Neither Ethical nor Prudent: Why Not to Choose Normothermic Regional Perfusion.

In transplant medicine, the use of normothermic regional perfusion (NRP) in donation after circulatory determination of death raises ethical difficulties. NRP is objectionable because it restores the donor's circulation, thus invalidating a death declaration based on the permanent cessation of circulation. NRP's defenders respond with arguments that are tortuous and factually inaccurate and depend on introducing extraneous concepts into the law. However, results comparable to NRP's-more and higher-quality organs and more efficient allocation-can be achieved by removing organs from deceased donors and using normothermic machine perfusion (NMP) to support the organs outside the body, without jeopardizing confidence in transplantation's legal and ethical foundations. Given the controversy that NRP generates and the convoluted justifications made for it, we recommend a prudential approach we call "ethical parsimony," which holds that, in the choice between competing means of achieving a result, the ethically simpler one is to be preferred. This approach makes clear that policy-makers should favor NMP over NRP.

Advancing the Scientific Basis for Determining Death in Controlled Organ Donation After Circulatory Determination of Death.

In controlled organ donation after circulatory determination of death (cDCDD), accurate and timely death determination is critical, yet knowledge gaps persist. Further research to improve the science of defining and determining death by circulatory criteria is therefore warranted. In a workshop sponsored by the National Heart, Lung, and Blood Institute, experts identified research opportunities pertaining to scientific, conceptual, and ethical understandings of DCDD and associated technologies. This article identifies a research strategy to inform the biomedical definition of death, the criteria for its determination, and circulatory death determination in cDCDD. Highlighting knowledge gaps, we propose that further research is needed to inform the observation period following cessation of circulation in pediatric and neonatal populations, the temporal relationship between the cessation of brain and circulatory function after the withdrawal of life-sustaining measures in all patient populations, and the minimal pulse pressures that sustain brain blood flow, perfusion, activity, and function. Additionally, accurate predictive tools to estimate time to asystole following the withdrawal of treatment and alternative monitoring modalities to establish the cessation of circulatory, brainstem, and brain function are needed. The physiologic and conceptual implications of postmortem interventions that resume circulation in cDCDD donors likewise demand attention to inform organ recovery practices. Finally, because jurisdictionally variable definitions of death and the criteria for its determination may impede collaborative research efforts, further work is required to achieve consensus on the physiologic and conceptual rationale for defining and determining death after circulatory arrest.

Knowledge gaps in heart and lung donation after the circulatory determination of death: Report of a workshop of the National Heart, Lung, and Blood Institute.

In a workshop sponsored by the U.S. National Heart, Lung, and Blood Institute, experts identified current knowledge gaps and research opportunities in the scientific, conceptual, and ethical understanding of organ donation after the circulatory determination of death and its technologies. To minimize organ injury from warm ischemia and produce better recipient outcomes, innovative techniques to perfuse and oxygenate organs postmortem in situ, such as thoracoabdominal normothermic regional perfusion, are being implemented in several medical centers in the US and elsewhere. These technologies have improved organ outcomes but have raised ethical and legal questions. Re-establishing donor circulation postmortem can be viewed as invalidating the condition of permanent cessation of circulation on which the earlier death determination was made and clamping arch vessels to exclude brain circulation can be viewed as inducing brain death. Alternatively, TA-NRP can be viewed as localized in-situ organ perfusion, not whole-body resuscitation, that does not invalidate death determination. Further scientific, conceptual, and ethical studies, such as those identified in this workshop, can inform and help resolve controversies raised by this practice.

Research opportunities and ethical considerations for heart and lung xenotransplantation research: A report from the National Heart, Lung, and Blood Institute workshop.

Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include the appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potentially novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report.

Taking the pulse of brain death: A meta-analysis of the natural history of brain death with somatic support.

BACKGROUND AND PURPOSE: The conceptualization of brain death (BD) was pivotal in the shaping of judicial and medical practices. Nonetheless, media reports of alleged recovery from BD reinforced the criticism that this construct is a self-fulfilling prophecy (by treatment withdrawal or organ donation). We meta-analyzed the natural history of BD when somatic support (SS) is maintained. METHODS: Publications on BD were eligible if the following were reported: aggregated data on its natural history with SS; and patient-level data that allowed censoring at the time of treatment withdrawal or organ donation. Endpoints were as follows: rate of somatic expiration after BD with SS; BD misdiagnosis, including "functionally brain-dead" patients (FBD; i.e. after the pronouncement of brain-death, ≥1 findings were incongruent with guidelines for its diagnosis, albeit the lethal prognosis was not altered); and length and predictors of somatic survival. RESULTS: Forty-seven articles were selected (1610 patients, years: 1969-2021). In BD patients with SS, median age was 32.9 years (range = newborn-85 years). Somatic expiration followed BD in 99.9% (95% confidence interval = 89.8-100). Mean somatic survival was 8.0 days (range = 1.6 h-19.5 years). Only age at BD diagnosis was an independent predictor of somatic survival length (coefficient = -11.8, SE = 4, p < 0.01). Nine BD misdiagnoses were detected; eight were FBD, and one newborn fully recovered. No patient ever recovered from chronic BD (≥1 week somatic survival). CONCLUSIONS: BD diagnosis is reliable. Diagnostic criteria should be fine-tuned to avoid the small incidence of misdiagnosis, which nonetheless does not alter the prognosis of FBD patients. Age at BD diagnosis is inversely proportional to somatic survival.

Author Response: Challenges to Brain Death in Revising the Uniform Determination of Death Act: The UDDA Revision Series.

I thank Dr. Machado for his comments about my article summarizing the recent work of the US Uniform Law Commission to revise the Uniform Determination of Death Act.1.

Ethical issues of nosology in disorders of consciousness.

The current classification scheme for severe disorders of consciousness (DoC) has several shortcomings. First, there is no consensus on how to incorporate patients with covert consciousness. Second, there is a mismatch between the definitions of severe DoC, based on consciousness, and the diagnosis of these same DoC, which is based on observable motoric responsiveness. Third, current categories are grouped into large heterogeneous syndromes which share phenotype, but do not incorporate underlying pathophysiology. Here we discuss several ethical issues pertaining to the current nosology of severe DoC. We conclude by proposing a revised nosology which addresses these shortcomings.

Inconsistency between the Circulatory and the Brain Criteria of Death in the Uniform Determination of Death Act.

The Uniform Determination of Death Act (UDDA) provides that "an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead." We show that the UDDA contains two conflicting interpretations of the phrase "cessation of functions." By one interpretation, what matters for the determination of death is the cessation of spontaneous functions only, regardless of their generation by artificial means. By the other, what matters is the cessation of both spontaneous and artificially supported functions. Because each UDDA criterion uses a different interpretation, the law is conceptually inconsistent. A single consistent interpretation would lead to the conclusion that conscious individuals whose respiratory and circulatory functions are artificially supported are actually dead, or that individuals whose brain is entirely and irreversibly destroyed may be alive. We explore solutions to mitigate the inconsistency.

Black Patients Matter in Neurology: Race, Racism, and Race-Based Neurodisparities.

Black people living in the United States suffer disproportionate morbidity and mortality across a wide range of neurologic conditions. Despite common conceptions to the contrary, "race" is a socially defined construct with little genetic validity. Therefore, racial health inequities in neurology ("neurodisparities") are not a consequence of biologic differences between races. Instead, racism and associated social determinants of health are the root of neurodisparities. To date, many neurologists have neglected racism as a root cause of neurologic disease, further perpetuating the problem. Structural racism, largely ignored in current neurologic practice and policy, drives neurodisparities through mediators such as excessive poverty, inferior health insurance, and poorer access to neurologic and preventative care. Interpersonal racism (implicit or explicit) and associated discriminatory practices in neurologic research, workforce advancement, and medical education also exacerbate neurodisparities. Neurologists cannot fulfill their professional and ethical responsibility to care for Black patients without understanding how racism, not biologic race, drives neurodisparities. In our review of race, racism, and race-based disparities in neurology, we highlight the current literature on neurodisparities across a wide range of neurologic conditions and focus on racism as the root cause. We discuss why all neurologists are ethically and professionally obligated to actively promote measures to counteract racism. We conclude with a call for actions that should be implemented by individual neurologists and professional neurologic organizations to mitigate racism and work towards health equity in neurology.

Emerging Subspecialties in Neurology: Neuroethics: An Emerging Career Path in Neurology.

Essential to responsible practice and progress in neurology and neuroscience research is robust engagement with associated ethical dimensions and challenges. By virtue of the privileged relationship between personhood and the brain, and the importance of properties of the nervous system to what for most makes life worth living, conditions that affect neurologic function introduce a growing host of novel ethical and philosophical issues. Rather than serving a reactionary role, it is important for neurologists to anticipate such issues and develop familiarity with ethical analysis to inform quality medical practice and to safeguard neuroscience research. The field of neuroethics is an emerging career path devoted to identifying and evaluating such issues with the aim of informing optimal clinical practice and responsible neuroscience research. This article describes the past, present, and future of neuroethics, informed by an interview with one of the field's key founders and luminaries, Dr. James Bernat, with specific focus on training and career opportunities for neurologists in training.