Reply: Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation (PILOT)
Authors: Keri E. Lunsford, Guergana G. Panayotova, James V. Guarrera
Journal: Hepatology (2024)

We appreciate the comments by Czignay and colleagues regarding the Perfusion to Improve Liver Outcomes in Transplantation trial.1 Our senior author (James V. Guarrera) was first to report ex vivo hypothermic machine perfusion in clinical liver transplants worldwide.2 HOPE/D-HOPE was subsequently described with the introduction of continuous oxygenation. Our protocol, abbreviated as HMP-O2, (hypothermic oxygenated machine perfusion) employs an oxygenation protocol distinct from HOPE/D-HOPE. Considering our >20 years of experience in perfusion, we believe that the novel nomenclature is appropriate and adds this distinction. The LifePort Liver Transporter utilizes Vasosol perfusion solution, with enhanced protection against ischemia-reperfusion injury, allowing oxygen "precharging." This improves pump portability, given regulatory restrictions on compressed gas transportation. Preclinical verification indicates oxygen delivery (>100 mm Hg) >90 minutes and persistent tissue oxygen tension during perfusion.3 Liver mitochondrial energetic recovery and ATP-loading occur early during oxygenated perfusion,4 priming stressed mitochondria. Decreased metabolic activity of cold preservation sustains cryoprotective effects. To date, no studies have assessed threshold oxygen tension or delivery duration for optimal outcomes. With regard to study design, US Food and Drug Administration (FDA) regulatory requirements differ substantially from other countries. Limited federal funding is available for novel device safety/efficacy assessment, so, industry sponsorship is standard, including other organ perfusion devices. To avoid bias, the sponsor had no role in data analysis, interpretation, or manuscript writing.1 FDA Pivotal trials require "the least burdensome" approach.5 Center outcomes in transplant trials must also align with Scientific Registry of Transplant Recipients metrics to maintain program accreditation. Noninferiority design met these requirements. This Pivotal Trial design included broad inclusion and minimal donor exclusions to optimize enrollment. Centers were encouraged to employ standard organ acceptance practices. While most donors were standard criteria, 38.1% met the extended criteria donor threshold (Liver Donor Risk Index >1.70).1 European randomized control trials targeted donation after cardiac death/extended criteria donor donors exclusively. Perfusion time differences are due to device portability and center logistics. Preperfusion static cold storage was shorter in PILOT, as 43% of livers were immediately perfused, unlike exclusive end-ischemic perfusion in European randomized control trials.1 Median perfusion duration was actually longer in PILOT compared to European randomized control trials. We have now entered the unrestricted continued access phase and have performed 117 additional transplants with HMP-O2. Given initial findings of noninferiority and decreased early allograft failure, center practice changes have resulted in increased HMP-O2 to facilitate expanded organ acceptance and improved logistics. For the first 100 cases, the median Liver Donor Risk Index is 1.876 (IQR 1.615–2.158), with 68.0% having Liver Donor Risk Index >1.70. There has been no primary nonfunction. We are excited by continued research regarding the efficacy and optimal conditions for HMP-O2 and anticipate that continued experience with the LifePort Liver Transporter will expand utilization and improve liver transplant outcomes.