In Situ Normothermic Regional Perfusion in Controlled Donation After Circulatory Determination Death: Organ Utilization, Outcomes, and Elusiveness of a Randomized Clinical Trial.

Abstract

At present, preservation in solid organ transplant is undergoing a paradigm shift away from continuous static hypothermia toward greater application of dynamic machine perfusion (MP) preservation modalities. A PubMed search of MP and transplantation reveals a sharp increase in publications in the past 15 y: there were <20 MP studies published in 2006; in 2021, there were nearly 300. Randomized clinical trials (RCTs) have been published demonstrating both improved early function and survival among transplanted kidneys and reduced transaminases and complications among recipients of livers undergoing ex situ MP.1-3 Use of in situ normothermic regional perfusion (NRP) in controlled donation after circulatory determination of death (cDCD) is another important part of this transformation. Although promising clinical results have been reported for recipients of cDCD kidneys and livers recovered with NRP,4 RCTs on NRP are still lacking. In this issue of Transplantation, UK authors analyze cDCD organ offers and actual transplants recorded in their national transplant registry between 2011 and 2019.5 They evaluate organ utilization rates with in situ NRP versus the alternative—immediate in situ cold preservation (ISP) and recovery. The authors claim use of NRP significantly increased transplantation of cDCD grafts from 2.6 organs/donor with ISP to 3.3 organs/donor with NRP. Furthermore, in line with previous observational studies published from other settings,6,7 posttransplant kidney and liver outcomes appeared improved with NRP. Study results are impressive, and the authors should be congratulated. At the same time, they highlight once again important issues related to the subjectivity of organ acceptance and discard and the consequent complexity of designing and executing RCTs on NRP. In the context of cDCD, in situ NRP restores flow of oxygenated blood to the abdomen (abdominal NRP) or chest and abdomen (thoracoabdominal NRP) following a period of progressive hypoperfusion and cardiac arrest in the donor. Although ISP is performed quickly and does not offer any feedback to the donor surgeon beyond limited gross findings, NRP eliminates the rush to remove organs, largely restores their normal macroscopic aspect and semi-physiological conditions, and even offers some concrete data related to their functionality. This combination of perceived benefits offered by NRP undoubtedly impacts organ acceptance and ultimate transplantation, regardless of any improvements NRP may produce in actual organ quality. In the UK study, the liver was the organ in which recovery technique had the greatest impact on utilization. Interestingly, a major difference in liver utilization rates in the UK study arose as early as the point of acceptance of the liver offer. For cDCD livers offered with NRP, 91% of those offers were accepted to be evaluated in situ versus only 61% among cDCD livers offered with ISP.5 A liver (or any organ, for that matter) will never be transplanted if it is never evaluated in situ. These results indicate that an important benefit of NRP might be added confidence in initially accepting cDCD offers, likely based on knowledge that viability of seemingly marginal grafts can be further assessed by measuring different parameters during NRP in a manner that is simply not possible with ISP. For cDCD donor offers included in the UK analysis, donor age and body mass index were both lower when NRP was the recovery method. In contrast, donor warm ischemia times were slightly but statistically longer in relation to additional time needed to establish the NRP circuit. Although the authors performed multivariate regression analyses attempting to adjust for these covariates, lack of randomization of donors between the 2 recovery methods and ongoing influence of other relevant confounders—both known and unknown—represent potential sources of bias when estimating the true impact of NRP on posttransplant outcomes. Unlike ex situ MP, which is capable of treating an organ individually, any effects of in situ NRP unavoidably extend to all organs in the region of perfusion (abdominal NRP: kidneys, liver, pancreas, and intestines; thoracoabdominal NRP: all the aforementioned organs plus the heart and lungs). NRP has yet to be evaluated in the context of an RCT based on the complexity of identifying an appropriate study endpoint for a preservation and recovery method that affects multiple organs and has to be applied before any of these organs have actually been accepted for transplantation. Even if cDCD donors are randomized at the point of their acceptance for in situ evaluation, it remains wholly impossible to blind donor surgeons to the method that has been assigned. As in the UK study, disparate numbers of organs would likely be accepted for transplantation and donor profiles among the transplanted organs vary significantly according to the recovery method used. Furthermore, any posttransplant endpoint that might be assessed (graft or recipient complications, survival, etc) would be conditioned by these confounding variables. The alternate option of comparing in situ NRP with ex situ MP in the liver or kidneys still does not ensure the absence of selection bias; does not adequately address risk to and collateral effects on “bystander” organs (pancreas ± intestines, heart, and lungs); and is somewhat nonsensical, given that in situ NRP and ex situ MP are not competitive preservation strategies and can and have been successfully applied sequentially in the same transplant grafts.8,9 Pursuit of an RCT on NRP in cDCD should not be abandoned, but the issues outlined above need to be adequately addressed before performing a complex study of limited clinical utility. In the meantime, this and other observational studies as well as anyone who has used NRP personally can speak to the tangible improvements it offers in cDCD organ quality. Moreover, its relatively low cost10 and the intangible benefit of the confidence it provides serve as indicators that application of NRP in cDCD will continue to spread, even without existence of a level 1 study in its support.