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.

The Unified Brain-Based Determination of Death Conceptually Justifies Death Determination in DCDD and NRP Protocols.

Organ donation after the circulatory determination of death requires the permanent cessation of circulation while organ donation after the brain determination of death requires the irreversible cessation of brain functions. The unified brain-based determination of death connects the brain and circulatory death criteria for circulatory death determination in organ donation as follows: permanent cessation of systemic circulation causes permanent cessation of brain circulation which causes permanent cessation of brain perfusion which causes permanent cessation of brain function. The relevant circulation that must cease in circulatory death determination is that to the brain. Eliminating brain circulation from the donor ECMO organ perfusion circuit in thoracoabdominal NRP protocols satisfies the unified brain-based determination of death but only if the complete cessation of brain circulation can be proved. Despite its medical and physiologic rationale, the unified brain-based determination of death remains inconsistent with the Uniform Determination of Death Act.

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.

Policies for Mandatory Ethics Consultations at U.S. Academic Teaching Hospitals: A Multisite Survey Study.

OBJECTIVES: To determine the number of top-ranked U.S. academic institutions that require ethics consultation for specific adult clinical circumstances (e.g., family requests for potentially inappropriate treatment) and to detail those circumstances and the specific clinical scenarios for which consultations are mandated. DESIGN: Cross-sectional survey study, conducted online or over the phone between July 2016 and October 2017. SETTING: We identified the top 50 research medical schools through the 2016 U.S. News and World Report rankings. The primary teaching hospital for each medical school was included. SUBJECTS: The chair/director of each hospital's adult clinical ethics committee, or a suitable alternate representative familiar with ethics consultation services, was identified for study recruitment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A representative from the adult ethics consultation service at each of the 50 target hospitals was identified. Thirty-six of 50 sites (72%) consented to participate in the study, and 18 (50%) reported having at least one current mandatory consultation policy. Of the 17 sites that completed the survey and listed their triggers for mandatory ethics consultations, 20 trigger scenarios were provided, with three sites listing two distinct clinical situations. The majority of these triggers addressed family requests for potentially inappropriate treatment (9/20, 45%) or medical decision-making for unrepresented patients lacking decision-making capacity (7/20, 35%). Other triggers included organ donation after circulatory death, initiation of extracorporeal membrane oxygenation, denial of valve replacement in patients with subacute bacterial endocarditis, and posthumous donation of sperm. Twelve (67%) of the 18 sites with mandatory policies reported that their protocol(s) was formally documented in writing. CONCLUSIONS: Among top-ranked academic medical centers, the existence and content of official policies regarding situations that mandate ethics consultations are variable. This finding suggests that, despite recent critical care consensus guidelines recommending institutional review as standard practice in particular scenarios, formal adoption of such policies has yet to become widespread and uniform.

Inconsistencies Between the Criterion and Tests for Brain Death.

The whole-brain criterion of death provides that a person who has irreversibly lost all clinical functions of the brain is dead. Bedside brain death (BD) tests permit physicians to determine BD by showing that the whole-brain criterion of death has been fulfilled. In a nonsystematic literature review, we identified and analyzed case reports of a mismatch between the whole-brain criterion of death and bedside BD tests. We found examples of patients diagnosed as BD who showed (1) neurologic signs compatible with retained brain functions, (2) neurologic signs of uncertain origin, and (3) an inconsistency between standard BD tests and ancillary tests for BD. Two actions can resolve the mismatch between the whole-brain criterion of death and BD tests: (1) loosen the whole-brain criterion of death by requiring only the irreversible cessation of relevant brain functions and (2) tighten BD tests by requiring an ancillary test proving the cessation of intracranial blood flow. Because no one knows the precise brain functions whose loss is necessary to fulfill the whole-brain criterion of death, we advocate tightening BD tests by requiring the absence of intracranial blood flow.

Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project.

IMPORTANCE: There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries. OBJECTIVE: To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel. PROCESS: Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery. EVIDENCE SYNTHESIS: Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed. RECOMMENDATIONS: Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability. CONCLUSIONS AND RELEVANCE: This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.

The ethical obligation of the dead donor rule.

The dead donor rule (DDR) originally stated that organ donors must not be killed by and for organ donation. Scholars later added the requirement that vital organs should not be procured before death. Some now argue that the DDR is breached in donation after circulatory determination of death (DCDD) programs. DCDD programs do not breach the original version of the DDR because vital organs are procured only after circulation has ceased permanently as a consequence of withdrawal of life-sustaining therapy. We hold that the original rendition of the DDR banning killing by and for organ donation is the fundamental norm that should be maintained in transplantation ethics. We propose separating the DDR from two other fundamental normative rules: the duties to prevent harm and to obtain informed consent.

The Organism as a Whole in an Analysis of Death.

Although death statutes permitting physicians to declare brain death are relatively uniform throughout the United States, academic debate persists over the equivalency of human death and brain death. Alan Shewmon showed that the formerly accepted integration rationale was conceptually incomplete by showing that brain-dead patients demonstrated a degree of integration. We provide a more complete rationale for the equivalency of human death and brain death by defending a deeper understanding of the organism as a whole (OaaW) and by using a novel strategy with shared objectives to justify death determination criteria. Our OaaW account describes different types of OaaW, defining human death as the loss of status as a human OaaW. We defend human death as similar to nonhuman death in terms of wakefulness, but also distinct in terms of the sui generis properties, particularly conscious awareness. We thereby defend the equivalency of brain death and human death using a resulting neurocentric rationale.

Aligning the Criterion and Tests for Brain Death.

Disturbing cases continue to be published of patients declared brain dead who later were found to have a few intact brain functions. We address the reasons for the mismatch between the whole-brain criterion and brain death tests, and suggest solutions. Many of the cases result from diagnostic errors in brain death determination. Others probably result from a tiny amount of residual blood flow to the brain despite intracranial circulatory arrest. Strategies to lessen the mismatch include improving brain death determination training for physicians, mandating a test showing complete intracranial circulatory arrest, or revising the whole-brain criterion.

Refinements in the Organism as a Whole Rationale for Brain Death.

Death can be defined as the permanent cessation of the organism as a whole. Although the organism as a whole is a century-old concept, it remains better intuited than analyzed. Recent concepts in theoretical biology including hierarchies of organization, emergent functions, and mereology have informed the idea that the organism as a whole is the organism's critical emergent functions. Because the brain conducts the critical emergent functions including conscious awareness and control of respiration and circulation, the cessation of brain functions is death of the organism. A newer concept, the brain as a whole, may offer a superior criterion of death to the whole-brain criterion, because it more closely matches accepted clinical brain death tests and confirms the cessation of the organism's emergent functions. Although the concepts of organism as a whole and brain as a whole remain vague and in need of rigorous biophilosophical analysis, their future precision will be restricted by the categorical limitations intrinsic to theoretical biological models.

Uncontrolled Donation After Circulatory Determination of Death: A Systematic Ethical Analysis.

Uncontrolled donation after circulatory determination of death (uDCDD) refers to organ donation after a refractory cardiac arrest. We analyzed ethical issues raised by the uDCDD protocols of France, Madrid, and New York City. We recommend: (1) Termination of resuscitation (TOR) guidelines need refinement, particularly the minimal duration of resuscitation efforts before considering TOR; (2) Before enrolling in an uDCDD protocol, physicians must ascertain that additional resuscitation efforts would be ineffective; (3) Inclusion in an uDCDD protocol should not be made in the outpatient setting to avoid error and conflicts of interest; (4) The patient's condition should be reassessed at the hospital and reversible causes treated; (5) A no-touch period of at least 10 minutes should be respected to avoid the risk of autoresuscitation; (6) Once death has been determined, no procedure that may resume brain circulation should be used, including cardiopulmonary resuscitation, artificial ventilation, and extracorporeal membrane oxygenation; (7) Specific consent is required prior to entry into an uDCDD protocol; (8) Family members should be informed about the goals, risks, and benefits of planned uDCDD procedures; and (9) Public information on uDCDD is desirable because it promotes public trust and confidence in the organ donation system.

Ethical, Palliative, and Policy Considerations in Disorders of Consciousness.

This essay complements the scientific and practice scope of the American Academy of Neurology Guideline on Disorders of Consciousness by providing a discussion of the ethical, palliative, and policy aspects of the management of this group of patients. We endorse the renaming of "permanent" vegetative state to "chronic" vegetative state given the increased frequency of reports of late improvements but suggest that further refinement of this class of patients is necessary to distinguish late recoveries from patients who were misdiagnosed or in cognitive-motor dissociation. Additional nosologic clarity and prognostic refinement is necessary to preclude overestimation of low probability events. We argue that the new descriptor "unaware wakefulness syndrome" is no clearer than "vegetative state" in expressing the mismatch between apparent behavioral unawareness when patients have covert consciousness or cognitive motor dissociation. We advocate routine universal pain precautions as an important element of neuropalliative care for these patients given the risk of covert consciousness. In medical decision-making, we endorse the use of advance directives and the importance of clear and understandable communication with surrogates. We show the value of incorporating a learning health care system so as to promote therapeutic innovation. We support the Guideline's high standard for rehabilitation for these patients but note that those systems of care are neither widely available nor affordable. Finally, we applaud the Guideline authors for this outstanding exemplar of engaged scholarship in the service of a frequently neglected group of brain-injured patients.

Headache Professional Societies: Ethical Challenges and Suggested Solutions.

Codes of professional conduct continue to be an essential component of maintaining the integrity of individuals, academic institutions, and medical societies. We review ethical issues of professional conduct focusing on conflicts of interest (COI). We explain how to manage or mitigate COI in the context of professionals involved in headache medicine and its medical specialty societies. We identify the roles of institutional, medical society, and governmental regulation in the protection of patients and maintaining the integrity of physicians and others involved in patient care.

Minority Representation in Migraine Treatment Trials.

BACKGROUND: Minorities have historically been underrepresented in clinical research trials despite having comparatively poor health indicators. Recognizing the dual inequalities of increased disease burden and decreased research participation, the National Institute of Health (NIH) Revitalization Act of 1993 mandated the inclusion and reporting of women and minorities in NIH-funded research. While progress has been made in the subsequent decades, this underrepresentation of minorities in research trials persists and has been documented in multiple disciplines. However, the extent of adequate representation and reporting of minority inclusion in clinical trials for migraine remains unknown. OBJECTIVES: In this systematic review and study, we review the literature examining the representation of women and minorities in migraine clinical research trials METHODS: First we searched PubMed for pertinent articles examining the inclusion of women and minorities in migraine clinical research trials. Second, we identified controlled-trials for migraine published since 2011 in major neurology, headache, and general medicine journals using the terms "migraine randomized controlled trial." We then reviewed the results manually and excluded pilot studies and those with fewer than 50 participants. We next determined (a) how frequently representation of minorities and women were reported in these major trials; (b) what factors correlated with reporting; and (c) whether women and minority inclusion comprised their ratios in the general population. RESULTS: We identified 128 relevant clinical trials, of which 36 met our inclusion criteria. All 36 trials (100%) reported gender frequency, and 25 of 36 (69.4%) reported ethnicity or race. Among all studies, women and Whites represented 84.2 and 82.9% of participants (mean), respectively. Studies conducted in the United States and funded by a private company were more likely to report race than studies conducted exclusively outside of the U.S. or with a public sponsor. No studies stratified efficacy or safety by ethnicity or gender. Men and non-Whites in the U.S. were statistically underrepresented. CONCLUSIONS: Most recent headache studies comply with the NIH mandate to include women and minorities in research trials, particularly U.S.-based and industry-funded studies. Whites are overrepresented compared to both the general population and the population of migraineurs. Future studies should strive to increase minority participation and investigate race-based differences in migraine expression, treatment response, and medication toxicity.