatures whilst ensuring sufficient oxygen and nutrient supply. While past and current clinical trials were designed to compare different MP approaches with CCS as the clinical standard, a direct comparison between different end-ischemic MP techniques (HOPE versus NMP) is still lacking.

The purpose of this study is to test the effects of end-ischemic NMP versus end-ischemic HOPE technique in a multicentre prospective randomized controlled clinical trial (RCT) on ECD liver grafts in DBD liver-transplantation (HOPE-NMP). Two-hundred-thirteen (n = 213) human whole organ liver grafts will be submitted to either NMP (n = 85) or HOPE (n = 85) directly before implantation and going to be compared to a control-group of patients (n = 43) transplanted with static cold storage preserved ECD-allografts. Primary (surgical complications as assessed by the comprehensive complication index [CCI]) and secondary (graft- and patient survival, hospital costs, hospital stay) endpoints are going to be analysed.

HOPE-NMP is an investigator initiated, open-label, phase-II, prospective multi-centre randomised controlled trial on the effects of HOPE and NMP versus CCS on ECD-allografts in donation after brain death (DBD) OLT. Recruitment for the HOPE-NMP trial was initiated in January 2021. First results are expected in 2024.

HOPE-NMP is supported by federal and local research funds. The study is performed at three major European Liver Transplantation Centers (Charité Universitätsmedizin Berlin, Germany; University Hospital Heidelberg, Germany; University Hospital Hannover, Germany) and is currently recruiting at 2 sites.