Normothermic Regional Perfusion Requires Careful Ethical Analysis Before Adoption Into Donation After Circulatory Determination of Death

We believe that normothermic regional perfusion (NRP) requires careful ethical evaluation before its widespread incorporation into donation after circulatory determination of death (DCD). A review of the literature identifies reasons why NRP, particularly thoraco-abdominal NRP (NRP-TA), should not be used: violation of the dead donor rule (DDR) (1), causing death by intentional ligation of arch vessels (ILAVs) (2), and risking donor suffering by collateral blood flow to the brain (3). Numerous organizations and position papers have clarified that, if NRP-TA is performed, it should be part of an institutional review board-approved protocol with brain monitoring and a plan to abort if brain flow or activity is detected (4,5). Yet, some U.S. transplant centers have incorporated NRP-TA without acknowledging the need to obtain specific consent from vulnerable donors on the above issues (6,7). No donor should be exposed to this risk without an ethics committee or IRB first performing due diligence to understand the ethical debates surrounding NRP-TA. In this Viewpoint, we summarize the ethical and practical shortcomings of NRP-TA.

NRP DOES NOT CONFORM TO THE UNITED STATES LEGAL DEFINITION OF DEATH

Death determination by U.S. statutory law under the Uniform Determination of Death Act (UDDA) requires the irreversible cessation of circulation, though, in practice, it is widely interpreted as the permanent cessation of circulation. With NRP-TA, circulation is restarted in the entire body except the brain because of ILAV, assuming no collateral blood flow. Because of the postmortem restoration of systemic circulation, NRP is not performed in Australia (8). In a recent essay, an organ procurement organization (OPO) chief executive and the principal author of the UDDA concluded that death declaration with NRP is inconsistent with the wording and intent of the UDDA and could subject those involved to prosecution (9). The counterclaim that death declaration is valid (10) invents a new standard of “spontaneous” circulation because an awake patient on extracorporeal membrane oxygenation lacks spontaneous circulation yet is obviously alive. Furthermore, the claim that Uniform Anatomical Gift Act is protective is circular logic in that it applies only after death. No U.S. court has ruled that declaration of death in the setting of NRP is valid.

NRP-TA MAY VIOLATE THE DEAD DONOR RULE

The DDR, the ethical foundation of deceased organ donation, requires that vital organs can be donated only after death and that death cannot be caused by organ donation. Proponents of NRP state that death determination in NRP-TA is circulatory, not brain-based. Yet if brain perfusion and function continue, the patient remains alive. Animal data show that NRP-TA started after 8 minutes of asystole can induce restoration of some brain function (11). Therefore, the claim that death occurs after 5 minutes of asystole regardless of what happens thereafter is biologically incorrect. NRP death declaration following 5 minutes of asystole, while planning to later restart circulation, is completely different from usual DCD declaration in which circulation will not be restarted. Circulatory death requires permanent cessation of circulation, irrespective of whether the circulation is spontaneous or induced and is independent of motive.

NRP MAY VIOLATE THE DONOR’S RELIGIOUS BELIEFS

Most religions support organ donation after death with some variation if brain death is accepted as death (12,13). However, given the novelty of NRP and concern in the medical community over whether death declaration is valid, NRP may violate some donors’ religious beliefs. For example, the Roman Catholic Church supports organ donation from the “body of someone who is certainly dead.” (14) Cultural respect, therefore, demands a proactive approach to disclose relevant information that might allow one to object to NRP on religious or moral grounds.

CANADA DOES NOT PERMIT NRP

A Canadian consensus conference of multiple stakeholders decided not to perform NRP though they permit direct procurement (15). Unresolved issues included “current concepts and practices of death determination after cardiac arrest, the act of surgical interruption of brain blood flow, and whether this surgical interruption of aortic arch vessels ensures cessation of brain blood flow… ” We believe that thoughtful stakeholders should know that other countries have decided not to proceed with NRP. Their arguments merit thoughtful reflection.

UNIQUE TO DCD PROCEDURES, NRP REQUIRES ILAVs TO PREVENT BRAIN FLOW/RESUSCITATION

In routine DCD, death is declared by circulatory criteria. The unified theory of brain circulatory death (16) maintains that cessation of systemic circulation causes death by cessation of brain blood flow. In NRP-TA, circulation is restarted quickly enough after its initial cessation that brain perfusion and resultant function could resume. ILAV aims to prevent brain perfusion, which would otherwise resume when systemic circulation was restored. The procurement surgeon performs an action contrived to ensure that the brain will not be perfused (17). Because ILAV ensures only that resuscitation of the brain will not occur, it is the cause of death with resumed systemic circulation because brain blood flow would occur otherwise. The claim that “the donor is dead at the time of procurement” (7) is erroneous because the use of NRP-TA shows that circulatory cessation was not permanent, a prerequisite for circulatory death determination. Thus, it is misleading to claim that NRP is identical to other DCD methods and does not raise unique ethical issues.

MULTIPLE GUIDELINES REQUIRE MONITORING FOR BRAIN PERFUSION

A critical issue in any postmortem restoration of circulation is the potential for resumption of brain blood flow. Brain blood flow can occur despite the ligation of the principal arteries perfusing the brain due to collateral blood flow, anatomical variations, or technical failures. This risk is of such concern that European guidelines (18), a cardiothoracic ethics forum (19), and others (5) recommend brain monitoring during NRP. They additionally require a plan to abort the procedure should signs of brain activity or perfusion occur. A recent article recommended technical modifications of the procurement technique to reduce this risk (3). However, they warn that whether these methods are effective remains unknown and requires further investigation. Monitoring by cerebral oximetry or bispectral index cannot exclude minimal blood flow, particularly in the posterior circulation, despite claims to the contrary (20). It remains unclear why U.S. surgeons have chosen not to perform brainstem brain monitoring or assume ILAV “makes any clinically meaningful blood flow impossible” in the absence of data (21,22).

We know of no human data proving that ligation of the arch vessels completely excludes all brain blood flow; thus, it remains possible that NRP could restore enough brain blood flow to permit awareness or pain perception. In a pig model, one of five animals showed collateral flow through the internal mammary artery associated with a rise in cerebral oximetry (23). Therefore, we believe it is inappropriate for OPOs or transplant surgeons to eschew these recommended safeguards. Each institution should review this issue and decide if organ donors should be exposed to this risk of unknown magnitude and severity. We, therefore, strongly disagree with those who deny that additional authorization should be required for NRP over that for DCD (6).

Given the dearth of safety information, we believe that donor patients are best protected by an expert independent determination of how brain monitoring should be conducted and the necessary elements of a donor consent form. An international consensus statement concluded, “Given the complexity of techniques to ensure absence of circulation to the brain during TA-NRP, this should only be performed in the context of specific research protocols by teams with sufficient training and expertise” (4). The need for review by the hospital ethics committee does not disappear because NRP previously had been introduced into clinical practice.

Many physicians feel that circulatory death determination is valid because brain perfusion and function inevitably cease. This unified approach that one of us called “donation after brain circulation determination of death” is valid, however, only if no brain circulation resumes after death determination (16). Although it is true that the intent of NRP is to produce permanent cessation of brain circulation, if brain blood flow does occur, the permanence requirement was never met, and therefore, the declaration of death was not valid. A recent international conference emphasized this point stating, “Restoring brain circulation would invalidate the death determination because the unifying concept of death requires brain circulation to have ceased indefinitely, resulting in the permanent cessation of brain function” (4). The lack of intent to resuscitate the patient with Do–Not-Resuscitate status does not change the biological reality. It is erroneous to claim that a declaration of death based on permanent cessation of circulation cannot be invalidated by subsequent restoration of circulation (24).

ORGANIZATIONAL ETHICS

No U.S. guidelines govern what actions will be taken if brain perfusion is detected. Is the treatment team responsible? Will OPOs or transplant centers indemnify the risk borne by hospitals and physicians for their actions? OPOs advocating NRP-TA must disclose the ethical controversies, so hospitals can make informed decisions. We agree with Parent et al (25) that informed consent “requires giving morally relevant information.” We believe that a reasonable person would want to know that multiple organizations feel that the risk of brain flow requires monitoring to prevent risk of reanimation and possible suffering, yet procurement will be done without employing this safety step. Prudent organizations might wish to reexamine permission previously granted if members were unaware of the breadth of opposition to NRP, the issue of brain flow monitoring, and the issue of informed consent.

DISCUSSION

It has been more than 20 years since the Institute of Medicine produced three reports endorsing and encouraging DCD (26). Given controversial new DCD technologies and protocols, reconvening this body is a step that all stakeholders should embrace. Until there are universally accepted standards, local ethics committees must provide necessary oversight. OPO’s and transplant centers must assiduously disclose real and perceived conflicts of interest (27). Key society statements and articles are listed in Table 1, and key educational points for an ethics committee are summarized in Table 2.

TABLE 1. - Excerpts of Key Papers and Society Statements ACP 2021 (2) “It is more accurately described as organ retrieval after cardiopulmonary arrest and the induction of brain death.” … "NRP-[controlled heart donation after circulatory determination of death (cDCD)] appears to violate one of the ethical foundations of organ donation, the 'dead donor rule.'" European Society for Organ Transplantation’s Transplant Learning Journey (18) “Need to monitor and define brain perfusion and contingency plan to abort if occurs.” International collaborative (4) “… should only be performed in the context of specific research protocols…” Monitoring absence of brain circulation (perfusion or function) during TA-NRP is an essential component of such protocols. International Society for Heart and Lung Transplantation (5) “...monitoring the absence of brain perfusion or function during the NRP is an essential component of such protocols..." "Transplant centers should prepare contingency plans to abort the organ procurement and the NRP procedures in the event that there are concerns that criteria for death may not be satisfied." ACP 2022 (27) “Parent’s article does not lessen those concerns...” “Rather than follow the legal definition of death‚ the authors redefine it...” “This is resuscitation of the donor, not reperfusion of an organ; if not resuscitation, ligating blood vessels would not be part of the protocol.” Canadian consensus building process (15) "Principal challenges with NRP to resolve include consistency with current concepts and practices of death determination after cardiac arrest, the act of surgical interruption of brain blood flow and whether this surgical interruption of aortic arch vessels ensures cessation of brain blood flow from collateral sources." Glazier and Capron (9) “...the legal standard for determining death is bare of intent: a patient is dead when circulation neither can nor will resume...” "...meaningful existence is not possible..." "...or even that the NRP protocol is consistent with the donor’s wishes, are all irrelevant…." Cardiothoracic Ethics forum (19) "TA-NRP is acceptable at this time only under a research protocol that has been approved by an institutional review board and that includes assessment of perfusion to the brain stem, and, if any is found, determination of its effect on brain function." Australian and New Zealand Intensive Care Society (8) "In the context of donation after circulatory death, once circulatory arrest has occurred, interventions that may restore circulation must not be undertaken." Manara et al U.K., Canada proposal (3) "We propose refinements to current protocols to monitor and exclude brain reperfusion during in situ NRP. Our findings in TA-NRP currently cannot categorically confirm or refute the absence of some brain blood flow even if this is small."

ACP = American College of Physicians, ‚ NRP = normothermic regional perfusion‚ TA = thoraco-abdominal.


TABLE 2. - Ten Top Reasons to Defer Normothermic Regional Perfusion at This Time NRP death declaration does not comport with the current U.S. legal definition of death Organ procurement after restoration of circulation violates the Dead Donor Rule Ligation of arch vessels by transplant surgeon may be viewed as causing death Brain blood flow may occur, inducing reanimation and possible suffering Monitors that are currently used to monitor blood flow cannot exclude flow to the brainstem Many societies recommend additional brain blood flow monitoring but are not used in United States Australia and Canada do not permit NRP for many reasons including those listed Advocates of NRP do not believe donors/families need to be warned about risk of brain flow NRP may violate religious beliefs by removing organs prior to certainty of death Hospitals are ultimately responsible for patients’ rights; not the organ procurement organization

NRP = normothermic regional perfusion.


CONCLUSIONS

The preceding arguments justify why NRP should now be paused. Centers that have granted permission should reevaluate it with the information and position statements described. Institutions should require special informed consent, particularly on the issue of brain perfusion, because many organizations and groups regard it as a risk. Each institution must ensure that staff and patients are properly informed and protected. Public trust in organ donation, which has been jeopardized by the lack of transparency and the absence of truly informed discussions about NRP-TA with donor families and hospitals, needs to be restored.

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