Reply.

Abstract

1 To The Editor: We appreciate the comments made by Patrono et al. regarding our study on normothermic machine perfusion (NMP) of donor livers without the need for human blood products, using a bovine hemoglobin‐based oxygen carrier (HBOC; HBOC‐201).1 We agree with Patrono et al. that the increased hepatic adenosine triphosphate (ATP) content and ATP‐dependent processes can be attributed to both the HBOC‐201 molecule’s decreased affinity for oxygen, causing it to release oxygen more easily than red blood cells, and the decreased viscosity of HBOC‐201–based perfusion solution with resultant higher flows. We agree that the reduced viscosity should also be regarded as a major advantage of HBOC‐based perfusate. Indeed, using a perfusion solution with a lower viscosity allows for lower vascular pressures during perfusion, thereby protecting the endothelium. We agree that the reported perfusate alanine aminotransferase (ALT) levels may seem relatively high at first sight. However, these values are comparable to and even lower than those reported in similar studies by others. The study by Fondevila et al.,2 which the authors refer to, can, however, not be compared with the current study for a number of reasons. First, the ALT cutoff value of <200 U/L as reported by Fondevila et al. concerns values at the start of in situ normothermic regional perfusion (NRP) in donation after circulatory death donors. These values cannot be compared with perfusate ALT values obtained during end ischemic ex situ NMP using a closed circuit, in which ALT accumulates over time. Second, the circulating volume during in situ NRP is generally higher than the volume during ex situ NMP, resulting in a greater dilution. When compared with more similar machine perfusion studies, our perfusate ALT values are very much in line with those previously reported in the literature. In the case series reported by Watson et al., in which NMP was performed after a period of cold ischemia using the same Liver Assist device, a perfusate ALT level <6000 U/L was associated with successful transplantation.3 This cutoff value is higher than the levels reported by us. Watson et al. reported 1 liver with a perfusate ALT level of 9490 U/L at 2 hours of NMP, which developed primary nonfunction after transplantation. In contrast with this, Nasralla et al. recently reported a liver with perfusate transaminases >20,000 U/L during NMP (using the OrganOx perfusion device), which was successfully transplanted.4 These data highlight the difficulty in comparing studies with different devices, timing, and settings. It is important to note that both in our study and in the study by Watson et al., ALT values remained relatively stable during NMP.1 This indicates that, after the initial reperfusion and wash‐out of transaminases, there is little or no additional hepatocellular injury during NMP. We are currently running a clinical trial to identify transplantable livers that were initially declined for transplantation nationwide, using an HBOC‐201–based perfusion solution (www.trialregister.nl; NTR5972). One of the major advantages of an HBOC‐201–based perfusion solution is its applicability at different temperatures, avoiding the need to switch perfusion solutions for different temperature phases. As highlighted in the editorial accompanying our article, hypothermic oxygenated machine perfusion (HOPE) has been shown to resuscitate mitochondria, which play a crucial role in the protection against ischemia/reperfusion injury.5 Indeed, we have previously shown that the combination of HOPE and NMP results in less injury and improved hepatobiliary function compared with NMP alone.6 For this reason, we have designed a clinical trial in which livers undergo a period of HOPE for mitochondrial resuscitation, followed by gradual rewarming and subsequent NMP for viability assessment. Perfusate ALT levels in livers that were deemed viable during NMP generally remained <2000 U/L, and all livers displayed excellent function after transplantation. 2 Potential conflict of interest Nothing to report.