Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial

Am J Transplant. 2022 Oct;22(10):2401-2408 doi: 10.1111/ajt.17115.

Hypothermic Oxygenated Perfusion (HOPE) of the liver can reduce the incidence of early allograft dysfunction (EAD) and failure in extended criteria donors (ECD) grafts, although data from prospective studies are very limited. In this monocentric, open-label study, from December 2018 to January 2021, 110 patients undergoing transplantation of an ECD liver graft were randomized to receive a liver after HOPE or after static cold storage (SCS) alone. The primary endpoint was the incidence of EAD. The secondary endpoints included graft and patient survival, the EASE risk score, and the rate of graft or other graft-related complications. Patients in the HOPE group had a significantly lower rate of EAD (13% vs. 35%, p = .007) and were more frequently allocated to the intermediate or higher risk group according to the EASE score (2% vs. 11%, p = .05). The survival analysis confirmed that patients in the HOPE group were associated with higher graft survival one year after LT (p = .03, log-rank test). In addition, patients in the SCS group had a higher re-admission and overall complication rate at six months, in particular cardio-vascular adverse events (p = .04 and p = .03, respectively). HOPE of ECD grafts compared to the traditional SCS preservation method is associated with lower dysfunction rates and better graft survival.

CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is an interesting and well-conducted trial in ECD liver transplantation. Livers were randomised to standard static cold storage (SCS) or to a period of Hypothermic Oxygenated Perfusion (HOPE), using the Vitasmart device (Bridge to Life, DG, USA). Organs in the HOPE group had a period of SCS of 4-5 hours on average prior to starting HOPE for 2-3 hours on average. No organ was discarded during perfusion. The study was single centre and designed with a prior power calculation to determine sample size. The primary endpoint was Early Allograft Dysfunction (EAD) using a well-established composite definition. There was a significant reduction in EAD with HOPE compared to SCS (13% versus 35%) and also a significant reduction in re-transplantation (0% versus 11%). This form of HOPE, using just portal vein perfusion in ECD liver transplantation, is associated with better early allograft function, which is very likely to impact on longer term function and graft survival.
Expert Review
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating 4
Review: The shortage of suitable donors to meet demand has resulted in increasing use of extended criteria donor (ECD) organs to try to address the mismatch. ECD donor organs are known to be more at risk of adverse post-operative outcomes due to increased vulnerability to ischaemia-reperfusion injury. In attempts to counter this additional risk, there has been a great deal of interest in novel perfusion technologies to recondition, repair and assess grafts prior to transplant. Such technologies can be used in the donor (normothermic regional perfusion, NRP) or ex-vivo (hypothermic oxygenated perfusion, HOPE or normothermic machine perfusion, NMP). The technologies differ in their simplicity/ease of use, ability to assess organ viability and the duration of safe perfusion. In a recent paper in the American Journal of Transplantation, Ravaioli and colleagues report a single centre randomised controlled trial of HOPE after static cold storage (SCS) versus SCS alone in ECD liver grafts (1). 110 recipients were randomised and followed for a median of 473 days. The authors report a significant reduction in the risk of the primary endpoint of early allograft dysfunction with HOPE, from 35% to 13%. This reduction is similar in magnitude to that seen in previous studies of NMP (2) and HOPE in DCD livers (3). Unlike in these previous studies there was no difference in incidence of biliary complications, most likely as this study does not include DCD livers which are at higher risk for ischaemic-type biliary lesions. Perhaps the most striking finding is that graft survival was significantly higher in the HOPE arm of the study, a finding not seen in the larger multicentre studies of HOPE or NMP. A detailed breakdown of causes and timings of graft loss is not provided, making the role of perfusion in this finding difficult to interpret. Another interesting finding is the numerically lower incidence of acute rejection in HOPE livers. This has been seen previously with use of HOPE in kidney transplantation (4), and may offer at least a partial explanation for the difference in graft survival seen. Overall, these findings support previous studies in both liver and kidney transplantation that HOPE is a safe, simple and effective method of preservation which may be beneficial in marginal donor organs. References 1. Ravaioli M, Germinario G, Dajti G et al. Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2022; 2. Nasralla D, Coussios CC, Mergental H et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018; 557: 50. 3. van Rijn R, Schurink IJ, de Vries Y et al. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial. The New England Journal of Medicine 2021; 384: 1391. 4. Jochmans I, Brat A, Davies L et al. Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial. Lancet (London, England) 2020; 396: 1653.
Methodological quality
Jadad score 2
Allocation concealment NO
Data analysis PER PROTOCOL
Study Details
Aims: The aim of this study was to compare the effect of hypothermic oxygenated perfusion (HOPE) versus static cold storage (SCS) in extended criteria donor (ECD) liver transplantation.
Interventions: Participants undergoing transplantation of an ECD liver graft were randomly assigned to receive a liver after HOPE or after SCS alone.
Participants: 135 potential ECD liver grafts were randomised, of which 110 were used for liver transplantation.
Outcomes: The primary outcome was the incidence of early allograft dysfunction (EAD). The secondary outcome were patient survival, graft survival, the early allograft failure simplified estimation (EASE) risk score, and the rate of graft or other graft-related complications.
Follow Up: 1 year
Funding: Non-industry funding
Publication type: Randomized Controlled Trial, Randomised Controlled Trial
Trial registration: ClinicalTrials.gov - NCT03837197
Organ: Liver
Language: English
Author email: mrava1@hotmail.com
MeSH terms: Graft Survival; Humans; Liver Transplantation; Living Donors; Organ Preservation; Perfusion; Postoperative Complications; Prospective Studies; Tissue Donors