Dual Hypothermic Oxygenated Machine Perfusion in Liver Transplantation Using Allografts From Donors After Brain Death

Summary

This will be a randomized study on the effects of hypothermic oxygenated machine perfusion in patients undergoing liver transplantations from donors after brain death with allocation of patients to either end-ischemic hypothermic oxygenated machine perfusion group (at least 2 hours of allograft perfusion at 12 degrees Celsius though hepatic artery and portal vein prior to implantation) or simple cold storage group in a 1:3 ratio. The primary outcome measure of the study will be model for early graft dysfunction (MEAF) score. A total number of 104 patients, including 26 in the hypothermic perfusion group and 78 in simple cold storage group will be included. Data on potential risk factors for worse allograft function and increased ischemia-reperfusion injury will be collected perioperatively. Circulating levels of proinflammatory cytokines (IL-2, IL-10, TNFα), nuclear damage (HMGB-1, 8-OHdG), serum activity of transaminases, gamma-glutamyl-transpeptidase, bilirubin concentration, and INR will be assessed in the perioperative period. Wedge allograft biopsies will be performed 90 minutes post-reperfusion to evaluate activation of innate immunity (TLR4), activation of endothelium (vWF, P-selectin), hepatocyte necrosis, hepatocyte apoptosis (TUNEL assay), ATP content, and oxidative damage (malondialdehyde content). Further, wedge biopsies will be performed at the end of simple cold storage and at the beginning and after two hours of perfusion to determine steatosis and ATP content. During the perfusion, perfusate samples will be periodically tested for lactate, sodium, and potassium concentration, CO2 partiall pressure, and flavin mononucleotide concentration. Patients will be closely monitored in the postoperative period for allograft function and secondary end-points: 2-year recipient and graft survival, 2-year incidence of biliary complications, and 90-day complication rate. Both groups will be compared with respect to the primary and secondary end-points, circulating levels of IL-2, IL-10, TNFα, HMGB-1, 8-OHdG, activity of transaminases and gamma-glutamyl-transpeptidase, and findings in post-reperfusion allograft biopsies. Further, changes of hepatic steatosis and hepatic ATP content during perfusion will be evaluated, and the results of perfusate analyses will be tested as predictors of allograft function in the post-transplant period.

Conditions

• Liver Cirrhosis
• Liver Tumor
• Liver Transplant Failure and Rejection

Interventions

PROCEDURE

Hypothermic oxygenated machine perfusion

Hypothermic oxygenated perfusion using a Liver Assist device (Organ Assist, Groningen, the Netherlands). Temperature of the perfusate will be set to 12 degrees Celsius. Dedicated cannulas will be placed in the aorta for arterial perfusion and in the portal vein for portal perfusion. Pressure will be set at 25 mmHg for arterial line (pulsatile flow, 30 mmHg systolic pressure and 20 mmHg diastolic pressure, 60 beats per minute) and 3 mmHg for portal line (continuous flow). 100% oxygen will be supplied to the oxygenators with a flow of 500 ml / min or higher, in order to achieve pO2 of at least 450 mmHg.

PROCEDURE

Simple cold storage

Following back-table preparation, the allograft will either be transferred to the operating room for implantation or stored in preservation solution at 4 degrees Celsius in a refrigerator

Sponsors & Collaborators

• National Science Centre, Poland

  collaborator OTHER_GOV

• Medical University of Warsaw

  lead OTHER

Principal Investigators

• Michal Grat, MD, PhD · Medical University of Warsaw

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-04-05

Primary Completion

2022-04-30

Completion

2024-04-30

Countries

• Poland

Study Locations