Pilot, Open, Randomized, Prospective Trial for Normothermic Machine Perfusion Evaluation in Liver Transplantation From Older Donors

Abstract

Ex situ normothermic machine perfusion (NMP) might minimize ischemia/reperfusion injury (IRI) of liver grafts. In this study, 20 primary liver transplantation recipients of older grafts (≥70 years) were randomized 1:1 to NMP or cold storage (CS) groups. The primary study endpoint was to evaluate graft and patient survival at 6 months posttransplantation. The secondary endpoint was to evaluate liver and bile duct biopsies; IRI by means of peak transaminases within 7 days after surgery; and incidence of biliary complications at month 6. Liver and bile duct biopsies were collected at bench surgery, end of ex situ NMP, and end of transplant surgery. Interleukin (IL) 6, IL10, and tumor necrosis factor α (TNF-α) perfusate concentrations were tested during NMP. All grafts were successfully transplanted. Median (interquartile range) posttransplant aspartate aminotransferase peak was 709 (371-1575) IU/L for NMP and 574 (377-1162) IU/L for CS (P = 0.597). There was 1 hepatic artery thrombosis in the NMP group and 1 death in the CS group. In NMP, we observed high TNF-α perfusate levels, and these were inversely correlated with lactate (P < 0.001). Electron microscopy showed decreased mitochondrial volume density and steatosis and an increased volume density of autophagic vacuoles at the end of transplantation in NMP versus CS patients (P < 0.001). Use of NMP with older liver grafts is associated with histological evidence of reduced IRI, although the clinical benefit remains to be demonstrated. The use of very old donors in liver transplantation (LT)is showing favorable results, (1) but this practice is not universally implemented (2) because of concerns about a higher risk for primary nonfunction (PNF), delayed graft function (DGF), (3) and worse longterm graft survival. (4) In our recent series of octogenarian donors, we reported favorable overall longterm results, and we found that hepatitis C virus (HCV) recurrence and ischemic-type biliary lesions (ITBLs) were 2 independent causes of graft loss in this population. (5) Although availability of direct antiviral agents is reducing the impact of donor age on HCV recurrence, (6) prevention of ischemia/reperfusion injury (IRI) is pivotal to the practice of elderly donor LT and for donation after circulatory death (DCD) donors. (7,8) Even though the concept of the ideal donor is well defined, (4,9) the definition of extended criteria donors remains controversial. Increased donor age contributes to a higher risk ghinOlfi et al.

Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial

“…Simplicity, outcome benefits for liver and kidney transplantation and low-costs equipment are the winning points of our HOPE system. The safety of our new machine perfusion system was confirmed by the absence of adverse events and by the observation that liver hypothermic oxygenation could be effective to improve graft function, similarly to other reported series in the setting of normothermic blood perfusion 30,33 .…”

Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials

“…In two studies, there was a period of initial SCS approximately 4 hours prior to NMP. 49,50 Red blood cells were the oxygen transporter in all the mentioned studies in association with either Gelofusine or FFP or Steen solution.…”

“…To do this, NMP requires the use of oxygenators and the presence of oxygen transporters in the perfusate, with human red blood cells being the most common oxygen transporter used in current protocols. [45][46][47][48][49][50] Unlike the HMP configuration, in NMP protocols, liver grafts are normally dually perfused through the portal vein and the hepatic artery. The maintenance of the organ metabolic activity during NMP offers the possibility to assess organ viability by measuring many metabolic parameters, such as lactate clearance, pH and glycemic levels, as well as bile production and its constitution.…”

“…A patient in the NMP group received a second graft due to hepatic artery thrombosis 10 days after LT. On the other hand, one patient in the SCS group died 31 days after LT due to an episode of intestinal occlusion that evolved into sepsis shock. 49 A single-center study from the Cleveland group tested the use of fresh-frozen plasma (FFP) as a constituent of the perfusate in association with RBC units. Using a noncommercial custom-made perfusion device, Liu et al compared the outcome of 21 LT performed with NMP-preserved livers to a historical series of LT performed with livers preserved by SCS in a 1:4 ratio.…”

Machine Perfusions in Liver Transplantation: The Evidence‐Based Position Paper of the Italian Society of Organ and Tissue Transplantation

“…Quality of evidence in the selected articles for RCT according to Jadad scale Nasralla et al (29) (Multicenter, Europe) 3 Ghinolfi et al (38) (Pisa, Italy) 3…”