Normothermic Machine Perfusion: A New World Deserving Careful Exploration

To the Editor: We read with interest “Preliminary Single-Center Canadian Experience of Human Normothermic Ex Vivo Liver Perfusion: Results of a Clinical Trial,” by Bral et al. (1Bral M Gala-Lopez B Bigam D et al.Preliminary single-center Canadian experience of human normothermic ex vivo liver perfusion: Results of a clinical trial.Am J Transplant. 2016; (doi: 10.1111/ajt.14049.)PubMed Google Scholar). The authors compared their experience transplanting 10 livers using normothermic machine perfusion (NMP) with 30 historic controls matched on five different characteristics. The primary objective of the study was to “assess safety of NMP in continuous liver preservation.” No statistically significant differences were detected in 30-day patient survival (primary outcome). Among the secondary outcomes, only intensive care unit and hospital stay were statistically significantly more prolonged in the NMP group. One graft was lost because of technical problems during perfusion. We congratulate the authors for their innovative endeavor on a technology that holds the potential to revolutionize the field of organ preservation. Important aspects of this study, which deserve attention, pertain to the methodology used to design and execute the trial. Although the study was defined by the authors as a safety trial, NMP livers sustained a median overall preservation time (defined as cold ischemia time [CIT] + NMP time) three times more than historic controls (NMP group median 13 h [range 5–27] vs. static cold storage group median 4 h [range 1–15]). Moreover, 40% of the livers in the study group were donation after cardiac death (DCD), one being outside of the program-accepted age limit (55 years of age). By significantly extending the total organ preservation time, including a high proportion of marginal livers (DCDs), and expanding the indications for graft acceptance, the authors assumed the scientifically unproved (yet) notion that NMP provides superior preservation outcomes. We believe that incorporating scientifically unsupported methods in a safety study exposed the perfused grafts, the transplant patients, and the NMP technology to unnecessary risks. A very marginal DCD was lost due to an unrecognized twist of the portal vein (properly identified by the device monitoring system). We believe that safety studies should be designed keeping in mind the inherent learning curve present in every new technology and particularly NMP. This could be achieved in preliminary studies by perfusing only organs that would be accepted for transplantation regardless of the preservation modality used (2Selzner M Goldaracena N Echeverri J et al.Normothermic ex vivo liver perfusion using STEEN Solution as perfusate for human liver transplantation: First North American results.Liver Transpl. 2016; 22: 1501-1508Crossref PubMed Scopus (134) Google Scholar,3Liu Q Soliman B Diago-Uso T et al.Pilot report of the clinical trial on liver normothermic perfusion preservation for transplantation: The first in the United States [abstract].Am J Transplant. 2017; 17: 77Google Scholar). Last, an important point of discussion pertains to matching. We question the rationale of matching on donor risk index (DRI) as a surrogate for donor quality and preservation time. While DRI is a proven marker of overall donor quality, it was never designed and validated for the purpose of comparing different preservation modalities. For example, a locally procured whole liver from a 45-year-old, DCD, white, 170-cm-tall donor died for anoxia preserved in cold storage for 4 h has a DRI of 1.90, while the same organ preserved for 14 h has a DRI of only 2.02, clearly underestimating the contribution of CIT on DCD graft viability (4Feng S Goodrich NP Bragg-Gresham JL et al.Characteristics associated with liver graft failure: The concept of a donor risk index.Am J Transplant. 2006; 6 (Available from: https://gastro.cchmc.org/calculators/donor-risk-index/): 783-790Abstract Full Text Full Text PDF PubMed Scopus (1469) Google Scholar). We propose that the total preservation time (TPT = CIT + NMP time + CIT until reperfusion) be used as a more inclusive preservation parameter to match for when investigating different preservation technologies (Figure 1). In summary, we believe the potential of new preservation technologies should be explored only when their safety and noninferiority have been established. Further, we propose that future trials used greater rigor in establishing controls, which would allow for better inferences about the efficacy and safety of the study findings. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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