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Oxygenation of Preserved Organs—Hot or Cold?

Paraskevas, Steven, MD, PhD1

doi: 10.1097/TP.0000000000002556
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Clear and updated overview on the pros and cons of hypothermic, subnormothermic and normothermic perfusionsystems in their applications to preserve liver, pancreas, lung, heart and particularly kidney prior to transplantation.

1Associate Professor of Surgery Director, Transplantation Research McGill University Health Centre.

Received 13 November 2018.

Accepted 16 November 2018.

The author has no conflicts of interest relevant to the topics discussed in this article.

Correspondence: Steven Paraskevas, MD, PhD, McGill University Health Centre, Canada. (steven.paraskevas@mcgill.ca).

We are currently witnessing a remarkable technological revolution which brings a variety of options to the way organs are preserved, assessed, and even improved before transplantation. After decades in which “cold ischemia” was an accepted fact of transplantation, many are challenging the notion that any amount of ischemia is necessary at all. This sea change in the way we preserve organs between their recovery and their transplantation has been largely driven by the development of systems designed to maintain organs at physiologic temperature while providing oxygen for aerobic metabolism. In parallel with these technological developments, the field has been driven by a need to better utilize organs from older donors, as well as those recovered after circulatory death.

Among the first such systems have been several designed for normothermic lung preservation. These have capitalized on the ability to oxygenate lung tissue directly via endotracheal intubation. Clinical experience with these devices has illustrated the potential not only to maintain organs for extended periods of time, but to use this interval to assess quality, and potentially deliver therapeutics that will diminish reperfusion injury or promote tolerance.1

Analogous devices for other organs are in various stages of development, have seen limited deployment, and reflect a dimension common to all nonpulmonary grafts: the complexity of meeting temperature-based metabolic demand with oxygen delivery. In general, normothermic machine preservation (NMP) in the maintenance of organs usually requires blood-based oxygenation, as well as attention to nutrient supply, acid-base balance, and disposition of products of metabolism. This entails greater complexity of systems and greater cost. In addition, in the event of mechanical failure, the organ is at risk of loss. These drawbacks must therefore be weighed against the potential advantages of such an approach. At the opposite end of the scale, hypothermic machine preservation (HMP) provides a low-risk avenue for organ maintenance, albeit with less potential gain: functional evaluation and therapeutic intervention strategies are limited, and benefits, although certainly tangible, have been less than dramatic.2 HMP systems have become widely deployed, particularly for kidney grafts.

Between these extremes, several new concepts are emerging. Hypothermic or subnormothermic oxygenated perfusion (HOPE) systems allow for oxygen delivery at rates not requiring blood-based carriers, commensurate with the reduced metabolic rate at these temperatures. Their potential advantage is in reduced device complexity, and in the case of hypothermic systems, greater safety margin.3 Less well developed, but similarly promising, subnormothermic machine perfusion and controlled-rewarming systems aim to minimize the transition between cold preservation and warm reperfusion, for which some evidence points to a deleterious role.4

In liver transplantation, preliminary clinical trials of NMP and HOPE have shown their safety, their ability to maintain livers for extended periods, and the potential to minimize cellular injury.5 Some evidence also exists to suggest the potential for reduction in ischemic cholangiopathy may be realized.6 More ambitious goals, such as treating steatosis, remain in the experimental realm.

Ex vivo mechanical preservation systems for kidney transplants have begun to evolve from the widespread HMP, to HOPE and NMP, with potential for significant improvements in organ quality and utilization. Trials of such systems are currently under way with preliminary results suggesting a dramatic improvement in delayed graft function, particularly with the use of NMP.7 Hypothermic or subnormothermic oxygenated perfusion and NMP concepts are also being applied to pancreas,8 islet,9 and heart transplantation.10 In these organs, transplantation rates have remained low due to risks of inflammation and complications in the former, and graft dysfunction in the latter. It remains to be seen if such systems will have a positive impact on organ utilization, particularly in donors after circulatory death, or those where prolonged arrest, hypotension or graft injury are feared.

In this issue, Patel et al11 illustrate the potential benefits of HOPE in an experimental kidney context. This middle road toward ex vivo preservation could be an important answer to modulating the effects of lengthy cold ischemia while allowing for prevention of the worst effects of anaerobic conditions in organ preservation. It is an avenue certainly worthy of deeper exploration.

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