Novel Real-time Prediction of Liver Graft Function During Hypothermic Oxygenated Machine Perfusion Before Liver Transplantation :

Translational studies in liver transplantation often require an endpoint of graft function or dysfunction beyond graft loss. Prior definitions of early allograft dysfunction (EAD) vary, and none have been validated in a large multicenter population in the Model for End-Stage Liver Disease (MELD) era. We examined an updated definition of EAD to validate previously used criteria, and correlated this definition with graft and patient outcome. We performed a cohort study of 300 deceased donor liver transplants at 3 U.S. programs. EAD was defined as the presence of one or more of the following previously defined postoperative laboratory analyses reflective of liver injury and function: bilirubin >or=10mg/dL on day 7, international normalized ratio >or=1.6 on day 7, and alanine or aspartate aminotransferases >2000 IU/L within the first 7 days. To assess predictive validity, the EAD definition was tested for association with graft and patient survival. Risk factors for EAD were assessed using multivariable logistic regression. Overall incidence of EAD was 23.2%. Most grafts met the definition with increased bilirubin at day 7 or high levels of aminotransferases. Of recipients meeting the EAD definition, 18.8% died, as opposed to 1.8% of recipients without EAD (relative risk = 10.7 [95% confidence interval: 3.6, 31.9] P < 0.0001). More recipients with EAD lost their grafts (26.1%) than recipients with no EAD (3.5%) (relative risk = 7.4 [95% confidence interval: 3.4, 16.3] P < 0.0001). Donor age and MELD score were significant EAD risk factors in a multivariate model. In summary a simple definition of EAD using objective posttransplant criteria identified a 23% incidence, and was highly associated with graft loss and patient mortality, validating previously published criteria. This definition can be used as an endpoint in translational studies aiming to identify mechanistic pathways leading to a subgroup of liver grafts with clinical expression of suboptimal function. (c) 2010 AASLD.

Normothermic ex situ liver perfusion might allow viability assessment of livers before transplantation. Perfusion characteristics were studied in 47 liver perfusions, of which 22 resulted in transplants. Hepatocellular damage was reflected in the perfusate transaminase concentrations, which correlated with posttransplant peak transaminase levels. Lactate clearance occurred within 3 hours in 46 of 47 perfusions, and glucose rose initially during perfusion in 44. Three livers required higher levels of bicarbonate support to maintain physiological pH, including one developing primary nonfunction. Bile production did not correlate with viability or cholangiopathy, but bile pH, measured in 16 of the 22 transplanted livers, identified three livers that developed cholangiopathy (peak pH 7.5). In the 11 research livers where it could be studied, bile pH > 7.5 discriminated between the 6 livers exhibiting >50% circumferential stromal necrosis of septal bile ducts and 4 without necrosis; one liver with 25‐50% necrosis had a maximum pH 7.46. Liver viability during normothermic perfusion can be assessed using a combination of transaminase release, glucose metabolism, lactate clearance, and maintenance of acid‐base balance. Evaluation of bile pH may offer a valuable insight into bile duct integrity and risk of posttransplant ischemic cholangiopathy.

Due to ethical rules in most countries, long ischemia times are unavoidable prior to organ procurement of donors without a heartbeat, which can cause early graft failure after liver transplantation or late biliary strictures. Hypothermic oxygenated machine perfusion, used prior to graft implantation, may rescue these high risk organs. Eight patients with end stage liver diseases received human livers, obtained after controlled cardiac death (Maastricht category III), with a median donor warm ischemia time of 38 min, followed by a standard cold flush and static storage at 4 °C. Hypothermic oxygenated perfusion (HOPE) was applied for 1-2h prior to implantation through the portal vein. The HOPE-perfusate was cooled at 10 °C and oxygenated (pO2 60 kPa) using an ECOPS device (Organ Assist®). Perfusion pressure was maintained below 3 mmHg. Each machine perfused liver graft disclosed excellent early function after transplantation. The release of liver enzymes and kidney function, as well as ICU and hospital stays were comparable or better than in matched liver grafts from brain death donors. No evidence of intrahepatic biliary complications could be documented within a median follow up of 8.5 months. This is the first report on cold machine perfusion of human liver grafts obtained after cardiac arrest and subsequent transplantation. Application of HOPE appears well tolerated, easy-to-use, and protective against early and later injuries. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.