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Hypo- and normothermic perfusion of the liver: Which way to go?

https://doi.org/10.1016/j.bpg.2017.04.001Get rights and content

Abstract

The demand of donor livers for transplantation exceeds the supply. In an attempt to maximize the number of potentially usable donor livers, several centers are exploring the role of machine perfusion. This review provides an update on machine perfusion strategies and basic concepts, based on current clinical issues, and discuss challenges, including currently used biomarkers for assessing the quality and viability of perfused organs. The potential benefits of machine perfusion on immunogenicity and the consequences on post-operative immunosuppression management are discussed.

Introduction

The success of liver transplantation has driven increased indication, resulting in far more candidates on waiting lists, than donor organs available [1], [2], [3]. This still growing gap between liver supply and demand has forced professionals to utilize livers from older, fattier, ischemically damaged or otherwise extended criteria donors (ECD) [4]. Such livers carry high risk of post-transplant complications, including primary-non-function (PNF), early allograft dysfunction (EAD), biliary complications and graft loss [5], [6], [7]. Key factors for liver graft dysfunction include donor warm ischemia (donation after circulatory arrest (DCD) donation), graft steatosis and prolonged cold storage of more than 10 h [2], [3], [8]. Graft optimization or repair strategies are therefore currently emerging to improve clinical outcomes. This review will focus first on underlying mechanisms of injury throughout the process of organ donation, preservation and implantation. Furthermore, we will report on perfusion strategies and discuss the clinical implementations and potential future developments.

Section snippets

Accumulation of injury from the donor to the recipient

Organ injury already starts before organ procurement, due to donor warm ischemia in donation after cardiac death (DCD) or during brain death (DBD) [8]. Following this initial hit, donor livers undergo the process of retrieval surgery, including cold flush and static cold storage (SCS). Cooling slows down metabolism and prolongs the time of oxygen deprivation with minimal loss of viability [9]. However, energy consumption is not completely stopped, but reduced (approximately 12-fold, Fig. 1) and

Machine perfusion and perfusion strategies

The field of liver preservation has shown slow progress in the last decades. The use of ECD donor livers however recently rocketed ex vivo machine perfusion (MP). Starzl et al. introduced the concept of machine perfusion as a preservation method as early as 1960 using a heart-lung machine to pump cold perfusion fluids through the portal vein [30]. The high costs, invention of improved preservation solutions and good results without MP, led to a decline in research on machine perfusion. The

Hypothermic machine perfusion

Hypothermic machine perfusion (HMP) has been implemented in the setting of kidney transplantation and more recently in liver transplantation [33]. Additional hypothermic oxygenation of the mitochondrial electron chain using perfusion (HOPE) seems the key element for the protection against reperfusion injury [21], [26], [34]. Three effects of this strategy are reported. First, adenine nucleotides are significantly restored to high levels during cold oxygenation (Fig. 2A). Secondly, function of

Subnormothermic perfusion SNMP (12 °C–30 °C), including Controlled Oxygenated Rewarming (COR)

Subnormothermic machine perfusion is an alternative perfusion technique at 12–35 °C with the advantage of sufficient oxygen supply without red blood cells in the lower temperature range [45], [46]. Compared to NMP, reperfusion injury is expected to occur less due slowdown of mitochondrial electron transfer [47], [48], [49]. However, it is not clear if all metabolic processes are equally reduced, and therefore viability testing can be more challenging [48], [50], [51]. The favorable outcomes of

Normothermic machine perfusion (NMP) (35 °C–37 °C)

The principle of NMP is to avoid cold ischemia and maintain normal metabolism throughout the preservation period and provide oxygen and essential substrates via dual perfusion (portal vein and hepatic artery) (Fig. 4B). Usually, NMP is therefore started at the place of organ procurement and continued during organ transport for 4–18 h [57]. Normothermic temperatures ensure metabolic activity, facilitating for example reduction of hepatic steatosis and pharmacological interventions [58], [59].

Normothermic regional perfusion (NRP)

Normothermic regional perfusion (NRP) in organ donors is used for Maastricht type II and III DCD donors. Following cardiac arrest, vessel are cannulated and normothermic perfusion is started [75]. Importantly, while in Maastricht II donors, normothermic perfusion allows to gain more time for the consenting process of donation, the idea behind NRP in Maastricht type III is to assess graft viability before implantation (Fig. 3, row 6&7) [76], [77]. Of note, type II DCD donors experience generally

Future perspectives

Improvement of the quality of liver grafts and prediction of organ function before implantation are the two main concerns to allow the safe use of organs that were previously deemed unsuitable. In this context, thresholds need to be defined to determine which graft requires machine perfusion treatment. Highly attractive are center bound relative short perfusion treatments of liver grafts before implantation, which can provide significantly uploads in cellular energy stores as lifesaving but

Funding

None.

Conflict of interest

The authors declare to have no conflict of interest.

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    JS and AS contributed equally as first authors.

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