Letter to the Editor: Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation (PILOT)
Authors: Zoltan Czigany, Aghnia J. Putri, Christoph W. Michalski, Arianeb Mehrabi
Journal: Hepatology (2024)

To the editor, We read with great interest the findings of the recent US randomized controlled trial (RCT) on hypothermic machine perfusion with preoxygenation-Hypothermic Machine Perfusion (HMP)-O2 published in Hepatology.1 Over a 3-year period, 6 RCTs have been published on HMP in liver transplantation (LT), involving 794 recipients and 330 perfused allografts in total (Figure 1).2 Few areas in LT research, other than machine perfusion, exhibit such rapid clinical development.FIGURE 1: Main characteristics and differences of the 6 published randomized controlled trials on hypothermic oxygenated and preoxygenated liver machine perfusion. Important differences regarding the aspects of trial design and characteristics between the 6 published randomized controlled trials initiated from the Netherlands, Germany, Italy, Switzerland, Poland, and the United States on hypothermic machine perfusion of human liver allografts before liver transplantation. The figure depicts study-specific values for the HMP/HOPE groups. Created with BioRender.com. Abbreviations: ALT, alanine aminotransferase; CD, Clavien-Dindo Classification; DBD, donation after brain death; DCD, donation after circulatory death; (D)-HOPE, (dual) hypothermic oxygenated machine perfusion; DRI, donor risk index; EAD, early allograft dysfunction; ECD, extended criteria donation; ET-DRI, Eurotransplant donor risk index; MEAF, Model for Early Allograft Function; MELD, Model of End-Stage Liver Disease; min, minutes; SCS, static cold storage; yr, years.Several questions arise concerning this significant manuscript: First, Panayotova et al claim in their manuscript title and text that they employed hypothermic oxygenated machine perfusion, which is more commonly known as HOPE.1,3 However, the study perfusion protocol refers to a "pre-oxygenated" perfusate with oxygen insufflation over 20 minutes before the allograft was connected to the device, without further oxygen administration during the actual perfusion. This is somewhat misleading in its current form. The title and text should have provided a clear distinction from conventional HOPE used in all previous RCTs, where continuous oxygenation was maintained by a membrane oxygenator throughout the entire perfusion (eg,"hypothermic machine perfusion with a pre-oxygenated perfusate"). Second, the authors state that the trial was sponsored directly by the device manufacturer (OrganRecoverySystems) and was primarily designed as an FDA-PivotalTrial for marketing approval rather than to detect the superiority of HMP-O2. In the trial, the binary primary endpoint (early allograft dysfunction) confirmed noninferiority but failed to establish superiority. From the academic point of view, this represents a notable limitation and potential source of bias. This trial is unique among all HMP/HOPE trials in LT, being the only one with a noninferiority design and commercial focus. Given the cost-intensive and resource-intensive nature of Machine Perfusion compared to simple cold storage, trials with a clinical-academic focus should strive to show the superiority of this potent technology rather than just noninferiority, as demonstrated.4 Third, the trial demonstrates characteristic differences compared to most previous RCTs on HMP/HOPE in LT, such as using relatively short preservation times and high-quality allografts with low donor risk (Figure 1). These, coupled with the noninferiority design, resulted in modest intertreatment differences and predictable findings. In conclusion, we would like to commend this pioneering group led by Professor Guarrera for meticulously executing and reporting this RCT. Despite the accumulated evidence, joint efforts and future trials are still necessary to eliminate various design flaws identified in each of the previous RCTs (Figure 1).