Ethical Issues in Normothermic Regional Perfusion in Controlled Organ Donation After Determination of Death by Circulatory Criteria: A Scoping Review

Identifying the Research Question

Our review question was broad in scope, necessitating the iterative development of several subquestions consistent with our overall aim of documenting the extent and nature of perspectives on the ethics of NRP (Table 1).

Identifying Relevant Literature

A clinical research librarian developed a search strategy with controlled vocabulary using 15 known relevant articles for validation. We applied a common search string across MEDLINE and Embase from inception to June 2023 to identify relevant English-language publications (Supplemental Digital Content 1, SDC, http://links.lww.com/TP/D129). We undertook a hand-search of reference lists from frequently cited publications to identify articles not captured by the search strategy. Gray literature was sourced through searches of English-language organ donation organization websites and consultation with our research network.

Study Selection

Three reviewers (M.B., M.G., and N.M.) screened all titles and abstracts against inclusion and exclusion criteria (Supplemental Digital Content 2, SDC, http://links.lww.com/TP/D129). All potentially relevant articles then underwent full-text review by a minimum of 2 reviewers meeting regularly to achieve consensus on inclusion or exclusion. To maximize the inclusiveness of viewpoints, we retained articles if they included at least 1 substantive argument or position relating to the ethical issues surrounding NRP. We defined “substantive” to mean offering a reason in support of an ethical proposition.

Data Charting

We used AirTable software to chart extracted data. Three reviewers knowledgeable in ethics (N.B.M.), medicine (M.B.), and law (M.G.) participated in data charting. Each article was independently assessed by a minimum of 2 reviewers. Our preliminary data chart was iteratively revised as recurring categories of interest emerged from the first 15 articles, then finalized in a consensus meeting (Supplemental Digital Content 3, SDC, http://links.lww.com/TP/D129). Reviewers met virtually 2 times a week to achieve consensus on the relevance of the information extracted and to discuss emerging themes and patterns.

Data Analysis

Extracted data were classified according to our identified categories of interest, after which we undertook thematic categorization by iteratively folding interrelated categories under overarching themes, with some categories informing multiple themes (Table 2). To ensure disconfirming patterns were not overlooked, reviewers regularly discussed emerging findings with each other and other members of the research team familiar with NRP literature. Consistent with the scoping review methodology, we did not assess article quality.³⁷

Dead Donor Rule

The DDR is an ethical injunction stipulating that organ recovery cannot be the cause of death. By protecting donors from harm, the rule upholds stakeholder trust in donation systems.⁴⁰

After its introduction in the 1990s, cDCDD was subjected to controversy as a result of perceptions that it violated the DDR.^41-43 The debate centered around whether for the purposes of clinical practice and organ donation death should be considered irreversible—that is, cannot be reversed under any circumstances—or merely permanent—that is, will not be reversed under these circumstances.⁴⁴ Despite reasoned dissent from some critics,⁴⁵ it is now widely accepted that death in conventional cDCDD is justifiably determined based on permanence.^46,47

The advent of NRP reignited debates regarding cDCDD and the DDR.²⁴ Recognizing that the debates regarding cDCDD-NRP and the DDR are interwoven, below we sequentially describe 3 strands of argument and counterargument discernible in the literature (Table 5).

Resuscitation and Death Determination

By reinstituting circulation after death determination based on the permanent cessation of circulation, NRP seems to upset the cDCDD death determination framework.²⁵ This is particularly problematic in jurisdictions such as the United States and Australia, where legislation implies that the reinstitution of circulation would legally invalidate death determination.¹ Whether resumption of circulation has ethical implications for the DDR is widely discussed in the literature.

Critics argue that NRP not only invalidates death determination from a medico-legal perspective,²⁹ but also that the resumption of circulation implies that the donor has been “successfully resuscitated.”⁴⁸ It follows that subsequent organ recovery violates the DDR. This argument has most traction with respect to TA-NRP, where spontaneous cardiac function can be restored, allowing the donor to be weaned from the extracorporeal circuit.

Proponents of cDCDD-NRP respond to this charge in at least 4 ways. First, because the donor has been declared dead, no subsequent action could invalidate death determination because this would be a contradiction.⁴⁹ After death determination, argue Parent et al,⁵⁰ the donor is dead by definition: “a dead donor cannot be ‘made’ dead, nor can organ retrieval cause death in a dead body.” In response, critics suggest that this argument begs the question because it presupposes what is at issue—the physiologic state of the donor.⁵¹ As DeCamp et al⁵² note, “[i]t is no defense to suggest the patient was already dead when the action [recirculation] negates the conditions upon which that determination was made.”

Second, supporters of NRP argue that while on a “rigid and impractical”⁵³ reading, it is plausible to suggest reinstitution of circulation technically invalidates death determination; this ignores the role of intent.^50,54 To resuscitate a patient, they argued, one must intend resuscitation. “Resuscitation efforts require attempting to restart the heart for life-saving/prolonging purposes. In undertaking [cDCDD-NRP], there is no intention or attempt to resuscitate…”⁵⁰ The donor is not alive; rather, regions of their body are perfused for the purposes of donation. Opponents reject this reasoning, implying that it strains semantics. “Even if the stated intent of [cDCDD-NRP] is to preserve the organs (not to resuscitate the patient), this obscures and cannot be separated from what actually happens: NRP does resuscitate the patient.”⁴⁸

Capitalizing on a well-known definition of death, a third response to the charge that NRP resuscitates the patient and violates the DDR posits that, while TA-NRP restores the function of several vital organs, it does not restore the integrated function of the organism as a whole.⁵⁵ Indeed, argue Wall et al,⁵⁶ the donor is restored to life no more than they would be were all vital organs save the brain removed and perfused en bloc: “While it is optically different to see a heart restart in the body rather than on a perfusion device, there is no ethical difference…” Opponents do not find this compelling, holding that TA-NRP—unlike conventional cDCDD—is predicated on (induced) brain death.⁵⁷

The fourth response to the argument that NRP violates the DDR acknowledges that the traditional criteria for death determination in cDCDD are plausibly invalidated by the resumption of circulation but denies that this says anything about the physiologic state of death of the donor.^58-60 With some exceptions,⁴⁷ clinical guidelines for death determination in cDCDD hold that death is determinable based on the permanent cessation of circulation but do not go further to explain why that is so. Defenders of NRP attempt to do so, arguing that the only reason circulatory criteria were ever valid was because they identify, by extension, the permanent cessation of brain function.^2,3,10 As Bernat et al⁵⁸ argue, “the use of the unified brain-based concept of death resolves the dilemma by clarifying that the relevant circulation that must cease is circulation to the brain.”⁵⁸ So long as intracranial blood flow has stopped, the brain cannot function, and the donor is deceased; whether circulation continues extracranially is beside the point.⁶¹ Critics respond that this redefinition of death is at worst gerrymandering, at best not within the purview of supporters of NRP.⁵²

Prevention of Intracranial Blood Flow

Another prominent strand of argument for why NRP violates the DDR focuses on the surgical act of ligating, transecting, or occluding the major vessels to the brain to prevent intracranial blood flow and ensure the permanent cessation of brain function in TA-NRP.^62,63 In April 2021, the American College of Physicians (ACP)⁴⁸ argued provocatively that, far from being a postmortem procedure, cDCDD-NRP is “more accurately described as organ retrieval after cardiopulmonary arrest and the induction of brain death.” Citing a commonly accepted theory of causation, Courtwright⁶⁴ elucidates the argument:

c is a cause of e just in case had c not occurred, e would not have occurred and there exists a causal chain leading from c to e. In NRP, the event (e) is the permanent loss of brain function, and the cause (c) is occlusion of the cerebral circulation. If occlusion of the cerebral circulation had not occurred, the donor would not predictably have had permanent loss of brain function.

After the reinstitution of circulation, the donor no longer meets the criteria for circulatory determination of death and brain function is not irreversibly lost in at least some cases. By preventing the resumption of brain activity or limited function during resuscitation, the surgical blockage causes neurologic death—defined in some jurisdictions as the irreversible loss of all brain function—and may render physicians complicit in the donor’s death.^65-67

Proponents of NRP respond to this argument in ways that roughly mirror the defenses described above. First, because the death of the donor has been determined, it is implausible to argue that the donor can be made dead a second time over.⁵⁰ Detractors retort by questioning why, if the donor is truly dead, it is thought necessary to prevent intracranial blood flow in the first place.^26,43

Second, highlighting the goals of the donor and healthcare team, defenders of NRP argue that surgical blockage merely ensures that the natural trajectory toward irreversible cessation of brain function is not interrupted:^30,50 The cause of death is not the surgical intervention, but the underlying medical condition that led to the decision to withdraw life-sustaining measures.^3,10,56 Critics respond that surgical blockage is anything but natural.^48,52

Third, supporters point to other measures intended to prevent the resumption of brain function in DCDD, such as prohibitions on cyclic ventilation, and ask whether surgical blockage is really so different.^30,59 Leaning on a distinction between “doing” and “allowing,” detractors respond that active intervention is morally different than an omission.^25,68

Fourth, given that death is the permanent cessation of brain function, surgical blockage merely maintains what has already occurred.⁴⁹ Furthermore, the permanent cessation of brain function was the agreed-upon outcome from the start.⁶⁰ Critics remain unconvinced, arguing that to “maintain” is to “cause” and that the use of misleading language is dishonest.^51,65

A final, somewhat indirect response to the charge that surgical blockage is the cause of death highlights alleged inconsistencies in that argument’s reasoning. The ACP contends that the donor is rendered dead by neurologic criteria in part because the donor undergoing NRP no longer meets the criteria for circulatory determination of death.⁴⁸ As Wall et al³⁰ argue, the statement from the ACP implies there are literally 2 types of death, that one can be dead in one way but not another, and that “one can be declared dead twice in 2 different ways.” An unwelcome consequence, Wall et al³⁰ continue, is that “in framing the act of excluding cerebral circulation as ‘bringing on brain death’ the ACP is implying that circulatory death is not death, which brings the entire practice of DCD donation… into question.” The implication is that we should not put too much stock in the bifurcated character of death determination standards, medico-legal constructs that are meant to identify the same phenomenon—death.

Brain Activity and Function

Another strand of argument regarding the consistency of NRP with the DDR concerns the potential for the resumption of brain activity or limited function through intracranial circulation. Under the unifying brain-based definition of death, death is the permanent cessation of brain function, determined using either circulatory or neurologic criteria.^47,58 Because in some cases the cDCDD donor has likely not irreversibly lost all brain function at the time NRP is initiated, “it is essential that all brain circulation has ceased completely and is not restored by NRP or any other means.”⁵⁸ Otherwise, the donor would no longer meet the definition of death, and organ recovery would violate the DDR.¹⁰

Even supporters of NRP raise concerns about the risk of intracranial circulation through the failure of surgical safeguards, collateral vessels, or anatomic variations.⁶⁹ Because the minimal pressures to sustain neuronal perfusion and function are unknown,⁷⁰ it is necessary to rely on the complete exclusion of intracranial flow to ensure the permanent cessation of brain function.⁷¹ However, in most protocols, this exclusion is only assumed, not monitored for—to the consternation of commentators who argue this should to be an “essential component” of NRP.^3,35 Asks Dalle Ave⁷²: “Is society ready to accept such ‘assumability’ of death?”

Recent studies with small sample sizes have found no intracranial blood flow during NRP (where intracranial blood pressure was used as a surrogate for flow).^73,74 Further prospective research will help to resolve the debate on the compatibility of NRP with the DDR when considered in relation to the unified, brain-based definition of death.

Donor Harm

Closely related to debates regarding NRP and the DDR are those concerning the potential for both welfare and dignitary harms to donors (some of which overlap). Although these debates are often subsumed under broader discussion of the compatibility of NRP with the DDR, they are important areas of focus for a minority of commentators.^75,76

Consent

The ethical issues described above fuel debates regarding how—or whether—specific informed consent to NRP should be sought. On one end of the spectrum are vocal detractors who argue that, because “consent cannot confer ethical legitimacy”⁴⁸ on an unethical practice, informed consent to NRP is not sufficient for moral permissibility. On the other end are those who contend that consent may not even be needed, provided NRP surgical safeguards are proven effective, because the procedure could be subsumed under consent to organ donation.⁸⁵ More frequently, the debate concerns how much information needs to be disclosed to surrogates to enable informed decision-making.⁸⁵

Although surgical detail regarding conventional cDCDD is not generally disclosed to surrogate decision-makers, some believe NRP is such a departure from usual practice that its use demands disclosure of specific aspects of the procedure.^26,65 These include surgical blockage of cerebral vessels, the resumption of circulation, and the restoration of spontaneous cardiac function in TA-NRP.^35,48,59 Some go further, suggesting that “a reasonable person would want to know” that while many commentators recommend neurologic monitoring during NRP to ensure donor safety, this is not standard protocol.⁶⁵ This latter view implies that some believe disclosing empirical uncertainties—and ethical ones—is necessary for valid informed consent as a result of what are perceived to be material risks.

The level of information surrogates need and desire is not known. As Parent et al⁸⁶ argue, “[i]nformed consent is not just dumping all details on grieving traumatized families.” Yet, what level of detail is too much, and what level is too little? In the absence of qualitative research involving donor families, this is difficult to judge.

Stakeholder Trust

Stakeholder trust is the cornerstone of deceased donation systems.²⁶ There is widespread concern in the literature that perceptions of NRP as an unethical practice could undermine this trust, exacerbating the organ shortfall. Although some speculate that the “potential loss of public trust… might be overstated” given that donation systems are resilient “even in the face of scandals and mistrust,”⁸⁷ others are not so sanguine. Any adverse event stemming from NRP, argue Shapey et al⁸⁵ , would have a “catastrophic impact. On the issue of the potential impact of NRP on stakeholder trust, there are 3 prominent areas of dispute.

Justice

An infrequently addressed theme in the NRP literature stems from a claim by the ACP that the use of NRP could disproportionately affect stigmatized and underserved populations, especially in North American jurisdictions affected by the opioid epidemic.⁴⁸ According to the ACP, victims of opiate or other drug overdose may be more likely than others to become candidates for cDCDD and, hence, NRP. The ACP asks rhetorically: “Does this fulfill the requirements of justice for an equitable distribution of benefits and burdens within society?”⁴⁸

Proponents of NRP dismiss this argument, not least because it presupposes that NRP is harmful.³⁰ Acknowledging that the opioid epidemic is indeed of great concern, James et al⁵³ argue that it is separable from the ethical issues in NRP:

The procurement of organs after the declaration of death has no impact on the medical care received by patients antemortem or the cause of their death. Refusing to allow this method of optimizing donation does nothing to subdue the opioid epidemic; instead, it denies donor/surrogate(s) what is perhaps the best opportunity to find purpose and altruism within profound grief.

Beneficence

The above quote points to a final theme in the literature, namely the disputed ethical significance of the acknowledged potential of NRP to advance the goals of beneficence by maximizing benefits to organ recipients, donors, their families, and society.^{49,50,84,90,99,100}

Whatever one thinks of the ethics of NRP, most agree that it is likely an effective intervention that may be more cost-effective than alternative organ recovery protocols.^17-23 Proponents note that the technique can contribute to the fulfillment of donors’ altruistic wishes, help families find meaning in loss, improve outcomes for recipients, and increase organ supply for the benefit of waitlisted patients, donation systems, and society. Donation and transplantation communities arguably have a duty to maximize benefits for stakeholders and honor the legacy of donors who have authorized donations.⁹⁹ Seen in this light, argues Lazaridis, NRP becomes a moral imperative, “not only permissible but ethically required.”¹⁰¹

Although acknowledging that NRP could benefit stakeholders, detractors remain skeptical. Commentators note that medical ethics requires judgment when principles come into conflict. The ends that NRP serves cannot be allowed to mask the ethical impropriety of NRP, some argue, “no matter how noble or good those ends may be.”⁴⁸

Limitations

This review benefited from a robust methodological approach including 3 reviewers knowledgeable in ethics, medicine, and law and an authorship group with content expertise in bioethics, critical care, donation science, law, transplantation, and perfusion technologies. However, for feasibility reasons, we included only English-language literature. As NRP (particularly A-NRP) is widely practiced in Europe, this is a limitation of the review. Furthermore, consistent with the scoping review methodology, we did not assess article quality, meaning publications of low quality may have been included. Finally, because we excluded articles that discussed only NRP in uncontrolled DCDD, we may not have captured all arguments relevant to cDCDD-NRP as the 2 applications of extracorporeal membrane oxygenation have commonalities.