Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial

Abstract

Background and aims: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial.

Approach and results: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4).

Conclusions: HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

Graphical abstract

FIGURE 1

Clinical trial design and randomization. Enrollment, subject randomization design, and study inclusion for the modified intent-to-treat and per-protocol analysis cohorts. Abbreviations: HMP-O₂, hypothermic oxygenated machine perfusion; mITT, modified intent-to-treat; PILOT, Perfusion to Improve Liver Outcomes in Transplantation; PP, per-protocol; SCS, static cold storage.

FIGURE 2

Donor liver allograft perfusion with the Lifeport Liver Transporter portable hypothermic oxygenated machine perfusion device. (A) Following backtable preparation of the liver, atraumatic cannulas are inserted into the donor portal vein and hepatic artery. (B) Perfusion inflow tubing is connected to the portal vein and hepatic artery for continuous hypothermic infusion of Vasosol perfusion solution. (C) Representative photo of the device pump head and device display, which provides continuous information regarding line pressures, flow, and temperature during perfusion. (D) Representative photo of the closed device ready for transport of the donor liver.

FIGURE 3

Noninferiority analysis of the risk difference for incidence of EAD following liver transplant (primary outcome). Risk difference and the upper limit of the 95% CI are plotted. The dashed line at 0% represents the threshold for no difference, while the dotted line at 7.5% represents the threshold of the noninferiority margin. The gray shaded area denotes the range for results within the noninferiority margin. The upper limit of the 95% CI for all patients falls within the noninferiority margin, establishing noninferiority. The upper limit of the 95% CI for the ECD subgroup exceeds the noninferiority margin. Abbreviation: ECD, extended criteria donors.

FIGURE 4

Graft and patient outcomes following liver preservation with HMP-O₂ and SCS in the first year following liver transplant. (A) The cumulative risk of graft failure demonstrates a decreased incidence following liver transplant with HMP-O₂ (blue line) compared with SCS (red line), but difference was not statistically significant (p=0.140). (B) Cumulative graft survival and (C) cumulative patient survival are not significantly different within the first year following liver transplant. Abbreviations: HMP-O₂, hypothermic oxygenated machine perfusion; SCS, static cold storage.

FIGURE 5

Adverse events in recipients of livers preserved by HMP-O₂ or SCS. (A) Violin plot demonstrating the distribution of AEs and SAEs occurring in each patient cohort. Thick black line represents the median value, and thin white line represents the quartiles. (B) The proportion of AEs classified as mild (green), moderate (yellow), and severe (red) for all AEs, infection-related AEs, and noninfection-related AEs. Proportion is related to the number of AEs for each subclassification per cohort. (C) The cumulative (additive) %incidence of major noninfection-related post-transplant complications in patients for each cohort is shown. Each bar subdivision represents the proportion of patients in the cohort develop the complication specified by the stacked colored bars. Abbreviations: AEs, adverse events; HMP-O₂, hypothermic oxygenated machine perfusion; LT, liver transplant; SAE, serious adverse event; SCS, static cold storage.