Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement From the American Heart Association and Neurocritical Care Society.

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

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.

The 2023 American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and Society of Critical Care Medicine Pediatric and Adult Brain Death/Death by Neurologic Criteria Determination Consensus Guidelines: What the Critical Care Team Needs to Know.

Guidelines for brain death/death by neurologic criteria (BD/DNC) determination were revised to provide a consistent and updated approach to BD/DNC evaluation across all ages by the American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and Society of Critical Care Medicine. This article is intended to complement the guidelines and highlight aspects relevant to the critical care community; the actual guidelines should be used to update hospital protocols and dictate clinical practice. Because BD/DNC evaluations are conducted in the ICU, it is essential for members of the critical care community to familiarize themselves with these guidelines. The fundamental concept of BD/DNC has not changed; BD/DNC is permanent loss of function of the brain as a whole, including the brain stem, resulting in coma, brainstem areflexia, and apnea in the setting of an adequate stimulus. The BD/DNC evaluation requires a sufficient observation period to ensure there is no chance of recovery, followed by exclusion of potentially confounding conditions like hypothermia, hypotension, severe metabolic disturbances, or medication effects. Specific guidance is provided for patients who were treated with therapeutic hypothermia or medical or surgical interventions to manage intracranial hypertension. The guidelines outline a structured and meticulous neurologic examination and detail the responses consistent with BD/DNC. A protocol is provided for how to safely perform apnea testing, including modifications needed for patients on extracorporeal membrane oxygenation. Controversial issues such as consent, BD/DNC evaluation in pregnancy, preservation of neuroendocrine function, and primary posterior fossa injuries are addressed. The ultimate goal is to ensure a consistent and accurate approach to BD/DNC evaluation in patients of all ages, fostering public trust in the medical community's ability to determine death. By adhering to these guidelines, critical care clinicians can confidently navigate the challenging aspects of BD/DNC determination.

A Modified Delphi Consensus Approach to Define Entrustable Professional Activities for Neurocritical Care Advanced Practice Providers.

OBJECTIVES: To define consensus entrustable professional activities (EPAs) for neurocritical care (NCC) advanced practice providers (APPs), establish validity evidence for the EPAs, and evaluate factors that inform entrustment expectations of NCC APP supervisors. DESIGN: A three-round modified Delphi consensus process followed by application of the EQual rubric and assessment of generalizability by clinicians not affiliated with academic medical centers. SETTING: Electronic surveys. SUBJECTS: NCC APPs ( n = 18) and physicians ( n = 12) in the United States with experience in education scholarship or APP program leadership. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The steering committee generated an initial list of 61 possible EPAs. The panel proposed 30 additional EPAs. A total of 47 unique nested EPAs were retained by consensus opinion. The steering committee defined six core EPAs addressing medical knowledge, procedural competencies, and communication proficiency which encompassed the nested EPAs. All core EPAs were retained and subsequently met the previously described cut score for quality and structure using the EQual rubric. Most clinicians who were not affiliated with academic medical centers rated each of the six core EPAs as very important or mandatory. Entrustment expectations did not vary by prespecified groups. CONCLUSIONS: Expert consensus was used to create EPAs for NCC APPs that reached a predefined quality standard and were important to most clinicians in different practice settings. We did not identify variables that significantly predicted entrustment expectations. These EPAs may aid in curricular design for an EPA-based assessment of new NCC APPs and may inform the development of EPAs for APPs in other critical care subspecialties.

Association of Dynamic Trajectories of Time-Series Data and Life-Threatening Mass Effect in Large Middle Cerebral Artery Stroke.

BACKGROUND: Life-threatening, space-occupying mass effect due to cerebral edema and/or hemorrhagic transformation is an early complication of patients with middle cerebral artery stroke. Little is known about longitudinal trajectories of laboratory and vital signs leading up to radiographic and clinical deterioration related to this mass effect. METHODS: We curated a retrospective data set of 635 patients with large middle cerebral artery stroke totaling 95,463 data points for 10 longitudinal covariates and 40 time-independent covariates. We assessed trajectories of the 10 longitudinal variables during the 72 h preceding three outcomes representative of life-threatening mass effect: midline shift ≥ 5 mm, pineal gland shift (PGS) > 4 mm, and decompressive hemicraniectomy (DHC). We used a "backward-looking" trajectory approach. Patients were aligned based on outcome occurrence time and the trajectory of each variable was assessed before that outcome by accounting for cases and noncases, adjusting for confounders. We evaluated longitudinal trajectories with Cox proportional time-dependent regression. RESULTS: Of 635 patients, 49.0% were female, and the mean age was 69 years. Thirty five percent of patients had midline shift ≥ 5 mm, 24.3% of patients had PGS > 4 mm, and 10.7% of patients underwent DHC. Backward-looking trajectories showed mild increases in white blood cell count (10-11 K/UL within 72 h), temperature (up to half a degree within 24 h), and sodium levels (1-3 mEq/L within 24 h) before the three outcomes of interest. We also observed a decrease in heart rate (75-65 beats per minute) 24 h before DHC. We found a significant association between increased white blood cell count with PGS > 4 mm (hazard ratio 1.05, p value 0.007). CONCLUSIONS: Longitudinal profiling adjusted for confounders demonstrated that white blood cell count, temperature, and sodium levels appear to increase before radiographic and clinical indicators of space-occupying mass effect. These findings will inform the development of multivariable dynamic risk models to aid prediction of life-threatening, space-occupying mass effect.

Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement from the American Heart Association and Neurocritical Care Society.

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

Comment on the 2023 Guidelines for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage can be a devastating disease, with an in-hospital mortality rate of up to 20%. The American Heart Association/American Stroke Association 2023 Aneurysmal Subarachnoid Hemorrhage Guidelines provide a comprehensive update to the 2012 Guidelines based on a systematic review of the intervening evidence. The guidelines are broad in scope, covering prehospital care, aneurysm treatment modality, medical complications, detection and treatment of delayed cerebral ischemia, and recovery. Here, we comment on salient aspects of aneurysmal subarachnoid hemorrhage care, compare these guidelines with the 2023 Neurocritical Care aneurysmal subarachnoid hemorrhage guidelines, and review relevant updates.

What does "brainstem death" mean? A review of international protocols.

PURPOSE: The term "brainstem death" is ambiguous; it can be used to refer either exclusively to loss of function of the brainstem or loss of function of the whole brain. We aimed to establish the term's intended meaning in national protocols for the determination of brain death/death by neurologic criteria (BD/DNC) from around the world. METHODS: Of 78 unique international protocols on determination of BD/DNC, we identified eight that referred exclusively to loss of function of the brainstem in the definition of death. Each protocol was reviewed to ascertain whether it 1) required assessment for loss of function of the whole brain, 2) required assessment only for loss of function of the brainstem, or 3) was ambiguous about whether loss of function of the higher brain was required to declare DNC. RESULTS: Of the eight protocols, two (25%) required assessment for loss of function of the whole brain, three (37.5%) only required assessment for loss of function of the brainstem, and three (37.5%) were ambiguous about whether loss of function of the higher brain was required to declare death. The overall agreement between raters was 94% (κ = 0.91). CONCLUSIONS: There is international variability in the intended meaning of the terms "brainstem death" and "whole brain death" resulting in ambiguity and potentially inaccurate or inconsistent diagnosis. Regardless of the nomenclature, we advocate for national protocols to be clear regarding any requirement for ancillary testing in cases of primary infratentorial brain injury who may fulfill clinical criteria for BD/DNC.

RéSUMé: OBJECTIF: Le terme « mort du tronc cérébral ¼ est ambigu; il peut être utilisé pour désigner soit la perte de fonction du tronc cérébral uniquement, soit la perte de fonction du cerveau entier. Nous avons cherché à établir la signification voulue du terme dans les protocoles nationaux utilisés pour la détermination de la mort cérébrale/du décès selon des critères neurologiques (MC/DCN) du monde entier. MéTHODE: Sur 78 protocoles internationaux uniques sur la détermination de la MC/DCN, nous en avons identifié huit qui faisaient exclusivement référence à la perte de fonction du tronc cérébral dans la définition de la mort. Chaque protocole a été examiné pour déterminer s'il 1) exigeait une évaluation de la perte de fonction du cerveau entier, 2) exigeait une évaluation uniquement pour la perte de fonction du tronc cérébral, ou 3) était ambigu quant à savoir si la perte de fonction du cerveau supérieur était requise pour déclarer un DCN. RéSULTATS: Sur les huit protocoles, deux (25 %) exigeaient une évaluation de la perte de fonction de l'ensemble du cerveau, trois (37,5 %) ne nécessitaient qu'une évaluation de la perte de fonction du tronc cérébral, et trois (37,5 %) étaient ambigus quant à savoir si la perte de fonction du cerveau supérieur était nécessaire pour déclarer le décès. L'accord global entre les évaluateurs était de 94 %, (κ = 0,91). CONCLUSION: Il existe une variabilité internationale quant au sens voulu des termes « mort du tronc cérébral ¼ et « mort cérébrale totale ¼ qui entraîne une ambiguïté et un diagnostic potentiellement inexact ou incohérent. Quelle que soit la nomenclature, nous préconisons que les protocoles nationaux soient clairs en ce qui concerne toute exigence d'examens auxiliaires dans les cas de lésion cérébrale infratentorielle primaire qui pourraient répondre aux critères cliniques de MC/DCN.

Clinical Characteristics and Outcomes of Patients with Aneurysmal Subarachnoid Hemorrhage: A Prospective Multicenter Study in a Middle-Income Country.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high mortality and long-term functional impairment. Data on clinical management and functional outcomes from developing countries are scarce. We aimed to define patient profiles and clinical practices and evaluate long-term outcomes after SAH in a middle-income country. METHODS: This was a prospective study including consecutive adult patients admitted with SAH to two reference centers in Brazil from January 2016 to February 2020. The primary outcome was functional status at 6 months using the modified Rankin Scale. Mixed multivariable analysis was performed to determine the relationship between clinical variables and functional outcomes. RESULTS: From 471patients analyzed, the median time from symptom onset to arrival at a study center was 4 days (interquartile range 0-9). Median age was 55 years (interquartile range 46-62) and 353 (75%) patients were women. A total of 426 patients (90%) were transferred from nonspecialized general hospitals, initial computed tomography revealed thick hemorrhage in 73% of patients (modified Fisher score of 3 or 4), and 136 (29%) had poor clinical grade (World Federation of Neurological Surgeons score of 4 or 5). A total of 312 (66%) patients underwent surgical clipping, and 119 (25%) underwent endovascular coiling. Only 34 patients (7%) underwent withdrawal or withholding of life-sustaining therapy during their hospital stay, and in-hospital mortality was 24%. A total of 187 (40%) patients had an unfavorable long-term functional outcome (modified Rankin Scale score of 4 to 6). Factors associated with unfavorable outcome were age (adjusted odds ratio [OR] 1.05, 95% confidence interval [CI] 1.03-1.08), hypertension (adjusted OR 1.81, 95% CI 1.04-3.16), poor clinical grade (adjusted OR 4.92, 95% CI 2.85-8.48), external ventricular drain (adjusted OR 3.8, 95% CI 2.31-6.24), postoperative deterioration (adjusted OR 2.33, 95% CI 1.32-4.13), cerebral infarction (adjusted OR 3.16, 95% CI 1.81-5.52), rebleeding (adjusted OR 2.95, 95% CI 1.13-7.69), and sepsis (adjusted OR 2.68, 95% CI 1.42-5.05). CONCLUSIONS: Our study demonstrated that SAH management in a middle-income country diverges significantly from published cohorts and current guidelines, despite comparable clinical profiles on presentation and admission to high-volume referral centers. Earlier aneurysm occlusion and increased use of endovascular therapy could potentially reduce modifiable in-hospital complications and improve functional outcomes in Brazil.

Anisocoria and Poor Pupil Reactivity by Quantitative Pupillometry in Patients With Intracranial Pathology.

OBJECTIVES: To describe the prevalence and associated risk factors of new onset anisocoria (new pupil size difference of at least 1 mm) and its subtypes: new onset anisocoria accompanied by abnormal and normal pupil reactivities in patients with acute neurologic injuries. DESIGN: We tested the association of patients who experienced new onset anisocoria subtypes with degree of midline shift using linear regression. We further explored differences between quantitative pupil characteristics associated with first-time new onset anisocoria and nonnew onset anisocoria at preceding observations using mixed effects logistic regression, adjusting for possible confounders. SETTING: All quantitative pupil observations were collected at two neuro-ICUs by nursing staff as standard of care. PATIENTS: We conducted a retrospective two-center study of adult patients with intracranial pathology in the ICU with at least a 24-hour stay and three or more quantitative pupil measurements between 2016 and 2018. MEASUREMENTS AND MAIN RESULTS: We studied 221 patients (mean age 58, 41% women). Sixty-three percent experienced new onset anisocoria. New onset anisocoria accompanied by objective evidence of abnormal pupil reactivity occurring at any point during hospitalization was significantly associated with maximum midline shift (ß = 2.27 per mm; p = 0.01). The occurrence of new onset anisocoria accompanied by objective evidence of normal pupil reactivity was inversely associated with death (odds ratio, 0.34; 95% CI, 0.16-0.71; p = 0.01) in adjusted analyses. Subclinical continuous pupil size difference distinguished first-time new onset anisocoria from nonnew onset anisocoria in up to four preceding pupil observations (or up to 8 hr prior). Minimum pupil reactivity between eyes also distinguished new onset anisocoria accompanied by objective evidence of abnormal pupil reactivity from new onset anisocoria accompanied by objective evidence of normal pupil reactivity prior to first-time new onset anisocoria occurrence. CONCLUSIONS: New onset anisocoria occurs in over 60% of patients with neurologic emergencies. Pupil reactivity may be an important distinguishing characteristic of clinically relevant new onset anisocoria phenotypes. New onset anisocoria accompanied by objective evidence of abnormal pupil reactivity was associated with midline shift, and new onset anisocoria accompanied by objective evidence of normal pupil reactivity had an inverse relationship with death. Distinct quantitative pupil characteristics precede new onset anisocoria occurrence and may allow for earlier prediction of neurologic decline. Further work is needed to determine whether quantitative pupillometry sensitively/specifically predicts clinically relevant anisocoria, enabling possible earlier treatments.

Natural Language Processing of Radiology Reports to Detect Complications of Ischemic Stroke.

BACKGROUND: Abstraction of critical data from unstructured radiologic reports using natural language processing (NLP) is a powerful tool to automate the detection of important clinical features and enhance research efforts. We present a set of NLP approaches to identify critical findings in patients with acute ischemic stroke from radiology reports of computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: We trained machine learning classifiers to identify categorical outcomes of edema, midline shift (MLS), hemorrhagic transformation, and parenchymal hematoma, as well as rule-based systems (RBS) to identify intraventricular hemorrhage (IVH) and continuous MLS measurements within CT/MRI reports. Using a derivation cohort of 2289 reports from 550 individuals with acute middle cerebral artery territory ischemic strokes, we externally validated our models on reports from a separate institution as well as from patients with ischemic strokes in any vascular territory. RESULTS: In all data sets, a deep neural network with pretrained biomedical word embeddings (BioClinicalBERT) achieved the highest discrimination performance for binary prediction of edema (area under precision recall curve [AUPRC] > 0.94), MLS (AUPRC > 0.98), hemorrhagic conversion (AUPRC > 0.89), and parenchymal hematoma (AUPRC > 0.76). BioClinicalBERT outperformed lasso regression (p < 0.001) for all outcomes except parenchymal hematoma (p = 0.755). Tailored RBS for IVH and continuous MLS outperformed BioClinicalBERT (p < 0.001) and linear regression, respectively (p < 0.001). CONCLUSIONS: Our study demonstrates robust performance and external validity of a core NLP tool kit for identifying both categorical and continuous outcomes of ischemic stroke from unstructured radiographic text data. Medically tailored NLP methods have multiple important big data applications, including scalable electronic phenotyping, augmentation of clinical risk prediction models, and facilitation of automatic alert systems in the hospital setting.

Health-care Professionals' Perceptions of Critical Care Resource Availability and Factors Associated With Mental Well-being During Coronavirus Disease 2019 (COVID-19): Results from a US Survey.

BACKGROUND: Assessing the impact of coronavirus disease 2019 (COVID-19) on intensive care unit (ICU) providers' perceptions of resource availability and evaluating the factors associated with emotional distress/burnout can inform interventions to promote provider well-being. METHODS: Between 23 April and 7 May 2020, we electronically administered a survey to physicians, nurses, respiratory therapists (RTs), and advanced practice providers (APPs) caring for COVID-19 patients in the United States. We conducted a multivariate regression to assess associations between concerns, a reported lack of resources, and 3 outcomes: a primary outcome of emotional distress/burnout and 2 secondary outcomes of (1) fear that the hospital is unable to keep providers safe; and (2) concern about transmitting COVID-19 to their families/communities. RESULTS: We included 1651 respondents from all 50 states: 47% were nurses, 25% physicians, 17% RTs, and 11% APPs. Shortages of intensivists and ICU nurses were reported by 12% and 28% of providers, respectively. The largest supply restrictions reported were for powered air purifying respirators (56% reporting restricted availability). Provider concerns included worries about transmitting COVID-19 to their families/communities (66%), emotional distress/burnout (58%), and insufficient personal protective equipment (PPE; 40%). After adjustment, emotional distress/burnout was significantly associated with insufficient PPE access (adjusted relative risk [aRR], 1.43; 95% confidence interval [CI], 1.32-1.55), stigma from community (aRR, 1.32; 95% CI, 1.24-1.41), and poor communication with supervisors (aRR, 1.13; 95% CI, 1.06-1.21). Insufficient PPE access was the strongest predictor of feeling that the hospital is unable to keep providers safe and worries about transmitting infection to their families/communities. CONCLUSIONS: Addressing insufficient PPE access, poor communication from supervisors, and community stigma may improve provider mental well-being during the COVID-19 pandemic.

Outcomes, Time-Trends, and Factors Associated With Ancillary Study Use for the Determination of Brain Death.

OBJECTIVES: Brain death determination often requires ancillary studies when clinical determination cannot be fully or safely completed. We aimed to analyze the results of ancillary studies, the factors associated with ancillary study performance, and the changes over time in number of studies performed at an academic health system. DESIGN: Retrospective cohort. SETTING: Multihospital academic health system. PATIENTS: Consecutive adult patients declared brain dead between 2010 and 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 140 brain death patients, ancillary studies were performed in 84 (60%). The false negative rate of all ancillary studies was 4% (5% of transcranial Doppler ultrasounds, 4% of nuclear studies, 0% of electroencephalograms, and 17% of CT angiography). In univariate analysis, ancillary study use was associated with female sex (odds ratio, 2.4; 95% CI, 1.21-5.01; p = 0.013) and the etiology of brain death being hypoxic-ischemic brain injury (odds ratio, 2.9; 95% CI, 1.43-5.88; p = 0.003), nontraumatic intracranial hemorrhage (odds ratio, 0.45; 95% CI, 0.21-0.96; p = 0.039), or traumatic brain injury (odds ratio, 0.22; 95% CI, 0.04-0.8; p = 0.031). In multivariable analysis, female sex (odds ratio, 5.7; 95% CI, 2.56-15.86; p = 0.004), the etiology of brain death being hypoxic-ischemic brain injury (odds ratio, 3.2; 95% CI, 1.3-8.8; p = 0.015), and the neurologists performing brain death declaration (odds ratio, 0.08; 95% CI, 0.004-0.64; p = 0.034) were factors independently associated with use of ancillary studies. Over the study period, the total number of ancillary studies performed each year did not significantly change; however, the number of electroencephalograms significantly decreased with time (odds ratio per 1-yr increase, 0.67; 95% CI, 0.49-0.90; p = 0.014). CONCLUSIONS: A large number of ancillary studies were performed despite a clinical determination of brain death; patients with hypoxic-ischemic brain injury are more likely to undergo ancillary studies for brain death determination, and neurologists were less likely to use ancillary studies for brain death. Recently, the use of electroencephalograms for brain death determination has decreased, likely reflecting significant concerns regarding its validity and reliability.

New perspectives on brain death.

Brain death, or death by neurological criteria (BD/DNC), has been accepted conceptually, medically and legally for decades. Nevertheless, some areas remain controversial or understudied, pointing to a need for focused research to advance the field. Multiple recent contributions have increased our understanding of BD/DNC, solidified our practice and provided guidance where previously lacking. There have also been important developments on a global scale, including in low-to-middle income countries such as in South America. Although variability in protocols and practice still exists, new efforts are underway to reduce inconsistencies and better train practitioners in accurate and sound BD/DNC determination. Various legal challenges have required formal responses from national societies, and the American Academy of Neurology has filled this void with much needed guidance. Questions remain regarding concepts such as 'whole brain' versus 'brainstem' death, and the intersection of BD/DNC and rubrics of medical futility. These concepts are the subject of this review.

Impact of Fever Prevention in Brain-Injured Patients (INTREPID): Study Protocol for a Randomized Controlled Trial.

BACKGROUND: Multiple studies demonstrate that fever/elevated temperature is associated with poor outcomes in patients with vascular brain injury; however, there are no conclusive studies that demonstrate that fever prevention/controlled normothermia is associated with better outcomes. The primary objective of the INTREPID (Impact of Fever Prevention in Brain-Injured Patients) trial is to test the hypothesis that fever prevention is superior to standard temperature management in patients with acute vascular brain injury. METHODS: INTREPID is a prospective randomized open blinded endpoint study of fever prevention versus usual care in patients with ischemic or hemorrhagic stroke. The fever prevention intervention utilizes the Arctic Sun System and will be compared to standard care patients in whom fever may spontaneously develop. Ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage patients will be included within disease-specific time-windows. Both awake and sedated patients will be included, and treatment is initiated immediately upon enrollment. Eligible patients are expected to require intensive care for at least 72 h post-injury, will not be deemed unlikely to survive without severe disability, and will be treated for up to 14 days, or until deemed ready for discharge from the ICU, whichever comes first. Fifty sites in the USA and worldwide will participate, with a target enrollment of 1176 patients (1000 evaluable). The target temperature is 37.0 °C. The primary efficacy outcome is the total fever burden by °C-h, defined as the area under the temperature curve above 37.9 °C. The primary secondary outcome, on which the sample size is based, is the modified Rankin Scale Score at 3 months. All efficacy analyses including the primary and key secondary endpoints will be primarily based on an intention-to-treat population. Analysis of the as-treated and per protocol populations will also be performed on the primary and key secondary endpoints as sensitivity analyses. DISCUSSION: The INTREPID trial will provide the first results of the impact of a pivotal fever prevention intervention in patients with acute stroke ( www.clinicaltrials.gov ; NCT02996266; registered prospectively 05DEC2016).

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

Standards for Studies of Neurological Prognostication in Comatose Survivors of Cardiac Arrest: A Scientific Statement From the American Heart Association.

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery. Inaccurate neurological prognostication leading to withdrawal of life-sustaining treatment and deaths may significantly bias clinical studies, leading to failure in detecting the true study outcomes. The American Heart Association Emergency Cardiovascular Care Science Subcommittee organized a writing group composed of adult and pediatric experts from neurology, cardiology, emergency medicine, intensive care medicine, and nursing to review existing neurological prognostication studies, the practice of neurological prognostication, and withdrawal of life-sustaining treatment. The writing group determined that the overall quality of existing neurological prognostication studies is low. As a consequence, the degree of confidence in the predictors and the subsequent outcomes is also low. Therefore, the writing group suggests that neurological prognostication parameters need to be approached as index tests based on relevant neurological functions that are directly related to the functional outcome and contribute to the quality of life of cardiac arrest survivors. Suggestions to improve the quality of adult and pediatric neurological prognostication studies are provided.

Intravenous Fibrinolysis for Central Retinal Artery Occlusion: A Cohort Study and Updated Patient-Level Meta-Analysis.

BACKGROUND AND PURPOSE: Central retinal artery occlusion results in sudden, painless, usually permanent loss of vision in the affected eye. There is no proven, effective treatment to salvage visual acuity and a clear, unmet need for an effective therapy. In this work, we evaluated the efficacy of intravenous tissue-type plasminogen activator (IV alteplase) in a prospective cohort study and an updated systematic review and meta-analysis. METHODS: We enrolled consecutive patients with acute central retinal artery occlusion within 48 hours of symptoms onset and with a visual acuity of <20/200 from January 2009 until May 2019. The primary outcomes were safety and functional visual acuity recovery. We compared rates of visual recovery between those treated with alteplase within 4.5 hours of symptom onset to those who did not receive alteplase (including an analysis restricted to untreated patients presenting within the window for treatment). We incorporated these results into an updated systematic review and patient-level meta-analysis. RESULTS: We enrolled 112 patients, of whom 25 (22.3% of the cohort) were treated with IV alteplase. One patient had an asymptomatic intracerebral hemorrhage after IV alteplase treatment. Forty-four percent of alteplase-treated patients had recovery of visual acuity when treated within 4.5 hours versus 13.1% of those not treated with alteplase (P=0.003) and 11.6% of those presenting within 4 hours who did not receive alteplase (P=0.03). Our updated patient-level meta-analysis of 238 patients included 67 patients treated with alteplase within 4.5 hours since time last known well with a recovery rate of 37.3%. This favorably compares with a 17.7% recovery rate in those without treatment. In linear regression, earlier treatment correlated with a higher rate of visual recovery (P=0.01). CONCLUSIONS: This study showed that the administration of intravenous alteplase within 4.5 hours of symptom onset is associated with a higher likelihood of a favorable visual outcome for acute central retinal artery occlusion. Our results strongly support proceeding to a randomized, placebo-controlled clinical trial.

Neuroprognostication Practices in Postcardiac Arrest Patients: An International Survey of Critical Care Providers.

OBJECTIVES: To characterize approaches to neurologic outcome prediction by practitioners who assess prognosis in unconscious cardiac arrest individuals, and assess compliance to available guidelines. DESIGN: International cross-sectional study. SETTING: We administered a web-based survey to members of Neurocritical Care Society, Society of Critical Care Medicine, and American Academy of Neurology who manage unconscious cardiac arrest patients to characterize practitioner demographics and current neuroprognostic practice patterns. SUBJECTS: Physicians that are members of aforementioned societies who care for successfully resuscitated cardiac arrest individuals. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: A total of 762 physicians from 22 countries responses were obtained. A significant proportion of respondents used absent corneal reflexes (33.5%) and absent pupillary reflexes (36.2%) at 24 hours, which is earlier than the recommended 72 hours in the standard guidelines. Certain components of the neurologic examination may be overvalued, such as absent motor response or extensor posturing, which 87% of respondents considered being very or critically important prognostic indicators. Respondents continue to rely on myoclonic status epilepticus and neuroimaging, which were favored over median nerve somatosensory evoked potentials for prognostication, although the latter has been demonstrated to have a higher predictive value. Regarding definitive recommendations based on poor neurologic prognosis, most physicians seem to wait until the postarrest timepoints proposed by current guidelines, but up to 25% use premature time windows. CONCLUSIONS: Neuroprognostic approaches to hypoxic-ischemic encephalopathy vary among physicians and are often not consistent with current guidelines. The overall inconsistency in approaches and deviation from evidence-based recommendations are concerning in this disease state where mortality is so integrally related to outcome prediction.