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Patients who are transplanted with an ECD liver after pretreatment with a liver perfusion machine

Patients who are not offered a liver transplantation during the inclusion period

Patients who receive an ECD liver after an ex-vivo liver perfusion where the liver has been tested for function and approved according to international functional criteria (Groeningen criteria)

Liver transplantation

Søren E Pischke, MD, PhD

Today, it is difficult to predict liver function after transplantation and therefore livers where poor function is assumed (marginal livers) become discarded. The study aim is to increase the number of available donor livers, especially for liver cancer patients, by pre-treating and testing marginal ones (extended criteria donor (ECD) livers) liver on a liver perfusion machine. A liver perfusion machine can simulate liver transplantation and enables functional/quality testing before transplantation. The machine will hopefully also make marginal livers more functional by reducing ischemia- \& reperfusion injury. A marginal donor liver is perfused ex situ with oxygenated blood from a blood donor on a machine. The liver can be tested here for function using internationally recognized criteria. At the same time, the investigators will carry out analyzes with microdialysis which can give a better picture of organ function and damage. Additionally, various samples of the liver and perfusate will be collected. Liver that achieves criteria for transplantation will be offered to the recipient.

The study is a single-center, prospective, open-label cohort study designed to determine the efficacy of liver perfusion of marginal ECD livers on a perfusion machine before liver transplantation. Donor livers will be preserved with standard cooling followed by three perfusion modes (Dual hypothermic oxygenated machine perfusion (DHOPE) / Controlled oxygenated rewarming (COR) / Normothermic machine perfusion (NMP)), a method used internationally to pre-treating marginal livers before liver transplantation and which able testing of function and quality before a transplantation is performed. Only livers that fulfill international criteria (Groningen criteria) will be approved for Ltx. In this study microdialysis will be used to monitoring the liver during machine perfusion and up to 14 days in the postoperative course to monitor the function of the liver. The hypothesis is that microdialysis will provide a better prediction of liver function than the existing Groeningen criteria. The investigators expect that most included patients, who receive ECD livers perfused on a machine, will receive a postoperative well-functioning liver graft which entails a significant survival benefit. The study is designed as a cohort study because included patients have a very poor prognosis (median overall survival of approx. 6 months) and others treatment options are lacking. The primary objective is to establish definitive, objective criteria for pre-transplant liver function by defining a threshold value for microdialysis parameters (especially lactate) between donor livers that will restore function and those that will not during ex vivo machine perfusion in ECD livers, which are superior to established criteria (Groeningen and Viability testing and transplantation of marginal livers (VITTAL) criteria)). The primary endpoint is microdialysis lactate level between donor livers after 4 hours of normothermic machine perfusion in ECD livers.

The follow-up period is 12 months.

Single center, prospective, open, observational study

Liver Transplantation After ex Vivo Liver Perfusion

Liver Transplantation After ex Vivo Liver Perfusion - The EVOLVE Study

Due to Norwegian laws individual participant data are not shared

Body mass index of donor (kilogram/meter2)

Estimation of warm ischemia time (minutes)

Estimation of cold ischemia time (minutes)

Donor risk index score - Increasing donor risk index is associated with higher discard rates among deceased donor livers procured for transplant. Low value of 1= best prognosis. High value of 40 = worst prognosis

Lactate level in microdialysate from hilar plate after normothermic machine perfusion in extended criteria donors livers.

Microdialysis lactate level in donor liver tissue after 2.5 hours of normothermic machine perfusion in extended criteria donors livers.

Microdialysis lactate level in donor liver tissue after 2 hours of Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Microdialysis pyruvate level in donor liver tissue after 2 hours of Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Microdialysis glycerol level in donor liver tissue after 2 hours of Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Microdialysis glucose level in donor liver tissue after 2 hours of Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Microdialysis lactate level in donor livers tissue after 1 hour of controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Microdialysis glycerol level in donor livers tissue after 1 hour of controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Microdialysis glucose level in donor livers tissue after 1 hour of controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Microdialysis pyruvate level in donor livers tissue after 1 hour of controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Microdialysis glucose level in donor liver tissue after 2.5 hours of normothermic machine perfusion in extended criteria donors livers.

Microdialysis glucose level in donor liver tissue after 4 hours of normothermic machine perfusion in extended criteria donors livers.

Microdialysis pyruvate level in donor liver tissue after 2.5 hours of normothermic machine perfusion in extended criteria donors livers.

Microdialysis pyruvate level in donor liver tissue after 4 hours of normothermic machine perfusion in extended criteria donors livers.

Microdialysis glycerol level in donor liver tissue after 2.5 hours of normothermic machine perfusion in extended criteria donors livers.

Microdialysis glycerol level in donor liver tissue after 4 hours of normothermic machine perfusion in extended criteria donors livers.

Microdialysis lactate level from bile after normothermic machine perfusion - 4 hours in extended criteria donors livers.

Microdialysis lactate level from bile after normothermic machine perfusion - 2.5 hours in extended criteria donors livers.

Microdialysis glucose levels from bile after normothermic machine perfusion - 4 hours in extended criteria donors livers.

Microdialysis glucose levels from bile after normothermic machine perfusion - 2.5 hours in extended criteria donors livers.

Microdialysis pyruvate levels from bile after normothermic machine perfusion - 4 hours in extended criteria donors livers.

Microdialysis pyruvate levels from bile after normothermic machine perfusion - 2.5 hours in extended criteria donors livers.

Glycerol levels from bile after normothermic machine perfusion - 4 hours in extended criteria donors livers.

Glycerol levels from bile after normothermic machine perfusion - 2.5 hours in extended criteria donors livers.

Glycerol levels from bile after controlled oxygenated rewarming machine perfusion - 1 hour - in extended criteria donors livers.

Glucose levels from bile after controlled oxygenated rewarming machine perfusion - 1 hour - in extended criteria donors livers.

Lactate levels from bile after controlled oxygenated rewarming machine perfusion - 1 hour - in extended criteria donors livers.

Pyruvate levels from bile after controlled oxygenated rewarming machine perfusion - 1 hour - in extended criteria donors livers.

Pyruvate levels from bile after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion - 2 hours - in extended criteria donors livers.

Glycerol levels from bile after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion - 2 hours - in extended criteria donors livers.

Lactate levels from bile after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion - 2 hours - in extended criteria donors livers.

Glucose levels from bile after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion - 2 hours - in extended criteria donors livers.

Bile gas pH - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas pH - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Lactate - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Lactate - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Glucose - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Glucose - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas O2 - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas O2 - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas CO2 - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas CO2 - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas HCO3 - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas HCO3 - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas BE - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Ischemia/reperfusion injury in liver biopsies, graded according to Ali JM et al, Liver transplant 2015; nil, mild, moderate, and severe. - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Ischemia/reperfusion damage in liver biopsies, graded according to Suzuki score (Tian Y et al, Stem Cell Research \& Therapy, 2016); score 0, 1, 2, 3, (0=none, 4= severe) - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Ischemia/reperfusion injury in liver biopsies, graded according to Tian Y et al et al, Liver transplant 2015; nil, mild, moderate, and severe. - after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Ischemia/reperfusion damage in liver biopsies, graded according to Suzuki score (Tian Y et al, Stem Cell Research \& Therapy, 2016); score 0, 1, 2, 3, (0=none, 4= severe) - after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Ischemia/reperfusion injury in liver biopsies, graded according to Ali JM et al, Liver transplant 2015; nil, mild, moderate, and severe. - before machine perfusion in extended criteria donors livers

Ischemia/reperfusion damage in liver biopsies, graded according to Suzuki score (Tian Y et al, Stem Cell Research \& Therapy, 2016); score 0, 1, 2, 3, (0=none, 4= severe) - before machine perfusion in extended criteria donors livers

Ischemia/reperfusion injury in liver biopsies, graded according to Ali JM et al, Liver transplant 2015; nil, mild, moderate, and severe - after controlled oxygenated rewarming machine perfusion - 1 hour in extended criteria donors livers

Ischemia/reperfusion damage in liver biopsies, graded according to Suzuki score (Tian Y et al, Stem Cell Research \& Therapy, 2016); score 0, 1, 2, 3, (0=none, 4= severe) - after controlled oxygenated rewarming machine perfusion - 1 hour in extended criteria donors livers

Ischemia/reperfusion injury in liver biopsies, graded according to Ali JM et al, Liver transplant 2015; nil, mild, moderate, and severe. - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Ischemia/reperfusion damage in liver biopsies, graded according to Suzuki score (Tian Y et al, Stem Cell Research \& Therapy, 2016); score 0, 1, 2, 3, (0=none, 4= severe) - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas BE - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas SO2- 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas SO2- 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Hb - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Hb - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Na - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Na - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas K - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas K - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Ca - 4 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas Ca - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Markers of injury, inflammation - 2.5 hours after normothermic machine perfusion in extended criteria donors livers.

Bile gas lactate 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Markers of injury, inflammation 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas Glucose 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas pH 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas O2 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas CO2 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas HCO3 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas SO2 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas Hemoglobin 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas Na 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas K 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas Ca 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Bile gas BE 2 hours after Dual-end-ischemic Hypothermic Oxygenated Perfusion machine perfusion in extended criteria donors livers.

Markers of injury, inflammation 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas lactate 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas Glucose 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas pH 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas O2 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas CO2 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas HCO3 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas BE 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas SO2 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas hemoglobin 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas Na 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas K 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Bile gas Ca 1 hour after controlled oxygenated rewarming machine perfusion in extended criteria donors livers.

Perfusate gas Ca during machine perfusion in extended criteria donors livers.

Perfusate gas pH during machine perfusion in extended criteria donors livers.

Perfusate gas SO2 during machine perfusion in extended criteria donors livers.

Perfusate gas O2 during machine perfusion in extended criteria donors livers.

Perfusate gas CO2 during machine perfusion in extended criteria donors livers.

Perfusate gas K during machine perfusion in extended criteria donors livers.

Perfusate gas Na during machine perfusion in extended criteria donors livers.

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