Beyond the Final Heartbeat: Neurological Perspectives on Normothermic Regional Perfusion for Organ Donation after Circulatory Death.

Normothermic regional perfusion (NRP) has recently been used to augment organ donation after circulatory death (DCD) to improve the quantity and quality of transplantable organs. In DCD-NRP, after withdrawal of life-sustaining therapies and cardiopulmonary arrest, patients are cannulated onto extracorporeal membrane oxygenation to reestablish blood flow to targeted organs including the heart. During this process, aortic arch vessels are ligated to restrict cerebral blood flow. We review ethical challenges including whether the brain is sufficiently reperfused through collateral circulation to allow reemergence of consciousness or pain perception, whether resumption of cardiac activity nullifies the patient's prior death determination, and whether specific authorization for DCD-NRP is required. ANN NEUROL 2024;95:1035-1039.

Guidelines for Neuroprognostication in Critically Ill Adults with Moderate-Severe Traumatic Brain Injury.

BACKGROUND: Moderate-severe traumatic brain injury (msTBI) carries high morbidity and mortality worldwide. Accurate neuroprognostication is essential in guiding clinical decisions, including patient triage and transition to comfort measures. Here we provide recommendations regarding the reliability of major clinical predictors and prediction models commonly used in msTBI neuroprognostication, guiding clinicians in counseling surrogate decision-makers. METHODS: Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, we conducted a systematic narrative review of the most clinically relevant predictors and prediction models cited in the literature. The review involved framing specific population/intervention/comparator/outcome/timing/setting (PICOTS) questions and employing stringent full-text screening criteria to examine the literature, focusing on four GRADE criteria: quality of evidence, desirability of outcomes, values and preferences, and resource use. Moreover, good practice recommendations addressing the key principles of neuroprognostication were drafted. RESULTS: After screening 8125 articles, 41 met our eligibility criteria. Ten clinical variables and nine grading scales were selected. Many articles varied in defining "poor" functional outcomes. For consistency, we treated "poor" as "unfavorable". Although many clinical variables are associated with poor outcome in msTBI, only the presence of bilateral pupillary nonreactivity on admission, conditional on accurate assessment without confounding from medications or injuries, was deemed moderately reliable for counseling surrogates regarding 6-month functional outcomes or in-hospital mortality. In terms of prediction models, the Corticosteroid Randomization After Significant Head Injury (CRASH)-basic, CRASH-CT (CRASH-basic extended by computed tomography features), International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)-core, IMPACT-extended, and IMPACT-lab models were recommended as moderately reliable in predicting 14-day to 6-month mortality and functional outcomes at 6 months and beyond. When using "moderately reliable" predictors or prediction models, the clinician must acknowledge "substantial" uncertainty in the prognosis. CONCLUSIONS: These guidelines provide recommendations to clinicians on the formal reliability of individual predictors and prediction models of poor outcome when counseling surrogates of patients with msTBI and suggest broad principles of neuroprognostication.

Guidelines for Neuroprognostication in Critically Ill Adults with Intracerebral Hemorrhage.

BACKGROUND: The objective of this document is to provide recommendations on the formal reliability of major clinical predictors often associated with intracerebral hemorrhage (ICH) neuroprognostication. METHODS: A narrative systematic review was completed using the Grading of Recommendations Assessment, Development, and Evaluation methodology and the Population, Intervention, Comparator, Outcome, Timing, Setting questions. Predictors, which included both individual clinical variables and prediction models, were selected based on clinical relevance and attention in the literature. Following construction of the evidence profile and summary of findings, recommendations were based on Grading of Recommendations Assessment, Development, and Evaluation criteria. Good practice statements addressed essential principles of neuroprognostication that could not be framed in the Population, Intervention, Comparator, Outcome, Timing, Setting format. RESULTS: Six candidate clinical variables and two clinical grading scales (the original ICH score and maximally treated ICH score) were selected for recommendation creation. A total of 347 articles out of 10,751 articles screened met our eligibility criteria. Consensus statements of good practice included deferring neuroprognostication-aside from the most clinically devastated patients-for at least the first 48-72 h of intensive care unit admission; understanding what outcomes would have been most valued by the patient; and counseling of patients and surrogates whose ultimate neurological recovery may occur over a variable period of time. Although many clinical variables and grading scales are associated with ICH poor outcome, no clinical variable alone or sole clinical grading scale was suggested by the panel as currently being reliable by itself for use in counseling patients with ICH and their surrogates, regarding functional outcome at 3 months and beyond or 30-day mortality. CONCLUSIONS: These guidelines provide recommendations on the formal reliability of predictors of poor outcome in the context of counseling patients with ICH and surrogates and suggest broad principles of neuroprognostication. Clinicians formulating their judgments of prognosis for patients with ICH should avoid anchoring bias based solely on any one clinical variable or published clinical grading scale.

Guidelines for neuroprognostication in adults with traumatic spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (tSCI) impacts patients and their families acutely and often for the long term. The ability of clinicians to share prognostic information about mortality and functional outcomes allows patients and their surrogates to engage in decision-making and plan for the future. These guidelines provide recommendations on the reliability of acute-phase clinical predictors to inform neuroprognostication and guide clinicians in counseling adult patients with tSCI or their surrogates. METHODS: A narrative systematic review was completed using Grading of Recommendations Assessment, Development, and Evaluation methodology. Candidate predictors, including clinical variables and prediction models, were selected based on clinical relevance and presence of an appropriate body of evidence. The Population/Intervention/Comparator/Outcome/Timing/Setting question was framed as "When counseling patients or surrogates of critically ill patients with traumatic spinal cord injury, should < predictor, with time of assessment if appropriate > be considered a reliable predictor of < outcome, with time frame of assessment >?" Additional full-text screening criteria were used to exclude small and lower quality studies. Following construction of an evidence profile and summary of findings, recommendations were based on four Grading of Recommendations Assessment, Development, and Evaluation criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. Good practice recommendations addressed essential principles of neuroprognostication that could not be framed in the Population/Intervention/Comparator/Outcome/Timing/Setting format. Throughout the guideline development process, an individual living with tSCI provided perspective on patient-centered priorities. RESULTS: Six candidate clinical variables and one prediction model were selected. Out of 11,132 articles screened, 369 met inclusion criteria for full-text review and 35 articles met eligibility criteria to guide recommendations. We recommend pathologic findings on magnetic resonance imaging, neurological level of injury, and severity of injury as moderately reliable predictors of American Spinal Cord Injury Impairment Scale improvement and the Dutch Clinical Prediction Rule as a moderately reliable prediction model of independent ambulation at 1 year after injury. No other reliable or moderately reliable predictors of mortality or functional outcome were identified. Good practice recommendations include considering the complete clinical condition as opposed to a single variable and communicating the challenges of likely functional deficits as well as potential for improvement and for long-term quality of life with SCI-related deficits to patients and surrogates. CONCLUSIONS: These guidelines provide recommendations about the reliability of acute-phase predictors of mortality, functional outcome, American Spinal Injury Association Impairment Scale grade conversion, and recovery of independent ambulation for consideration when counseling patients with tSCI or their surrogates and suggest broad principles of neuroprognostication in this context.

The Relationship Between Manifestation of Diabetes Insipidus and Estimated Glomerular Filtration Rate in Brain Death.

OBJECTIVES: Systematic reviews have revealed that up to 50% of patients with brain death have residual hypothalamic/pituitary activity based on the absence of central diabetes insipidus (DI). We hypothesized that different degrees of renal dysfunction may impact the presence of DI in patients with brain death. DESIGN: Single-center prospective data collection. SETTING: ICUs in a tertiary academic hospital. PATIENTS: All adult patients declared brain dead over 12 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: DI was diagnosed by polyuria, low urine specific gravity, and increasing serum sodium, measured in close proximity. Renal function was assessed by the estimated glomerular filtration rate (eGFR), calculated using the simplified modification of diet in renal disease equation. Analysis was completed in 192 of 234 patients with brain death after excluding those with missing data, those younger than 18 years and those on vasopressin infusions. One hundred twenty-two patients (63.5%) developed DI and 70 patients (36.5%) did not. The proportion of DI decreased significantly with decreasing eGFR: for eGFR greater than 60 mL/min, DI was present in 77.2%; for eGFR 15-60 mL/min, DI was present in 54.5%; for eGFR 14.9-9.8 mL/min, DI was present in 32%; none of the 14 patients with eGFR less than or equal to 9.7 mL/min ever experienced DI ( p < 0.001). Using logistic regression, for every 10 mL/min decrease in eGFR, the odds of DI decreased 0.83 times (95% CI, 0.76-0.90, p < 0.001). CONCLUSIONS: Renal dysfunction significantly impacts DI's clinical manifestation in brain death. We report that patients who experience brain death with severe renal dysfunction may not develop clinical signs of DI.

Pediatric and Adult Brain Death/Death by Neurologic Criteria Consensus Guideline.

BACKGROUND AND OBJECTIVES: The purpose of this guideline is to update the 2010 American Academy of Neurology (AAN) brain death/death by neurologic criteria (BD/DNC) guideline for adults and the 2011 American Academy of Pediatrics, Child Neurology Society, and Society of Critical Care Medicine guideline for infants and children and to clarify the BD/DNC determination process by integrating guidance for adults and children into a single guideline. Updates in this guideline include guidance related to conducting the BD/DNC evaluation in the context of extracorporeal membrane oxygenation, targeted temperature management, and primary infratentorial injury. METHODS: A panel of experts from multiple medical societies developed BD/DNC recommendations. Because of the lack of high-quality evidence on the subject, a novel, evidence-informed formal consensus process was used. This process relied on the panel experts' review and detailed knowledge of the literature surrounding BD/DNC to guide the development of preliminary recommendations. Recommendations were formulated and voted on, using a modified Delphi process, according to the 2017 AAN Clinical Practice Guideline Process Manual. MAJOR RECOMMENDATIONS: Eighty-five recommendations were developed on the following: (1) general principles for the BD/DNC evaluation, (2) qualifications to perform BD/DNC evaluations, (3) prerequisites for BD/DNC determination, (4) components of the BD/DNC neurologic examination, (5) apnea testing as part of the BD/DNC evaluation, (6) ancillary testing as part of the BD/DNC evaluation, and (7) special considerations for BD/DNC determination.

Guidelines for Neuroprognostication in Adults with Guillain-Barré Syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) often carries a favorable prognosis. Of adult patients with GBS, 10-30% require mechanical ventilation during the acute phase of the disease. After the acute phase, the focus shifts to restoration of motor strength, ambulation, and neurological function, with variable speed and degree of recovery. The objective of these guidelines is to provide recommendations on the reliability of select clinical predictors that serve as the basis of neuroprognostication and provide guidance to clinicians counseling adult patients with GBS and/or their surrogates. METHODS: A narrative systematic review was completed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Candidate predictors, including clinical variables and prediction models, were selected based on clinical relevance and presence of appropriate body of evidence. The Population/Intervention/Comparator/Outcome/Time frame/Setting (PICOTS) question was framed as follows: "When counseling patients or surrogates of critically ill patients with Guillain-Barré syndrome, should [predictor, with time of assessment if appropriate] be considered a reliable predictor of [outcome, with time frame of assessment]?" Additional full-text screening criteria were used to exclude small and lower quality studies. Following construction of an evidence profile and summary of findings, recommendations were based on four GRADE criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. In addition, good practice recommendations addressed essential principles of neuroprognostication that could not be framed in PICOTS format. RESULTS: Eight candidate clinical variables and six prediction models were selected. A total of 45 articles met our eligibility criteria to guide recommendations. We recommend bulbar weakness (the degree of motor weakness at disease nadir) and the Erasmus GBS Respiratory Insufficiency Score as moderately reliable for prediction of the need for mechanical ventilation. The Erasmus GBS Outcome Score (EGOS) and modified EGOS were identified as moderately reliable predictors of independent ambulation at 3 months and beyond. Good practice recommendations include consideration of both acute and recovery phases of the disease during prognostication, discussion of the possible need for mechanical ventilation and enteral nutrition during counseling, and consideration of the complete clinical condition as opposed to a single variable during prognostication. CONCLUSIONS: These guidelines provide recommendations on the reliability of predictors of the need for mechanical ventilation, poor functional outcome, and independent ambulation following GBS in the context of counseling patients and/or surrogates and suggest broad principles of neuroprognostication. Few predictors were considered moderately reliable based on the available body of evidence, and higher quality data are needed.

Guidelines for Neuroprognostication in Comatose Adult Survivors of Cardiac Arrest.

BACKGROUND: Among cardiac arrest survivors, about half remain comatose 72 h following return of spontaneous circulation (ROSC). Prognostication of poor neurological outcome in this population may result in withdrawal of life-sustaining therapy and death. The objective of this article is to provide recommendations on the reliability of select clinical predictors that serve as the basis of neuroprognostication and provide guidance to clinicians counseling surrogates of comatose cardiac arrest survivors. METHODS: A narrative systematic review was completed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Candidate predictors, which included clinical variables and prediction models, were selected based on clinical relevance and the presence of an appropriate body of evidence. The Population, Intervention, Comparator, Outcome, Timing, Setting (PICOTS) question was framed as follows: "When counseling surrogates of comatose adult survivors of cardiac arrest, should [predictor, with time of assessment if appropriate] be considered a reliable predictor of poor functional outcome assessed at 3 months or later?" Additional full-text screening criteria were used to exclude small and lower-quality studies. Following construction of the evidence profile and summary of findings, recommendations were based on four GRADE criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. In addition, good practice recommendations addressed essential principles of neuroprognostication that could not be framed in PICOTS format. RESULTS: Eleven candidate clinical variables and three prediction models were selected based on clinical relevance and the presence of an appropriate body of literature. A total of 72 articles met our eligibility criteria to guide recommendations. Good practice recommendations include waiting 72 h following ROSC/rewarming prior to neuroprognostication, avoiding sedation or other confounders, the use of multimodal assessment, and an extended period of observation for awakening in patients with an indeterminate prognosis, if consistent with goals of care. The bilateral absence of pupillary light response > 72 h from ROSC and the bilateral absence of N20 response on somatosensory evoked potential testing were identified as reliable predictors. Computed tomography or magnetic resonance imaging of the brain > 48 h from ROSC and electroencephalography > 72 h from ROSC were identified as moderately reliable predictors. CONCLUSIONS: These guidelines provide recommendations on the reliability of predictors of poor outcome in the context of counseling surrogates of comatose survivors of cardiac arrest and suggest broad principles of neuroprognostication. Few predictors were considered reliable or moderately reliable based on the available body of evidence.

Endocannabinoid System of the Blood-Brain Barrier: Current Understandings and Therapeutic Potentials.

The endocannabinoid system (ECS) has been found at the blood-brain barrier (BBB), as Cannabinoid receptors were characterized in human brain microvascular endothelial cells and astrocytes. In several in vitro and in vivo studies, cannabinoids decreased BBB permeability and enhanced membrane integrity, which may be achieved through endothelial tight junctions and other mechanisms. These permeability regulation effects of cannabinoids suggested that the ECS may protect the brain by enhancing barrier integrity. Related questions about cannabinoid-drug interaction and drug distribution across the BBB are also raised. Specifically, can cannabinoids significantly reduce drug bioavailability to the brain? More in-depth and systematic investigations are needed to characterize and quantify these effects of cannabinoids on brain microvasculature physiopathology. Therefore, this review summarizes literatures from different disciplines to promote more research on assessing the therapeutic benefits and risks of using cannabinoids to protect BBB from dysfunctions or breakdown, and to avoid consequent brain damages due to inflammation, neurodegenerations, hemorrhage, ischemia, or other causes.

Metabolic values precluding clinical death by neurologic Criteria/Brain death: Survey of neurocritical care society physicians.

BACKGROUND: There are no established ranges for metabolic values prior to death by neurologic criteria/brain death determination (DNC/BD) and the thresholds required by institutional protocols and accepted by neurointensivists is unknown. METHODS: We designed a survey that addressed 1) the metabolic tests required in institutional guidelines prior to brain death determination, 2) the metabolic tests the respondent reviewed prior to brain death determination, and 3) the metabolic test thresholds for laboratory tests that were perceived to preclude or permit clinical DNC/BD determination. The survey was distributed online to physicians in the Neurocritical Care Society from September to December 2019. Respondents were dichotomized based on the number of brain death evaluations they had performed (≤20 vs. > 20) and responses were compared between groups. RESULTS: The survey was completed by 84 physicians. Nearly half (47.6%) of respondents did not believe their institutions required metabolic testing. The metabolic testing for which institutions most commonly provided a defined threshold were arterial pH (34.5%, 29/84), sodium (28.6%, 24/84), and glucose (15.5%, 13/84). Nearly all (97.6%) respondents routinely reviewed metabolic tests prior to brain death evaluation, the most common of which were: sodium (91.7%, 77/84), arterial pH (83.3%, 70/84), and glucose (79.8%, 67/84). Respondents who had performed > 20 evaluations were less likely to check thyroxine and total bilirubin (3.6%, 2/55 vs. 20.7%, 6/29 (p = 0.011) and 12.7%, 7/55 vs. 31%, 9/29 (p = 0.042), respectively), and had a more liberal upper limit of potassium (6.3 mEq/L vs 6.0 mEq/L, p = 0.045). CONCLUSION: Prior to brain death evaluation, neurocritical care providers commonly review similar metabolic tests and have similar thresholds regarding values that would preclude clinical brain death determination. This finding is independent of experience with brain death determination.

Comparison of 1 vs 2 Brain Death Examinations on Time to Death Pronouncement and Organ Donation: A 12-Year Single Center Experience.

OBJECTIVE: To fill the evidence gap on the value of a single brain death (SBD) or dual brain death (DBD) examination by providing data on irreversibility of brain function, organ donation consent, and transplantation. METHODS: Twelve-year tertiary hospital and organ procurement organization data on brain death (BD) were combined and outcomes, including consent rate for organ donation and organs recovered and transplanted after SBD and DBD, were compared after multiple adjustments for covariates. RESULTS: A total of 266 patients were declared BD, 122 after SBD and 144 after DBD. Time from event to BD declaration was longer by an average of 20.9 hours after DBD (p = 0.003). Seventy-five (73%) families of patients with SBD and 86 (72%) with DBD consented for organ donation (p = 0.79). The number of BD examinations was not a predictor for consent. No patient regained brain function during the periods following BD. Patients with SBD were more likely to have at least 1 lung transplanted (p = 0.031). The number of organs transplanted was associated with the number of examinations (ß coefficient [95% confidence interval] -0.5 [-0.97 to -0.02]; p = 0.044), along with age (for 5-year increase, -0.36 [-0.43 to -0.29]; p < 0.001) and PaO2 level (for 10 mm Hg increase, 0.026 [0.008-0.044]; p = 0.005) and decreased as the elapsed time to BD declaration increased (p = 0.019). CONCLUSIONS: A single neurologic examination to determine BD is sufficient in patients with nonanoxic catastrophic brain injuries. A second examination is without additional yield in this group and its delay reduces the number of organs transplanted.

Apnea Testing for the Determination of Brain Death: A Systematic Scoping Review.

Apnea is one of the three cardinal findings in brain death (BD). Apnea testing (AT) is physiologically and practically complex. We sought to review described modifications of AT, safety and complication rates, monitoring techniques, performance of AT on extracorporeal membrane oxygenation (ECMO), and other relevant considerations regarding AT. We conducted a systematic scoping review to answer these questions by searching the literature on AT in English language available in PubMed or EMBASE since 1980. Pediatric or animal studies were excluded. A total of 87 articles matched our inclusion criteria and were qualitatively synthesized in this review. A large body of the literature on AT since its inception addresses a variety of modifications, monitoring techniques, complication rates, ways to perform AT on ECMO, and other considerations such as variability in protocols, lack of uniform awareness, and legal considerations. Only some modifications are widely used, especially methods to maintain oxygenation, and most are not standardized or endorsed by brain death guidelines. Future updates to AT protocols and strive for unification of such protocols are desirable.

Neurological determination of death in isolated brainstem lesions: A case report to highlight the issues involved.

The neurological determination of death in patients with isolated brainstem lesions or by disruption of the posterior cerebral circulation is uncommon and many intensivists may never see such a case in their career. It is also the only major difference between the "whole brain" and "brain stem" formulations for the neurological determination of death. We present a case of a patient with infarction of the structures supplied by the posterior cerebral circulation in whom death was diagnosed using neurological criteria, to illustrate the issues involved. We also suggest that international consensus may be achieved if ancillary tests, such as CT angiography, are made mandatory in this situation o demonstrate loss of blood flow in the anterior cerebral circulation as well the posterior circulation.

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.