The ethics surrounding normothermic regional perfusion in donors following circulatory death

INTRODUCTION

Donation after circulatory death (DCD) has been the largest driver of growth in deceased organ donation in the United States over the past 5 years. DCD is utilized for individuals who have a nonrecoverable medical condition, usually neurologic in nature, for which a decision has been made to withdraw life-sustaining treatment. If a decision is subsequently made for organ donation, the patient undergoes the withdraw life-sustaining treatment in a location amendable to quickly beginning the organ procurement procedure (usually the OR or perioperative holding area) and if the patient dies within the timeframe acceptable for organ utilization, the organ procurement procedure commences following a waiting period to ensure that autoresuscitation does not occur. While the number of DCD donors is growing, the utilization of organs from these donors lags significantly behind that of organs from donation after brain death (DBD) because of the ischemic injury done to the organs during the time that the donor is dying and the organs are not being adequately perfused (ie, agonal period). The ischemic injury is reflected as a higher rate of delayed graft function in kidney transplant recipients and ischemic cholangiopathy in recipients of liver transplants.^1,2 Because recipients of DCD organs have historically had worse outcomes than those of DBD organs, there is some hesitancy in the transplant community to utilize DCD organs. Therefore, techniques and storage modalities that improve the quality of organs and the ability to assess organ function before transplantation increase confidence in DCD organ quality and encourage higher utilization rates. The techniques and storage modalities that have shown promising results in improving the assessment of organ quality, potentially decreasing the incidence of poorer outcomes and, most importantly, increasing utilization of DCD organs are ex situ normothermic and hypothermic pumps and in situ normothermic regional perfusion (NRP).^3–6

NRP is a procurement technique used for DCD, which improves the assessment, quality, and utilization of organs for transplantation. NRP differs from super rapid recovery (SRR) in the way that organs are perfused and evaluated in the DCD donor. In NRP, the donation procedure begins with an incision and cannulation of a large artery and vein as well as clamping of the arterial vessels above and below the regions of the body that will be perfused. There are 2 types of NRP: abdominal NRP and thoracoabdominal NRP(TA-NRP). The difference in NRP procedures is the areas of the body that are being perfused and the locations of proximal clamps. In TA-NRP, both the abdominal and thoracic cavities are perfused. The proximal clamps are placed on the aortic arch vessels, and distal clamps are placed on the external iliac arteries. In abdominal normothermic regional perfusion, only the abdominal cavity is perfused, so the proximal clamp is placed on the supraceliac aorta (either in the abdomen or the chest), and the distal clamps are placed on the external iliac arteries. The perfusion used with NRP is oxygenated blood that is circulated through the donor organs with the assistance of either an extracorporeal membrane oxygenation circuit or a cardiopulmonary bypass circuit. In contrast, the SRR procedure involves an incision followed by cannulation and then flushing of the organs with a cold preservation solution.

CLINICAL ADVANTAGES TO NRP

The NRP procedure quickly reconditions organs using oxygenated blood and allows for an in-situ assessment of organ function. ⁷ The quick reconditioning of organs stops the damage that started with agonal time and resets the clock on the accrual of damage from preservation to implantation. NRP stops the deleterious impact of ischemia, which decreases ATP reserves and increases oxygen free radicals. All organs that are perfused will demonstrate their ability to function on NRP, which means that the heart will beat, the liver will make bile and clear lactate, and the kidneys will make urine.

From a transplant standpoint, NRP is associated with significant advantages. First of all, the recovery of function after the agonal period can be assessed with the organs fully perfused in a normal physiologic state. This simple initial functional assessment decreases or eliminates the uncertainty of primary nonfunction associated with SRR. This fact alone increases organ utilization, and several studies have shown a substantial increase in liver utilization when NRP is the planned procurement technique as compared to SRR. Moreover, organs procured with NRP are less prone to delayed graft function and are associated with overall outcomes that are comparable to DBD grafts and better than SRR grafts. ⁸ Several countries in Europe, including Spain and the United Kingdom, utilize NRP commonly as a procurement technique for abdominal DCD donation. ⁹ However, there remain barriers to expanding this to TA-NRP donation in these locations. Moreover, despite the clear advantages of NRP, there are ethical and logistical barriers to making NRP the standard of practice in many countries around the world.

ETHICAL DISCUSSION SURROUNDING NRP

Three ethical topics of discussion have been raised regarding NRP procurement, at least 2 of which are more applicable to TA-NRP than abnormal NRP, but all 3 will be discussed in general.^10,11 The first ethical discussion regards the concern that NRP negates the prior declaration of death by circulatory criteria. The argument is based on the definition of circulation as the movement of oxygenated blood within a body. DCD donors are declared dead based on circulatory and respiratory criteria, and NRP resumes circulation, so the declaration of death is negated by the NRP procedure. If the donor is no longer dead, then the dead donor rule is violated, and the procurement procedure would be the proximate cause of death when NRP is stopped and “circulation” is ceased. The counterargument to this challenge is that NRP is not circulation as it happens in a living individual. It is the in-situ regional perfusion of organs artificially driven by machines without which no oxygen could be delivered to the cells. The prior declaration of circulatory death is not violated because it is not natural, spontaneous, and independent circulation that NRP restores. The donor is dead at the time of incision and remains dead because circulatory and respiratory functions have not been restored but are replaced or supplemented by external machines. ¹² The absence of the ability to maintain circulatory and respiratory function without machine assistance is permanent, as demonstrated during the observation period.

The second ethical challenge to NRP is that NRP causes neurologic death in the donor. ¹³ This argument states that the NRP donor was never dead by circulatory criteria because the intent of NRP was to reestablish circulation, so the only defining criteria for death would be by neurologic criteria. If the donor is only dead by neurologic criteria, which in a DCD donor is demonstrated by a complete lack of flow to the brain, then clamping the proximal blood vessels that would otherwise deliver blood to the brain induces brain death. The counterargument to this is that the donor is already dead by circulatory criteria, which is separate and independent from neurologic criteria, at least in US law. ¹⁴ Therefore, if the person is already legally and medically dead at the start of the organ procurement, the actions that follow cannot cause death again. A second counterargument, conceptualized using the uniform brain-based definition of death, is that circulatory death is premised on permanent cessation of circulation to the brain, and since NRP is regional perfusion, it maintains a permanent state of cessation of circulation to the brain. ¹⁵

The third challenge to NRP is that, even if there is agreement that NRP donors are dead based on circulatory and respiratory criteria and remain dead at the initiation of the procedure because circulatory function is not restored, there is a lack of certainty that neurologic function has ceased and a concern that the oxygenated blood perfusing the organs may have avenues to the brain through collateral vessels. ¹⁶ In theory, if there is enough collateral flow, then some level of brain function could be re-established. A small series of NRP donors have had brain flow studied during the NRP procedure and show no evidence of flow.^17,18 Because flow is necessary for function, these studies suggest that the NRP procedure does not allow for even the possibility of brain function.

A PRACTICAL APPROACH TO IMPLEMENTING NRP

The introduction of NRP for DCD donation has made 1 thing abundantly clear: the definition of death remains a strongly debated topic, despite the fact that the legal definition of death in the United States has remained the same since the 1980s. A person is dead if she meets either the cardiopulmonary or neurologic definition of death. While some countries are moving toward a unified brain-based definition of death that would consider the lack of flow to the brain as confirmation of death in NRP, that is not currently the case in the United States. In the United States, NRP fits within the legal construct of death as it is a postmortem organ perfusion modality. DCD donors are declared dead using accepted circulatory and pulmonary criteria and remain dead because NRP is the regional perfusion of the organs. The regionalization of perfusion avoids the theoretical risk of flow to the brain.

Because NRP differs from SRR, there has been much debate about how donor families should be informed about the use of this procedure. Some organ procurement organizations in the United States inform every donor family that NRP may be used, while others consider it a standard postmortem technique that does not require additional consent. Given the novelty and debate around NRP, we recommend that families are informed that this technique may be used and given information about how it differs in morally relevant ways (eg, oxygenated blood is reintroduced into the body to perfuse the organs for transplantation and the organs start functioning again in the body before they are removed).

In our view, NRP represents the evolution in DCD donation aimed at decreasing the uncertainty associated with SRR and improving outcomes. It is innovative insofar as it applies existing technologies to organ donation, but it does not substantially alter the basic processes of SRR. Early clinical research was aimed at comparing NRP with DBD and SRR in terms of recipient outcomes. Future research should focus on using NRP and other technologies to assess the feasibility of using older donors, steatotic grafts, and increasing tolerance for longer agonal periods while maintaining excellent recipient outcomes.