Secondary Cold Ischemia After Normothermic Machine Perfusion: A Drawback to Centralized Organ Perfusion Centers?

The success and continued evolution of solid organ transplantation to treat an increasing number of pathologies have led to demand for allografts far outstripping the availability of suitable donor organs, creating pressure for the implementation of strategies to increase organ availability and utilization. The emergence of advanced machine perfusion technologies over at least the past 2 decades is transforming the field, pushing the boundaries of allograft utilization without compromising patient safety and outcomes.^1,2 A variety of dynamic perfusion modalities have facilitated the increased use of extended criteria donor organs, which typically carry increased risks of early dysfunction associated with a greater vulnerability to ischemic injury.^2,3 There is ample evidence that these techniques not only improve the preservation of organs during the ex situ period but also provide a unique setting for functional evaluation and graft reconditioning.³ This permits the safe assessment of questionable grafts, the educated improvement of borderline ones, and the avoidance of ones that should not be transplanted into a recipient, thus increasing utilization while minimizing the risk to recipients.

To take these powerful technologies to the next level with widespread implementation among all solid organs, we first need to overcome heterogeneous trial endpoints, a lack of uniformity in organ preservation protocols (and even terminology), disparate experiences with donor risk profiles, a lack of cost–benefit analyses, increased utilization costs and disparities in access, and the logistical and technical complexity of current technologies. Furthermore, with the advent of ex vivo normothermic machine perfusion (NMP), questions such as portability, feasibility, and technical expertise needed to implement NMP arise.

As a result, in recent years, there has been a move toward addressing many of these issues by establishing centralized locations to which all organs undergoing ex vivo perfusion are transported for assessment and optimization before transport to the recipient center (Figure 1). At such Centralized Regional Perfusion Sites (CRPSs), organ preservation and reconditioning can be performed with uniform protocols, diminished logistical obstacles, and potentially reduced costs because of high volumes and cost-sharing. Ideally, these organ intensive care units/cores (whether operated by organ procurement organizations, large transplant centers, governmental organizations, or commercial entities) would extend fair, equitable, and efficient implementation of graft preservation and optimization technologies to smaller centers that otherwise would not have the necessary resources, equipment, or staff to use them, particularly NMP.

FIGURE 1.: Schematic of CRPSs in the future landscape of liver transplantation. Organs, particularly marginal and extended criteria grafts, that are not immediately accepted for transplantation will be transported from donor hospitals to CRPSs, where they will undergo ex vivo machine perfusion. There they will be (1) assessed, (2) optimized, (3) treated, and (4) reallocated for transplantation based on their perfusion course and characteristics. CRPS, Centralized Regional Perfusion Site.

In a scenario in which a recipient transplant center does not have the resources to place the allograft on NMP, CRPSs would step in and provide the necessary expertise and technology.

After a standard warm ischemia time and cold preservation upon procurement, allografts would be transported to the CRPS while accruing cold ischemia time. There, the allograft would be placed on NMP and undergo functional analysis and possible rehabilitation, and the recipient transplant center would be able to decide whether to use the graft based on this assessment.

The simplest and least costly approach to centralizing NMP would likely require standard cold procurement techniques and the transportation of grafts. How much this compromises the graft quality compared with a more immediate placement on NMP is not yet well established. Another critical question that remains to be addressed is whether, to gain the benefit of NMP, the graft needs to be transported to the recipient on NMP and, if not, how much the quality of the organ would be compromised by a subsequent cold ischemia period.

The accompanying study by Horn et al¹ examined this aspect of the compromises being made by using regional centers for NMP of livers for ultimate transplantation, namely, the question of whether a second cold period of cold ischemia might influence organ function. The authors report decreased hepatic injury and improved liver function with NMP compared with cold static storage (CSS) only. Furthermore, they found that a second cold ischemia period did not negatively influence the improved liver function, providing some evidence for 1 piece of the puzzle.¹ The investigators used livers isolated from rats and subjected them to 18 h of CSS, after which groups were studied under 3 different conditions before reperfusion and functional assessment by NMP (what the authors term terminal machine perfusion): the control group was subjected only to 18-h CSS and then reperfusion, and the other 2 groups underwent preservation/reconditioning with NMP for an additional 2 h (Figure 2). One of them underwent terminal machine perfusion immediately after the preservation/reconditioning NMP; the other group was subjected to an additional cold storage period of 3 h (simulating travel time to a transplant center) after preservation/reconditioning NMP before terminal machine perfusion.

FIGURE 2.: Figure from the article by Horn et al. showing the treatment timeline and profile for each of the groups.¹

The results need to be taken within their limited context, however. The major limitation, and a natural next step, is that the organs were not transplanted; rather, the ultimate readout was terminal machine perfusion. This likely means that the observations are not as meaningful as they would be if transplantation had been performed because NMP reperfusion injury is quite mild because of a lack of an immune response from the recipient compared with in vivo reperfusion. Transplantation would further allow for the evaluation of in vivo parameters, not just bile or lactic acid production, perfusate enzyme levels, and histology. In addition, differences between the 2 groups (with and without the second cold ischemic period) are relatively small, which makes it difficult to translate the findings to clinical practice and raises questions about whether the study was powered adequately. Additional technical details such as the rationale behind the timing of the prepreservation 18-h cold ischemia time, the 2-h machine perfusion, and the 3-h post-NMP CIT will also need to be further explored. However, the field is still too young to have an established standard, and these factors need further refinement in general.

In the pursuit to truly end the “ice age” of allograft storage and to ensure fair access to both the technology and the potential organs reclaimed by implementation of this technology, a regionalized approach could be the way forward.