Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

In-Hospital Neurologic Complications, Neuromonitoring, and Long-Term Neurologic Outcomes in Patients With Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVES: Although delirium is well described in patients with sepsis, there are limited data on other neurologic complications. We aimed to systematically review the prevalence, neuromonitoring tools, and neurocognitive outcomes in sepsis patients with neurologic complications. DATA SOURCES: MEDLINE and six other databases (Embase, Web of Science, Cochrane CENTRAL, and ClinicalTrials.gov ) were searched through January 2023. STUDY SELECTION: Studies of adult patients with sepsis reported neurologic complications, use of neuromonitoring tools, neuropathology, and cognitive outcomes. DATA EXTRACTION: Two independent reviewers extracted the data. Random-effect meta-analyses were used to pool data. DATA SYNTHESIS: Seventy-four studies ( n = 146,855) were included. Neurologic complications were reported in 38 studies ( n = 142,193) including septic encephalopathy (36%, 95% CI, 27-46%; I 2 = 99%), ischemic stroke (5%, 95% CI, 2.1-11.5; I 2 = 99%), intracranial hemorrhage (2%, 95% CI, 1.0-4.4%; I 2 = 96%), seizures (1%, 95% CI, 0.2-7%; I 2 = 96%), posterior reversible encephalopathy syndrome (9%), and hypoxic-ischemic brain injury (7%). In the meta-regression analysis, pulmonary infection, sepsis induced by a gram-positive organism, higher sequential organ failure assessment score, acute physiology and chronic health evaluation II score at admission, and longer ICU length of stay were associated with higher risk of developing septic encephalopathy. Three studies ( n = 159) reported postmortem neuropathological findings, acute brain injury was noted in 47% of patients. Twenty-six studies ( n = 1,358) reported the use of neuromonitoring tools, electroencephalogram was the most used tool for seizure detection. Transcranial Doppler and near infrared spectroscopy were used for monitoring cerebral hemodynamic changes to detect early ischemia. Six studies reported cognitive outcomes ( n = 415) up to 12 months postdischarge and cognitive impairment (≥ one domain) was reported in 30%. CONCLUSIONS: In-hospital neurologic complications are common in patients with sepsis. However, the mechanism and timing of those sepsis-associated complications are poorly understood and there are limited data on standardized neuromonitoring in this population.

Neurological Complications of Cannabinoids.

Cannabinoid use, particularly for recreational purposes, is increasing exponentially across all age groups, especially in younger populations, due to its perceived low risk and legalization. While cannabinoids may be largely considered as safe, there is mounting evidence of increased risk of systemic and neurological complications through their interaction with the poorly understood endocannabinoid receptor network within the central nervous system and other organ systems. Acute cannabinoid exposure can cause neuropsychiatric symptoms in addition to altering cerebral blood flow, leading to cerebrovascular complications such as ischemic stroke, subarachnoid hemorrhage, and reversible cerebral vasoconstriction syndrome (RCVS). Chronic use, particularly among adolescents, may be associated with increased risk of long-term cognitive deficits, schizophrenia, and other neuropsychiatric effects. Synthetic cannabinoids have increased potency, with reports of causing profound neurological complications including coma, seizures, posterior reversible encephalopathy syndrome, and RCVS. Despite increasing evidence, the quality of literature describing neurologic complications with cannabinoids remains limited to case series and retrospective cohort studies, with significant confounding factors such as concomitant use of other illicit drugs, limiting interpretation. In this review, we summarize the effect of cannabinoids on the neurologic system and associated neurological complications.

An Update on Curing Coma Campaign.

The Curing Coma Campaign (CCC) and its contributing collaborators identified multiple key areas of knowledge and research gaps in coma and disorders of consciousness (DoC). This step was a crucial effort and essential to prioritize future educational and research efforts. These key areas include defining categories of DoC, assessing DoC using multimodal approach (e.g., behavioral assessment tools, advanced neuroimaging studies), discussing optimal clinical trials' design and exploring computational models to conduct clinical trials in patients with DoC, and establishing common data elements to standardize data collection. Other key areas focused on creating coma care registry and educating clinicians and patients and promoting awareness of DoC to improve care in patients with DoC. The ongoing efforts in these key areas are discussed.

Prevalence and Neurological Outcomes of Comatose Patients With Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate prevalence, risk factors, and in-hospital outcomes of comatose extracorporeal membrane oxygenation (ECMO) patients. DESIGN: Retrospective observational. SETTING: Tertiary academic hospital. PARTICIPANTS: Adults received venoarterial (VA) or venovenous (VV) ECMO support between November 2017 and April 022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined 24-hour off sedation as no sedative infusion (except dexmedetomidine) or paralytics administration over a continuous 24-hour period while on ECMO. Off-sedation coma (comaoff) was defined as a Glasgow Coma Scale score of ≤8 after achieving 24-hour off sedation. On-sedation coma (comaon) was defined as a Glasgow Coma Scale score of ≤8 during the entire ECMO course without off sedation for 24 hours. Neurological outcomes were assessed at discharge using the modified Rankin scale (good, 0-3; poor, 4-6). We included 230 patients (VA-ECMO 143, 65% male); 24-hour off sedation was achieved in 32.2% VA-ECMO and 26.4% VV-ECMO patients. Among all patients off sedation for 24 hours (n = 69), 56.5% VA-ECMO and 52.2% VV-ECMO patients experienced comaoff. Among those unable to be sedation free for 24 hours (n = 161), 50.5% VA-ECMO and 17.2% VV-ECMO had comaon. Comaoff was associated with poor outcomes (p < 0.05) in VA-ECMO and VV-ECMO groups, whereas comaon only impacted the VA-ECMO group outcomes. In a multivariable analysis, requirement of renal replacement therapy was an independent risk factor for comaoff after adjusting for ECMO configuration, after adjusting for ECMO configuration, acute brain injury, pre-ECMO partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide in arterial blood, pH, and bicarbonate level (worst value within 24 hours before cannulation). CONCLUSIONS: Comaoff was common and associated with poor outcomes at discharge. Requirement of renal replacement therapy was an independent risk factor.

Optimal Design of Clinical Trials Involving Persons with Disorders of Consciousness.

BACKGROUND: Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC. METHODS: The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC. RESULTS: There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC. CONCLUSIONS: Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care.

Evaluating the Strength and Quality of Evidence in American Heart Association/American Stroke Association's Guidelines for Aneurysmal Subarachnoid Hemorrhage and Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Clinical practice recommendations guide healthcare decisions. This study aims to evaluate the strength and quality of evidence supporting the American Heart Association (AHA)/American Stroke Association (ASA) guidelines for aneurysmal subarachnoid hemorrhage (aSAH) and spontaneous intracerebral hemorrhage (ICH). METHODS: We reviewed the current AHA/ASA guidelines for aSAH and spontaneous ICH and compared with previous guidelines. Guidelines were classified based on the Class of recommendation (COR) and Level of evidence (LOE). COR signifies recommendation strength (COR 1: Strong; COR 2a: Moderate; COR 2b: Weak; COR 3: No Benefit/Harm), while LOE denotes evidence quality (LOE A: High-Quality; LOE B-NR: Moderate-Quality, Not Randomized; LOE B-R: Moderate-Quality, Randomized; LOE C-EO: Expert Opinion; LOE C-LD: Limited Data). RESULTS: For aSAH, we identified 84 recommendations across 15 guideline categories. Of these, 31% were classified as COR I, 30% as COR 2a, 17% as COR 2b, and 18% as COR 3. In terms of LOE, 7% were based on LOE A, 10% on LOE B-R, 65% on LOE B-NR, 14% on LOE C-LD, and 5% on LOE C-EO. Compared to previous guidelines, there was a 46% decrease in LOE A, a 45% increase in LOE B, and an 11% decrease in LOE C. For spontaneous ICH, 124 guidelines were identified across 31 guideline categories. Of these, 28% were COR I, 32% COR 2b, and 9% COR 3. For LOE, 4% were based on LOE A, 35% on LOE B-NR, and 42% on LOE C-LD. Compared to previous guidelines, there was a 78% decrease in LOE A, an 82% increase in LOE B, and a 14% increase in LOE C. This analysis highlights that less than a third of AHA/ASA guidelines are classified as the highest class of recommendation, with less than 10% based on the highest LOE. CONCLUSION: Less than a third of AHA/ASA guidelines on aSAH and spontaneous ICH are classified as the highest class of recommendation with less than 10% based on highest LOE. There appears to be a decrease in proportion of guidelines based on highest LOE in most recent guidelines.

2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association.

AIM: The "2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage" replaces the 2012 "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage." The 2023 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with aneurysmal subarachnoid hemorrhage. METHODS: A comprehensive search for literature published since the 2012 guideline, derived from research principally involving human subjects, published in English, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline, was conducted between March 2022 and June 2022. In addition, the guideline writing group reviewed documents on related subject matter previously published by the American Heart Association. Newer studies published between July 2022 and November 2022 that affected recommendation content, Class of Recommendation, or Level of Evidence were included if appropriate. Structure: Aneurysmal subarachnoid hemorrhage is a significant global public health threat and a severely morbid and often deadly condition. The 2023 aneurysmal subarachnoid hemorrhage guideline provides recommendations based on current evidence for the treatment of these patients. The recommendations present an evidence-based approach to preventing, diagnosing, and managing patients with aneurysmal subarachnoid hemorrhage, with the intent to improve quality of care and align with patients' and their families' and caregivers' interests. Many recommendations from the previous aneurysmal subarachnoid hemorrhage guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

Tracheostomy timing and outcome in critically ill patients with stroke: a meta-analysis and meta-regression.

BACKGROUND: Stroke patients requiring mechanical ventilation often have a poor prognosis. The optimal timing of tracheostomy and its impact on mortality in stroke patients remains uncertain. We performed a systematic review and meta-analysis of tracheostomy timing and its association with reported all-cause overall mortality. Secondary outcomes were the effect of tracheostomy timing on neurological outcome (modified Rankin Scale, mRS), hospital length of stay (LOS), and intensive care unit (ICU) LOS. METHODS: We searched 5 databases for entries related to acute stroke and tracheostomy from inception to 25 November 2022. We adhered to PRISMA guidance for reporting systematic reviews and meta-analyses. Selected studies included (1) ICU-admitted patients who had stroke (either acute ischaemic stroke, AIS or intracerebral haemorrhage, ICH) and received a tracheostomy (with known timing) during their stay and (2) > 20 tracheotomised. Studies primarily reporting sub-arachnoid haemorrhage (SAH) were excluded. Where this was not possible, adjusted meta-analysis and meta-regression with study-level moderators were performed. Tracheostomy timing was analysed continuously and categorically, where early (< 5 days from initiation of mechanical ventilation to tracheostomy) and late (> 10 days) timing was defined per the protocol of SETPOINT2, the largest and most recent randomised controlled trial on tracheostomy timing in stroke patients. RESULTS: Thirteen studies involving 17,346 patients (mean age = 59.8 years, female 44%) met the inclusion criteria. ICH, AIS, and SAH comprised 83%, 12%, and 5% of known strokes, respectively. The mean time to tracheostomy was 9.7 days. Overall reported all-cause mortality (adjusted for follow-up) was 15.7%. One in five patients had good neurological outcome (mRS 0-3; median follow-up duration was 180 days). Overall, patients were ventilated for approximately 12 days and had an ICU LOS of 16 days and a hospital LOS of 28 days. A meta-regression analysis using tracheostomy time as a continuous variable showed no statistically significant association between tracheostomy timing and mortality (ß = - 0.3, 95% CI = - 2.3 to 1.74, p = 0.8). Early tracheostomy conferred no mortality benefit when compared to late tracheostomy (7.8% vs. 16.4%, p = 0.7). Tracheostomy timing was not associated with secondary outcomes (good neurological outcome, ICU LOS and hospital LOS). CONCLUSIONS: In this meta-analysis of over 17,000 critically ill stroke patients, the timing of tracheostomy was not associated with mortality, neurological outcomes, or ICU/hospital LOS. TRIAL REGISTRATION: PROSPERO-CRD42022351732 registered on 17th of August 2022.

Coagulopathy in Isolated Traumatic Brain Injury: Myth or Reality.

INTRODUCTION: Traumatic Brain Injury (TBI) has been shown to be associated with altered hemostasis and coagulopathy, that correlates with worsening secondary injury and clinical outcomes. Isolated Traumatic Brain Injury (iTBI), that is TBI without significant extracranial injuries, has also been shown to be associated with systemic coagulopathy and derangements in hemostasis. METHODS: Literature Review. RESULTS: Present your results in logical sequence in the text, tables, and figures, giving the main or most important findings first. Do not repeat all the data in the tables or figures in the text; emphasize or summarize only the most important observations. Provide data on all primary and secondary outcomes identified in the Methods section. Give numeric results not only as derivatives (e.g. percentages) but also as the absolute numbers from which the derivatives were calculated, and specify the statistical significance attached to them, if any. DISCUSSION: In this review, we provide an overview of the pathophysiology of the hemostatic disturbances caused by iTBI, review key clinical findings and discrepancies in the way this question has been approached, describe the use and role of global viscoelastic assays such as the thromboelastrogram, and detail principles for reversal of pre-injury blood thinners. CONCLUSIONS: iTBI is clearly associated with the development of coagulopathy, but the extent to which it occurs is confounded by the fact that many of the studies have included patients with moderate extracranial trauma into the iTBI category. The coagulopathy itself has been better studied in preclinical models, and the mechanisms driving it suggest a pattern consistent with disseminated intravascular coagulation with hyperfibrinolysis. We provide pragmatic clinical takeaways and suggestions for future research.

Therapies for Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is one of the most important complications of subarachnoid hemorrhage. Despite lack of prospective evidence, medical rescue interventions for DCI include hemodynamic augmentation using vasopressors or inotropes, with limited guidance on specific blood pressure and hemodynamic parameters. For DCI refractory to medical interventions, endovascular rescue therapies (ERTs), including intraarterial (IA) vasodilators and percutaneous transluminal balloon angioplasty, are the cornerstone of management. Although there are no randomized controlled trials assessing the efficacy of ERTs for DCI and their impact on subarachnoid hemorrhage outcomes, survey studies suggest that they are widely used in clinical practice with significant variability worldwide. IA vasodilators are first line ERTs, with better safety profiles and access to distal vasculature. The most commonly used IA vasodilators include calcium channel blockers, with milrinone gaining popularity in more recent publications. Balloon angioplasty achieves better vasodilation compared with IA vasodilators but is associated with higher risk of life-threatening vascular complications and is reserved for proximal severe refractory vasospasm. The existing literature on DCI rescue therapies is limited by small sample sizes, significant variability in patient populations, lack of standardized methodology, variable definitions of DCI, poorly reported outcomes, lack of long-term functional, cognitive, and patient-centered outcomes, and lack of control groups. Therefore, our current ability to interpret clinical results and make reliable recommendations regarding the use of rescue therapies is limited. This review summarizes existing literature on rescue therapies for DCI, provides practical guidance, and identifies future research needs.

Intracranial Pressure Monitoring Practice, Treatment, and Effect on Outcome in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Intracranial pressure (ICP) monitoring and its management in aneurysmal subarachnoid hemorrhage (aSAH) is variable worldwide. The present study aimed to explore the practice of ICP monitoring, its variability across countries, and the association with 6-month outcomes in aSAH. METHODS: This was a preplanned subanalysis of SYNAPSE-ICU, a multicenter, international, prospective, observational cohort study focused on patients diagnosed with aSAH. We evaluated the variability in ICP monitoring across countries through a logistic regression model adjusted for case-mix and considered countries as a random effect. The association between ICP probe insertion and 6-month mortality and a poor neurological outcome, defined as an Glasgow Outcome Score Extended ≤ 4, was assessed by using a propensity score approach. RESULTS: A total of 423 patients with aSAH from 92 centers across 32 countries were included in this analysis. ICP monitoring was used in 295 (69.7%) patients. Significant between-country variability in ICP insertion was observed, with an incidence ranging between 4.7% and 79.9% (median odd ratio 3.04). The median duration of ICP monitoring was 12 days (first quartile [Q1] through third quartile [Q3] range 8-18), with an overall daily median ICP value of 14 mm Hg (Q1-Q3 10-19) and a median maximum value of 21 mm Hg (Q1-Q3 16-30). Patients monitored with ICP received more aggressive therapy treatments compared with non-monitored patients (therapy intensity level, TIL, score 10.33 [standard deviation 3.61] vs. 6.3 [standard deviation 4.19], p < 0.001). In more severe patients, ICP monitoring was significantly associated with better 6-month outcome (poor neurological outcome: odds ratio 0.14, 95% confidence interval 0.02-0.53, p = 0.0113; mortality: hazard ratio 0.25, 95% confidence interval 0.13-0.49, p < 0.0001). However, no significant effect was observed in patients with both reactive pupils. CONCLUSIONS: Our cohort demonstrated high variability in ICP insertion practice among countries. A more aggressive treatment approach was applied in ICP-monitored patients. In patients with severe aSAH, ICP monitoring might reduce unfavorable outcomes and mortality at 6 months.

Proceedings of the First Pediatric Coma and Disorders of Consciousness Symposium by the Curing Coma Campaign, Pediatric Neurocritical Care Research Group, and NINDS: Gearing for Success in Coma Advancements for Children and Neonates.

This proceedings article presents the scope of pediatric coma and disorders of consciousness based on presentations and discussions at the First Pediatric Disorders of Consciousness Care and Research symposium held on September 14th, 2021. Herein we review the current state of pediatric coma care and research opportunities as well as shared experiences from seasoned researchers and clinicians. Salient current challenges and opportunities in pediatric and neonatal coma care and research were identified through the contributions of the presenters, who were Jose I. Suarez, MD, Nina F. Schor, MD, PhD, Beth S. Slomine, PhD Erika Molteni, PhD, and Jan-Marino Ramirez, PhD, and moderated by Varina L. Boerwinkle, MD, with overview by Mark Wainwright, MD, and subsequent audience discussion. The program, executively planned by Varina L. Boerwinkle, MD, Mark Wainwright, MD, and Michelle Elena Schober, MD, drove the identification and development of priorities for the pediatric neurocritical care community.

Guidelines for the Neurocritical Care Management of Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The neurointensive care management of patients with aneurysmal subarachnoid hemorrhage (aSAH) is one of the most critical components contributing to short-term and long-term patient outcomes. Previous recommendations for the medical management of aSAH comprehensively summarized the evidence based on consensus conference held in 2011. In this report, we provide updated recommendations based on appraisal of the literature using the Grading of Recommendations Assessment, Development, and Evaluation methodology. METHODS: The Population/Intervention/Comparator/Outcome (PICO) questions relevant to the medical management of aSAH were prioritized by consensus from the panel members. The panel used a custom-designed survey instrument to prioritize clinically relevant outcomes specific to each PICO question. To be included, the study design qualifying criteria were as follows: prospective randomized controlled trials (RCTs), prospective or retrospective observational studies, case-control studies, case series with a sample larger than 20 patients, meta-analyses, restricted to human study participants. Panel members first screened titles and abstracts, and subsequently full text review of selected reports. Data were abstracted in duplicate from reports meeting inclusion criteria. Panelists used the Grading of Recommendations Assessment, Development, and Evaluation Risk of Bias tool for assessment of RCTs and the "Risk of Bias In Nonrandomized Studies - of Interventions" tool for assessment of observational studies. The summary of the evidence for each PICO was presented to the full panel, and then the panel voted on the recommendations. RESULTS: The initial search retrieved 15,107 unique publications, and 74 were included for data abstraction. Several RCTs were conducted to test pharmacological interventions, and we found that the quality of evidence for nonpharmacological questions was consistently poor. Five PICO questions were supported by strong recommendations, one PICO question was supported by conditional recommendations, and six PICO questions did not have sufficient evidence to provide a recommendation. CONCLUSIONS: These guidelines provide recommendations for or against interventions proven to be effective, ineffective, or harmful in the medical management of patients with aSAH based on a rigorous review of the available literature. They also serve to highlight gaps in knowledge that should guide future research priorities. Despite improvements in the outcomes of patients with aSAH over time, many important clinical questions remain unanswered.

Effect of Cilostazol in Animal Models of Cerebral Ischemia and Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis.

BACKGROUND: Cilostazol, a phosphodiesterase III inhibitor, appears to be a promising agent for preventing cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage. Here, the authors perform a systematic review and meta-analysis to quantitatively assess the effects of cilostazol on brain structural and functional outcomes in animal models of cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm. METHODS: By using the PRISMA guidelines, a search of the PubMed, Scopus, and Web of Science was conducted to identify relevant studies. Study quality of each included study for both systematic reviews were scored by using an adapted 15-item checklist from the Collaborative Approach to Meta-Analysis of Animal Data from Experimental Studies. We calculated a standardized mean difference as effect size for each comparison. For each outcome, comparisons were combined by using random-effects modeling to account for heterogeneity, with a restricted maximum likelihood estimate of between-study variance. RESULTS: A total of 22 (median [Q1, Q3] quality score of 7 [5, 8]) and 6 (median [Q1, Q3] quality score of 6 [6, 6]) studies were identified for cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm, respectively. Cilostazol significantly reduced the infarct volume in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.88 (95% confidence interval [CI] [- 1.07 to - 0.70], p < 0.0001). Cilostazol significantly reduced neurofunctional deficits in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.66 (95% CI [- 1.06 to - 0.28], p < 0.0001). Cilostazol significantly improved the basilar artery diameter in subarachnoid hemorrhage-induced cerebral vasospasm with a pooled standardized mean difference estimate of 2.30 (95% CI [0.94 to 3.67], p = 0.001). Cilostazol also significantly improved the basilar artery cross-section area with a pooled standardized mean estimate of 1.88 (95% CI [0.33 to 3.43], p < 0.05). Overall, there was between-study heterogeneity and asymmetry in the funnel plot observed in all comparisons. CONCLUSIONS: Published animal data support the overall efficacy of cilostazol in reducing infarct volume and neurofunctional deficits in cerebral ischemia models and cerebral vasospasm in subarachnoid hemorrhage models.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Hospital Course, Confounders, and Medications.

The convergence of an interdisciplinary team of neurocritical care specialists to organize the Curing Coma Campaign is the first effort of its kind to coordinate national and international research efforts aimed at a deeper understanding of disorders of consciousness (DoC). This process of understanding includes translational research from bench to bedside, descriptions of systems of care delivery, diagnosis, treatment, rehabilitation, and ethical frameworks. The description and measurement of varying confounding factors related to hospital care was thought to be critical in furthering meaningful research in patients with DoC. Interdisciplinary hospital care is inherently varied across geographical areas as well as community and academic medical centers. Access to monitoring technologies, specialist consultation (medical, nursing, pharmacy, respiratory, and rehabilitation), staffing resources, specialty intensive and acute care units, specialty medications and specific surgical, diagnostic and interventional procedures, and imaging is variable, and the impact on patient outcome in terms of DoC is largely unknown. The heterogeneity of causes in DoC is the source of some expected variability in care and treatment of patients, which necessitated the development of a common nomenclature and set of data elements for meaningful measurement across studies. Guideline adherence in hemorrhagic stroke and severe traumatic brain injury may also be variable due to moderate or low levels of evidence for many recommendations. This article outlines the process of the development of common data elements for hospital course, confounders, and medications to streamline definitions and variables to collect for clinical studies of DoC.

Challenges in determining death by neurologic criteria in extracorporeal membrane oxygenation - A single center experience.

INTRODUCTION: Apnea test (AT) in patients on extracorporeal membrane oxygenation (ECMO) support is challenging, leading to variation in determining death by neurologic criteria (DNC). We aim to describe the diagnostic criteria and barriers for DNC in adults on ECMO in a tertiary care center. METHODS: A retrospective review of a prospective observational standardized neuromonitoring study was conducted in adult VA- and VV-ECMO patients at a tertiary center from June 2016 to March 2022. Brain death was defined according to the 2010 American Academy of Neurology guidelines and following the 2020 World Brain Death Project recommendations for performing AT in ECMO patients. RESULTS: Eight (2.7%) ECMO patients (median age = 44 years, 75% male, 50% VA-ECMO) met criteria for DNC, six (75%) of whom were determined with AT. In the other two patients who did not undergo AT due to safety concerns, ancillary tests (transcranial doppler and electroencephalography) were consistent with DNC. An additional seven (2.3%) patients (median age = 55 years, 71% male, 86% VA-ECMO) were noted to have absent brainstem reflexes but failed to complete determination of DNC as they underwent withdrawal of life-sustaining treatment (WLST) before a full evaluation was completed. In these patients, AT was never performed, and ancillary tests were inconsistent with either neurological exam findings and/or neuroimaging supporting DNC, or with each other. CONCLUSION: AT was used safely and successfully in 6 of the 8 ECMO patients diagnosed with DNC and was always consistent with the neurological exam and imaging findings, as opposed to ancillary tests alone.

Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage.

BACKGROUND: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. METHODS: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL-<180 and ≥180 mg/dL, respectively, measured at baseline, 24, 48, and 72 hours. Persistent hyperglycemia was defined by 2 consecutive (24 hours apart) serum glucose levels. We evaluated the relationship between moderate and severe hyperglycemia and death or disability (defined by modified Rankin Scale score of 4-6) at 90 days in the overall cohort and in groups defined by preexisting diabetes. RESULTS: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1-2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2-2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P=0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0-3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1-3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. CONCLUSIONS: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01176565.

Reexamining the Role of Postoperative ICU Admission for Patients Undergoing Elective Craniotomy: A Systematic Review.

OBJECTIVES: The standard-of-care for postoperative care following elective craniotomy has historically been ICU admission. However, recent literature interrogating complications and interventions during this postoperative ICU stay suggests that all patients may not require this level of care. Thus, hospitals began implementing non-ICU postoperative care pathways for elective craniotomy. This systematic review aims to summarize and evaluate the existing literature regarding outcomes and costs for patients receiving non-ICU care after elective craniotomy. DATA SOURCES: A systematic review of the PubMed database was performed following PRISMA guidelines from database inception to August 2021. STUDY SELECTION: Included studies were published in peer-reviewed journals, in English, and described outcomes for patients undergoing elective craniotomies without postoperative ICU care. DATA EXTRACTION: Data regarding study design, patient characteristics, and postoperative care pathways were extracted independently by two authors. Quality and risk of bias were evaluated using the Oxford Centre for Evidence-Based Medicine Levels of Evidence tool and Risk Of Bias In Non-Randomized Studies-of Interventions tool, respectively. DATA SYNTHESIS: In total, 1,131 unique articles were identified through the database search, with 27 meeting inclusion criteria. Included articles were published from 2001 to 2021 and included non-ICU inpatient care and same-day discharge pathways. Overall, the studies demonstrated that postoperative non-ICU care for elective craniotomies led to length of stay reduction ranging from 6 hours to 4 days and notable cost reductions. Across 13 studies, 53 of the 2,469 patients (2.1%) intended for postoperative management in a non-ICU setting required subsequent care escalation. CONCLUSIONS: Overall, these studies suggest that non-ICU care pathways for appropriately selected postcraniotomy patients may represent a meaningful opportunity to improve care value. However, included studies varied greatly in patient selection, postoperative care protocol, and outcomes reporting. Standardization and multi-institutional collaboration are needed to draw definitive conclusions regarding non-ICU postoperative care for elective craniotomy.

The Curing Coma Campaign and the Future of Coma Research.

Recovery from coma or disordered consciousness is a central issue in patients with acute brain injuries such as stroke, trauma, cardiac arrest, and brain infections. Yet, major gaps remain in the scientific underpinnings of coma and this has led to inaccuracy in prognostication and limited interventions for coma recovery. Even so, recent studies have begun to elucidate mechanisms of consciousness early and prolonged after acute brain injury and some pilot interventions have begun to be tested. The importance and scope of this led in 2019 to the development of the Curing Coma Campaign, an initiative of the Neurocritical Care Society designed to provide a platform for scientific collaboration across the patient care continuum and to empower a community for purposes of research, education, implementation science, and advocacy. Seen as a "grand challenge," the Curing Coma Campaign has developed an infrastructure of scientific working groups and operational modules, along with a 10-year roadmap.