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Background and Purpose: Cerebral infarction remains an important cause of death or disability in patients with aneurysmal subarachnoid hemorrhage (SAH). The prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal SAH at a national level are not known., Methods: We identified the proportion of patients who develop cerebral infarction (ascertained using validated methodology) among patients with aneurysmal SAH and annual trends using the Nationwide Inpatient Sample (NIS) from 2016 to 2021. We analyzed the effect of cerebral infarction on in-hospital mortality, routine discharge without palliative care (based on discharge disposition), poor outcome defined by the NIS SAH outcome measure, and length and costs of hospitalization after adjusting for potential confounders., Results: A total of 35,305 (53.6%) patients developed cerebral infarction among 65,840 patients with aneurysmal SAH over a 6-year period. There was a trend toward an increase in the proportion of patients who developed cerebral infarction from 51.5% in 2016 to 56.1% in 2021 (p trend p<.001). Routine discharge was significantly lower (30.5% vs. 37.8%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.75-0.89, p<.001), and poor outcome defined by NIS-SAH outcome measure was significantly higher among patients with cerebral infarction compared with those without cerebral infarction (67.4% vs. 59.3%, OR 1.29, 95% CI 1.18-1.40, p<.001). There was no difference in in-hospital mortality (13.0% vs. 13.6%, OR 0.94, 95% CI 0.85-1.05, p = .30). The length of stay (median 18 days [interquartile range [IQR] 13-25] vs. 14 days [IQR 9-20]), coefficient 3.04, 95% CI 2.44-3.52 and hospitalization cost (median $96,823 vs. $71,311, coefficient 22,320, 95% CI 20,053-24,587) were significantly higher among patients who developed cerebral infarction compared with those who did not develop cerebral infarction., Conclusions: Cerebral infarction was seen in 54% of the patients with a trend toward an increase in the affected proportion of patients with aneurysmal SAH. Patients with cerebral infarction had higher rates of adverse outcomes and required higher resources during hospitalization., (© 2024 American Society of Neuroimaging.)

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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

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., Competing Interests: Dr Kamel reports an ownership stake in TET Medical, compensation from American Medical Association and Javelin Medical for consultant services, compensation from Boehringer Ingelheim for end point review committee services, employment by Weill Cornell Medical College, compensation from Medtronic and Janssen Biotech for other services, and compensation from Novo Nordisk and AstraZeneca for end point review committee services. Dr Suarez reports compensation from Acasti Pharma for data and safety monitoring services and compensation from Cyban for consultant services. Dr Mack reports compensation from Viseon, Inc, for consultant services, compensation from Spartan Micro for consultant services, compensation from Cerebrotech for other services, compensation from Integra LifeSciences for consultant services, stock options in Spartan Micro, compensation from Egret for consultant services, stock options in Stream Biomedical, compensation from Viseon for other services, compensation from Endostream for other services, compensation from Vastrax for other services, stock holdings in Rebound Therapeutics, employment by the University of Southern California, compensation from Q’Apel for consultant services, compensation from Imperative Care, Inc, for consultant services, compensation from Radical Catheters for other services, compensation from Q’Apel for other services, stock options in Egret, compensation from Medtronic for other services, compensation from Stream Biomedical for consultant services, stock holdings in Truvic, compensation from Borvo for other services, and compensation from Stryker for data and safety monitoring services. Dr Chou reports compensation from Acasti for consultant services; employment by Northwestern Medicine; compensation from CSL Behring for consultant services; service as a member of the Board of Directors for the Neurocritical Care Society; grants from the Neurocritical Care Society; compensation from BioVie for consultant services; grants from the National Institute of Neurological Disorders and Stroke; and employment by Northwestern University. Dr Busl reports grants from the National Institutes of Health (NIH). Dr Derdeyn reports compensation from noNO for data and safety monitoring services, compensation from Silk Road Medical, Inc, for data and safety monitoring services, stock options in Euphrates Vascular, and compensation from Penumbra, Inc, for data and safety monitoring services. Dr Dangayach reports employment by Icahn School of Medicine at Mount Sinai, grants from Visionable, compensation from The Jacob’s Institute for consultant services, grants from Ceibahealth, grants from The Aneurysm and AVM Foundation (TAAF), grants from Neurosteer, and grants from American Academy of Neurology. Dr Elm reports compensation from CSL Behring for consultant services and grants from NIH. Dr Beall reports grants from NIH. Dr Ko reports compensation from Route 92 Medical, Inc, for data and safety monitoring services; service on the Board of Directors for TAAF; employment by the School of Medicine, University of California, San Francisco; and funding from the American Heart Association and NIH. The other authors report no conflicts.

Introduction: Cerebral infarction from delayed cerebral ischemia (DCI) is a leading cause of poor neurological outcome after aneurysmal subarachnoid hemorrhage (aSAH). We performed an international clinical practice survey to identify monitoring and management strategies for cerebral vasospasm associated with DCI in aSAH patients requiring intensive care unit admission., Methods: The survey questionnaire was available on the European Society of Intensive Care Medicine (May 2021-June 2022) and Neurocritical Care Society (April - June 2022) websites following endorsement by these societies., Results: There were 292 respondents from 240 centers in 38 countries. In conscious aSAH patients or those able to tolerate an interruption of sedation, neurological examination was the most frequently used diagnostic modality to detect delayed neurological deficits related to DCI caused by cerebral vasospasm (278 respondents, 95.2%), while in unconscious patients transcranial Doppler/cerebral ultrasound was most frequently used modality (200, 68.5%). Computed tomography angiography was mostly used to confirm the presence of vasospasm as a cause of DCI. Nimodipine was administered for DCI prophylaxis by the majority of the respondents (257, 88%), mostly by an enteral route (206, 71.3%). If there was a significant reduction in arterial blood pressure after nimodipine administration, a vasopressor was added and nimodipine dosage unchanged (131, 45.6%) or reduced (122, 42.5%). Induced hypertension was used by 244 (85%) respondents as first-line management of DCI related to vasospasm; 168 (59.6%) respondents used an intra-arterial procedure as second-line therapy., Conclusions: This survey demonstrated variability in monitoring and management strategies for DCI related to vasospasm after aSAH. These findings may be helpful in promoting educational programs and future research., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Improving the prognostication of acute brain injury is a key element of critical care. Standard assessment includes pupillary light reactivity testing with a hand-held light source, but findings are interpreted subjectively; automated pupillometry might be more precise and reproducible. We aimed to assess the association of the Neurological Pupil index (NPi)-a quantitative measure of pupillary reactivity computed by automated pupillometry-with outcomes of patients with severe non-anoxic acute brain injury., Methods: ORANGE is a multicentre, prospective, observational cohort study at 13 hospitals in eight countries in Europe and North America. Patients admitted to the intensive care unit after traumatic brain injury, aneurysmal subarachnoid haemorrhage, or intracerebral haemorrhage were eligible for the study. Patients underwent automated infrared pupillometry assessment every 4 h during the first 7 days after admission to compute NPi, with values ranging from 0 to 5 (with abnormal NPi being <3). The co-primary outcomes of the study were neurological outcome (assessed with the extended Glasgow Outcome Scale [GOSE]) and mortality at 6 months. We used logistic regression to model the association between NPi and poor neurological outcome (GOSE ≤4) at 6 months and Cox regression to model the relation of NPi with 6-month mortality. This study is registered with ClinicalTrials.gov, NCT04490005., Findings: Between Nov 1, 2020, and May 3, 2022, 514 patients (224 with traumatic brain injury, 139 with aneurysmal subarachnoid haemorrhage, and 151 with intracerebral haemorrhage) were enrolled. The median age of patients was 61 years (IQR 46-71), and the median Glasgow Coma Scale score on admission was 8 (5-11). 40 071 NPi measurements were taken (median 40 per patient [20-50]). The 6-month outcome was assessed in 497 (97%) patients, of whom 160 (32%) patients died, and 241 (47%) patients had at least one recording of abnormal NPi, which was associated with poor neurological outcome (for each 10% increase in the frequency of abnormal NPi, adjusted odds ratio 1·42 [95% CI 1·27-1·64]; p<0·0001) and in-hospital mortality (adjusted hazard ratio 5·58 [95% CI 3·92-7·95]; p<0·0001)., Interpretation: NPi has clinically and statistically significant prognostic value for neurological outcome and mortality after acute brain injury. Simple, automatic, repeat automated pupillometry assessment could improve the continuous monitoring of disease progression and the dynamics of outcome prediction at the bedside., Funding: NeurOptics., Competing Interests: Declaration of interests GC reports institutional research grants from Integra and NeurOptics; and received personal fees as a speakers’ bureau member and advisory board member from Integra, NeurOptics, Biogen, Idorsia, and Invex Therapeutics, all outside the submitted work; and is the Editor-in-Chief of Intensive Care Medicine. FST received consulting and lecture fees from NeurOptics; and received personal fees as an Advisory Board Member from NeurOptics, all outside the submitted work. MO received fee payments for consultancy roles for NeurOptics and honoraria for lectures by NeurOptics; received personal fees as an advisory board member from NeurOptics, all unrelated to the submitted work; and received institutional grants from the Swiss National Science Foundation. JIS reported personal fees as a member of the Clinical Endpoint Committee for the REACT Study funded by Idorsia; is member of the data safety and monitoring board for the INTREPID study; is a member of the board of directors of the Neurocritical Care Foundation and the Neurocritical Care Society; and is member of the editorial board of Stroke. NB-H received honoraria for lectures from ORION Pharma. ABO received honoraria for educational events from BD, support for attending meetings from Pfizer, and received equipment from NeurOptics. PB received honoraria for lectures from LFB Company and equipment from NeurOptics. RMC received institutional grants from the National Institutes of Health (National Institute of Child Health and Human Development; Fogarty International Centre). SG participated as a data safety and monitoring board member at Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, without payment. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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.

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., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Cerebral autoregulation (CA) prevents brain injury by maintaining a relatively constant cerebral blood flow despite fluctuations in cerebral perfusion pressure. This process is disrupted consequent to various neurologic pathologic processes, which may result in worsening neurologic outcomes. Herein, we aim to highlight evidence describing CA changes and the impact of CA monitoring in patients with cerebrovascular disease, including ischemic stroke, intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (aSAH). The study was preformed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. English language publications were identified through a systematic literature conducted in Ovid Medline, PubMed, and Embase databases. The search spanned the dates of each database's inception through January 2021. We selected case-control studies, cohort observational studies, and randomized clinical trials for adult patients (≥ 18 years) who were monitored with continuous metrics using transcranial Doppler, near-infrared spectroscopy, and intracranial pressure monitors. Of 2799 records screened, 48 studies met the inclusion criteria. There were 23 studies on ischemic stroke, 18 studies on aSAH, 5 studies on ICH, and 2 studies on systemic hypertension. CA impairment was reported after ischemic stroke but generally improved after tissue plasminogen activator administration and successful mechanical thrombectomy. Persistent impairment in CA was associated with hemorrhagic transformation, malignant cerebral edema, and need for hemicraniectomy. Studies that investigated large ICHs described bilateral CA impairment up to 12 days from the ictus, especially in the presence of small vessel disease. In aSAH, impairment of CA was associated with angiographic vasospasm, delayed cerebral ischemia, and poor functional outcomes at 6 months. This systematic review highlights the available evidence for CA disruption during cerebrovascular diseases and its possible association with long-term neurological outcome. CA may be disrupted even before acute stroke in patients with untreated chronic hypertension. Monitoring CA may help in establishing individualized management targets in patients with cerebrovascular disease., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background/objective: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality despite advances in management. We evaluated the prognostic significance of a qualitative score using brain magnetic resonance imaging (MRI) features obtained early after aSAH., Methods: Patients with aSAH were enrolled in a prospective observational cohort and underwent brain MRI during their acute hospitalization. MRIs were rated using a scoring system that considers the anatomical location of signal intensity changes on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences. The relationship between MRI scores and functional outcome defined by modified Rankin scale (mRS) at 6 months was evaluated in uni- and multivariable models., Results: The cohort included 45 aSAH patients (median World Federation of Neurologic Surgeons (IQR) 2 (1-4)) who underwent brain MRI a mean (SD) of 9.0 ± 8.0 days after aSAH. At 6 months after aSAH, 26 patients had achieved a favorable outcome (mRS ≤ 2) while 15 had an unfavorable outcome (mRS > 2). Deep gray nuclei (DGN) score (p = 0.016), cortex + DGN score (p = 0.015), FLAIR score (p = 0.016), DWI score (p = 0.0045), and overall score (p = 0.0081) were significantly lower in patients with favorable outcome compared to those with unfavorable outcome. However, MRI scores were not independent predictors of outcome in multivariable models adjusting for admission Hunt and Hess, Glasgow Coma Scale, or World Federation of Neurologic Surgeons scales., Conclusions: In this pilot study, a qualitative scoring system using anatomically defined MRI FLAIR and DWI signal abnormalities identified in the acute phase of aSAH was linked to 6-month functional outcome. However, these scores did not add prognostic value to established indices of neurological severity., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Objective: Rescue therapies have been recommended for patients with angiographic vasospasm (aVSP) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). However, there is little evidence from randomized clinical trials that these therapies are safe and effective. The primary aim of this study was to apply game theory-based methods in explainable machine learning (ML) and propensity score matching to determine if rescue therapy was associated with better 3-month outcomes following post-SAH aVSP and DCI. The authors also sought to use these explainable ML methods to identify patient populations that were more likely to receive rescue therapy and factors associated with better outcomes after rescue therapy., Methods: Data for patients with aVSP or DCI after SAH were obtained from 8 clinical trials and 1 observational study in the Subarachnoid Hemorrhage International Trialists repository. Gradient boosting ML models were constructed for each patient to predict the probability of receiving rescue therapy and the 3-month Glasgow Outcome Scale (GOS) score. Favorable outcome was defined as a 3-month GOS score of 4 or 5. Shapley Additive Explanation (SHAP) values were calculated for each patient-derived model to quantify feature importance and interaction effects. Variables with high SHAP importance in predicting rescue therapy administration were used in a propensity score-matched analysis of rescue therapy and 3-month GOS scores., Results: The authors identified 1532 patients with aVSP or DCI. Predictive, explainable ML models revealed that aneurysm characteristics and neurological complications, but not admission neurological scores, carried the highest relative importance rankings in predicting whether rescue therapy was administered. Younger age and absence of cerebral ischemia/infarction were invariably linked to better rescue outcomes, whereas the other important predictors of outcome varied by rescue type (interventional or noninterventional). In a propensity score-matched analysis guided by SHAP-based variable selection, rescue therapy was associated with higher odds of 3-month GOS scores of 4-5 (OR 1.63, 95% CI 1.22-2.17)., Conclusions: Rescue therapy may increase the odds of good outcome in patients with aVSP or DCI after SAH. Given the strong association between cerebral ischemia/infarction and poor outcome, trials focusing on preventative or therapeutic interventions in these patients may be most able to demonstrate improvements in clinical outcomes. Insights developed from these models may be helpful for improving patient selection and trial design.

Background: A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH)., Objective: To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects., Methods: Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated., Results: The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups., Conclusion: Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background and Purpose- EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods- Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results- The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P =0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P =0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P =0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions- There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02790632.

Background: Neurocritical care is devoted to the care of critically ill patients with acute neurological or neurosurgical emergencies. There is limited information regarding epidemiological data, disease characteristics, variability of clinical care, and in-hospital mortality of neurocritically ill patients worldwide. We addressed these issues in the Point PRevalence In Neurocritical CarE (PRINCE) study, a prospective, cross-sectional, observational study., Methods: We recruited patients from various intensive care units (ICUs) admitted on a pre-specified date, and the investigators recorded specific clinical care activities they performed on the subjects during their first 7 days of admission or discharge (whichever came first) from their ICUs and at hospital discharge. In this manuscript, we analyzed the final data set of the study that included patient admission characteristics, disease type and severity, ICU resources, ICU and hospital length of stay, and in-hospital mortality. We present descriptive statistics to summarize data from the case report form. We tested differences between geographically grouped data using parametric and nonparametric testing as appropriate. We used a multivariable logistic regression model to evaluate factors associated with in-hospital mortality., Results: We analyzed data from 1545 patients admitted to 147 participating sites from 31 countries of which most were from North America (69%, N = 1063). Globally, there was variability in patient characteristics, admission diagnosis, ICU treatment team and resource allocation, and in-hospital mortality. Seventy-three percent of the participating centers were academic, and the most common admitting diagnosis was subarachnoid hemorrhage (13%). The majority of patients were male (59%), a half of whom had at least two comorbidities, and median Glasgow Coma Scale (GCS) of 13. Factors associated with in-hospital mortality included age (OR 1.03; 95% CI, 1.02 to 1.04); lower GCS (OR 1.20; 95% CI, 1.14 to 1.16 for every point reduction in GCS); pupillary reactivity (OR 1.8; 95% CI, 1.09 to 3.23 for bilateral unreactive pupils); admission source (emergency room versus direct admission [OR 2.2; 95% CI, 1.3 to 3.75]; admission from a general ward versus direct admission [OR 5.85; 95% CI, 2.75 to 12.45; and admission from another ICU versus direct admission [OR 3.34; 95% CI, 1.27 to 8.8]); and the absence of a dedicated neurocritical care unit (NCCU) (OR 1.7; 95% CI, 1.04 to 2.47)., Conclusion: PRINCE is the first study to evaluate care patterns of neurocritical patients worldwide. The data suggest that there is a wide variability in clinical care resources and patient characteristics. Neurological severity of illness and the absence of a dedicated NCCU are independent predictors of in-patient mortality.

Background: Clinical studies of subarachnoid hemorrhage (SAH) and unruptured cerebral aneurysms lack uniformity in terms of variables used for assessments and clinical examination of patients which has led to difficulty in comparing studies and performing meta-analyses. The overall goal of the National Institute of Health/National Institute of Neurological Disorders and Stroke Unruptured Intracranial Aneurysms (UIA) and subarachnoid hemorrhage (SAH) Common Data Elements (CDE) Project was to provide common definitions and terminology for future unruptured intracranial aneurysm and SAH research., Methods: This paper summarizes the recommendations of the subcommittee on SAH Assessments and Clinical Examination. The subcommittee consisted of an international and multidisciplinary panel of experts in UIA and SAH. Consensus recommendations were developed by reviewing previously published CDEs for other neurological diseases including traumatic brain injury, epilepsy and stroke, and the SAH literature. Recommendations for CDEs were classified by priority into "core," "supplemental-highly recommended," "supplemental" and "exploratory.", Results: We identified 248 variables for Assessments and Clinical Examination. Only the World Federation of Neurological Societies grading scale was classified as "Core." The Glasgow Coma Scale was classified as "Supplemental-Highly Recommended." All other Assessments and Clinical Examination variables were categorized as "Supplemental.", Conclusion: The recommended Assessments and Clinical Examination variables have been collated from a large number of potentially useful scales, history, clinical presentation, laboratory, and other tests. We hope that adherence to these recommendations will facilitate the comparison of results across studies and meta-analyses of individual patient data.

Introduction: The Common Data Elements (CDEs) initiative is a National Institute of Health/National Institute of Neurological Disorders and Stroke (NINDS) effort to standardize naming, definitions, data coding, and data collection for observational studies and clinical trials in major neurological disorders. A working group of experts was established to provide recommendations for Unruptured Aneurysms and Aneurysmal Subarachnoid Hemorrhage (SAH) CDEs., Methods: This paper summarizes the recommendations of the Hospital Course and Acute Therapies after SAH working group. Consensus recommendations were developed by assessment of previously published CDEs for traumatic brain injury, stroke, and epilepsy. Unruptured aneurysm- and SAH-specific CDEs were also developed. CDEs were categorized into "core", "supplemental-highly recommended", "supplemental" and "exploratory"., Results: We identified and developed CDEs for Hospital Course and Acute Therapies after SAH, which included: surgical and procedure interventions; rescue therapy for delayed cerebral ischemia (DCI); neurological complications (i.e. DCI; hydrocephalus; rebleeding; seizures); intensive care unit therapies; prior and concomitant medications; electroencephalography; invasive brain monitoring; medical complications (cardiac dysfunction; pulmonary edema); palliative comfort care and end of life issues; discharge status. The CDEs can be found at the NINDS Web site that provides standardized naming, and definitions for each element, and also case report form templates, based on the CDEs., Conclusion: Most of the recommended Hospital Course and Acute Therapies CDEs have been newly developed. Adherence to these recommendations should facilitate data collection and data sharing in SAH research, which could improve the comparison of results across observational studies, clinical trials, and meta-analyses of individual patient data.

Objectives: The goal for this project was to develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in unruptured intracranial aneurysm (UIA) and subarachnoid hemorrhage (SAH) clinical research, as part of a new joint effort between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Library of Medicine of the US National Institutes of Health. These UIA and SAH CDEs will join several other neurological disease-specific CDEs that have already been developed and are available for use by research investigators., Methods: A Working Group (WG) divided into eight sub-groups and a Steering Committee comprised of international UIA and SAH experts reviewed existing NINDS CDEs and instruments, created new elements when needed and provided recommendations for UIA and SAH clinical research. The recommendations were compiled, internally reviewed by the entire UIA and SAH WG and posted online for 6 weeks for external public comments. The UIA and SAH WG and the NINDS CDE team reviewed the final version before posting the SAH Version 1.0 CDE recommendations., Results: The NINDS UIA and SAH CDEs and supporting documents are publicly available on the NINDS CDE ( https://www.commondataelements.ninds.nih.gov/#page=Default ) and NIH Repository ( https://cde.nlm.nih.gov/home ) websites. The recommendations are organized into domains including Participant Characteristics and Outcomes and Endpoints., Conclusion: Dissemination and widespread use of CDEs can facilitate UIA and SAH clinical research and clinical trial design, data sharing, and analyses of observational retrospective and prospective data. It is vital to maintain an international and multidisciplinary collaboration to ensure that these CDEs are implemented and updated when new information becomes available.

The aim of this study was to evaluate the impact of cerebral blood flow (CBF) recovery obtained from brain single-photon emission computed tomography (SPECT) images on postoperative outcome after aneurysmal subarachnoid haemorrhage (SAH). Twenty-nine patients who had undergone surgical clipping for ruptured anterior communicating artery aneurysms were analyzed prospectively. Routine measurements of CBF were performed using technetium-99 m hexamethyl propyleneamine oxine SPECT on days 4 and 14 after SAH. Regional voxel data analyzed by three dimensional stereotactic surface projection (3D-SSP) were compared between patients and age-matched normal database (NDB). In 3D-SSP analysis of all patients, cortical hypoperfusion around the surgical site in bilateral frontal lobes was evident on day 4 (P < .05 vs NDB), which was improved significantly on day 14. However, the recovery was less complete in patients with poor clinical grades (P < .05) and presenting symptoms attributable to delayed cerebral ischaemia (DCI) (P < .05) than those without. Multivariate analysis showed that patients with mild to moderate CBF recovery (relative Z-score differences of <4) (P = .014; odds ratio, 2.5; 95% confidence interval, 1.93-3.31) was independently associated with poor functional outcome at 3 months. We conclude that reduced CBF recovery detected by serial 3D-SSP SPECT image analyses can be a potential predictor of poor prognosis in postoperative patients after SAH., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size., Methods: To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage., Results: For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data., Conclusions: Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.

Background and Purpose: Experimental subarachnoid hemorrhage (SAH) by endovascular filament perforation method is used widely in mice, but it sometimes present acute cerebral infarctions with varied magnitude and anatomical location. This study aimed to determine the prevalence and location of the acute ischemic injury in this experimental model., Methods: Male C57BL/6 mice were subjected to SAH by endovascular perforation. Distribution of SAH was defined by T2*-weighted images within 1h after SAH. Prevalence and location of acute infarction were assessed by diffusion-weighted MR images on day 1 after the induction., Results: Among 72 mice successfully acquired post-SAH MR images, 29 (40%) developed acute infarction. Location of the infarcts was classified into either single infarct (ipsilateral cortex, n=12; caudate putamen, n=3; hippocampus, n=1) or multiple lesions (cortex and caudate putamen, n=6; cortex and hippocampus, n=2; cortex, hippocampus and thalamus/hypothalamus, n=3; bilateral cortex, n=2). The mortality rate within 24h was significantly higher in mice with multiple infarcts than those with single lesion (30% versus 0%; P=0.03). Distribution of the ischemic lesion positively correlated with MRI-evidenced SAH grading (r 2 =0.31, P=0.0002)., Conclusion: Experimental SAH immediately after the vessel perforation can induce acute cerebral infarction in varying vascular territories, resulting in increased mortality. The present model may in part, help researchers to interpret the mechanism of clinically-evidenced early multiple combined infarction., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality. We implemented an in-scanner rat model of mild SAH in which blood or vehicle was injected into the cistern magna, and applied multimodal MRI to study the brain prior to, immediately after (5min to 4h), and upto 7days after SAH. Vehicle injection did not change arterial lumen diameter, apparent diffusion coefficient (ADC), T2, venous signal, vascular reactivity to hypercapnia, or foot-fault scores, but mildly reduce cerebral blood flow (CBF) up to 4h, and open-field activity up to 7days post injection. By contrast, blood injection caused: (i) vasospasm 30min after SAH but not thereafter, (ii) venous abnormalities at 3h and 2days, delayed relative to vasospasm, (iii) reduced basal CBF and to hypercapnia 1-4h but not thereafter, (iv) reduced ADC immediately after SAH but no ADC and T2 changes on days 2 and 7, and (v) reduced open-field activities in both SAH and vehicle animals, but no significant differences in open-field activities and foot-fault tests between groups. Mild SAH exhibited transient and mild hemodynamic disturbances and diffusion changes, but did not show apparent ischemic brain injury nor functional deficits., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: The purpose of this article is to present the epidemiology, clinical presentation, and management of patients with subarachnoid hemorrhage (SAH). SAH is a neurologic emergency that carries high morbidity and mortality. Patients with SAH are at risk for several significant neurologic complications, including hydrocephalus, cerebral edema, delayed cerebral ischemia, rebleeding, seizures, and neuroendocrine abnormalities that lead to impaired body regulation of sodium, water, and glucose., Recent Findings: The incidence of SAH has remained stable, but mortality of hospitalized patients has significantly declined over the past 3 decades. Many common therapies for SAH have created controversy, and various recent neuroprotective clinical trials have produced negative results. However, the publication of two consensus guidelines by the American Heart Association/American Stroke Association and the Neurocritical Care Society have provided a clarification for what should constitute best practice for patients with SAH. The most important of those recommendations include the following: admission of patients to high-volume centers (defined as more than 35 patients with SAH per year) under the management of a specialized and multidisciplinary team; early identification and management of the bleeding source; evaluation and treatment decision for unsecured aneurysms by a multidisciplinary team made up of cerebrovascular neurosurgeons, endovascular practitioners, and neurointensivists; management of patients in the neurocritical care unit with oral nimodipine, blood pressure control, euvolemia, and frequent monitoring for neurologic and systemic complications; and delayed cerebral ischemia secondary to cerebral vasospasm should be treated with induced hypertension and endovascular therapies once confirmed., Summary: SAH is a devastating neurologic disease. Management of patients with SAH should adhere to currently available treatment guidelines. Several aspects of SAH management remain controversial and need further studies to clarify their role in improving patient outcome.

Neurogenic stunned myocardium (NSM) is a triad of transient left ventricular dysfunction, electrocardiogram changes, and elevation in cardiac enzymes, often mimicking a myocardial infarction. It has been described following acute brain injury. The purported mechanism is catecholamine excess resulting in cardiac dysfunction. From the clinical standpoint, the most frequently encountered electrocardiographic changes are QTc prolongation and ST-T changes, with modest elevations in troponin levels. Basal and mid-ventricular segments of the left ventricle are most commonly involved. NSM poses therapeutic challenges when it occurs secondary to aneurysmal subarachnoid hemorrhage, particularly in the setting of coexisting vasospasm. Overall, NSM carries good prognosis if recognized early, with appropriate management of hemodynamic and cardiopulmonary parameters., (© The Author(s) 2013.)

Background and Purpose: The neuroprotective effects of human albumin have been studied in animal models of stroke and in humans with various intracranial disorders. We investigated the effect of 25 % human albumin (ALB) on mean cerebral blood flow velocities (MCBFV), delayed cerebral ischemia (DCI), and cerebral infarction., Methods: We studied patients from the Albumin in Subarachnoid Hemorrhage (ALISAH) pilot clinical trial. We collected data on MCBFV as measured by transcranial Doppler ultrasound (TCD), incidence of DCI, and cerebral infarctions on head computed tomography (CT) scan at 90 days., Results: TCD showed vasospasm in 75 % (n = 15), 55 % (n = 11), and 29 % (n = 2) of subjects in dosage tiers 1, 2, and 3, respectively. DCI was present in 20 % (n = 4), 15 % (n = 3), and 14 % (n = 1) of subjects in dosage tiers 1, 2, and 3, respectively. Cerebral infarctions were seen in 45 % (5 of 9), 27 % (3 of 18), and 25 % (1 of 4) of subjects who had follow-up head CT scans in dosage tiers 1, 2, and 3, respectively., Conclusions: Higher dosages of ALB were associated with a lower incidence of TCD vasospasm, DCI, and cerebral infarction at 90 days in a dose-dependent manner.

Background: Subarachnoid hemorrhage (SAH) is a devastating disease. Nimodipine is the only medical treatment shown to improve outcome of SAH patients. Human albumin (ALB) may exert neuroprotection in SAH. However, current usage of ALB in SAH is not known. We conducted an international survey of clinicians involved in the care of SAH patients to determine current practice of ALB administration in SAH., Methods: We constructed a 27-question survey. Our sampling frame consisted of neurointensivists, general intensivists, neurocritical care nurses, critical care pharmacists, and neurosurgeons. The survey was available from 11/15/2012 to 12/15/2012. We performed mostly descriptive statistical analysis., Results: We obtained 362 responses from a diverse range of world regions. Most respondents were intensivist physicians (88 %), who worked in academic institutions (73.5 %) with a bed capacity >500 (64.1 %) and an established institutional management protocol for SAH patients (70.2 %). Most respondents (83.5 %) indicated that their institutions do not incorporate ALB in their protocol, but half of them (45.9 %) indicated using ALB outside it. ALB administration is influenced by several factors: geographic variation (more common among US respondents); institutions with a dedicated neuroICU; and availability of SAH management protocol. Most respondents (75 %) indicated that a clinical trial to test the efficacy of ALB in SAH is needed., Conclusions: In this survey we found that ALB administration in SAH patients is common and influenced by several factors. Majority of respondents support a randomized clinical trial to determine the safety and efficacy of ALB administration in SAH patients.

Background and Purpose: Human albumin has been shown to exert neuroprotective effects in animal models of cerebral ischemia and humans with various intracranial pathologies. We investigated the safety and tolerability of 25% human albumin in patients with subarachnoid hemorrhage., Methods: The Albumin in Subarachnoid Hemorrhage (ALISAH) Pilot Clinical Trial was an open-label, dose-escalation study. We intended to study 4 different dosages of albumin of increasing magnitude (0.625 g/kg: Tier 1; 1.25 g/kg: Tier 2; 1.875 g/kg: Tier 3; and 2.5 g/kg: Tier 4). Each dosage was to be given to 20 adult patients. Treatment was administered daily for 7 days. We investigated the maximum tolerated dose of albumin based on the rate of severe-to-life-threatening heart failure and anaphylactic reaction and functional outcome at 3 months., Results: We treated 47 adult subjects: 20 in Tier 1; 20 in Tier 2; and 7 in Tier 3. We found that doses ranging up to 1.25 g/kg/day×7 days were tolerated by patients without major dose-limiting complications. We also found that outcomes trended toward better responses in those subjects enrolled in Tier 2 compared with Tier 1 (OR, 3.0513; CI, 0.6586-14.1367) and with the International Intraoperative Hypothermia for Aneurysm Surgery Trial cohort (OR, 3.1462; CI, 0.9158-10.8089)., Conclusions: Albumin in doses ranging up to 1.25 g/kg/day×7 days was tolerated by patients with subarachnoid hemorrhage without major complications and may be neuroprotective. Based on these results, planning of the ALISAH II, a Phase III, randomized, placebo-controlled trial to test the efficacy of albumin, is underway., Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT00283400.

Subarachnoid hemorrhage (SAH) is an acute cerebrovascular event which can have devastating effects on the central nervous system as well as a profound impact on several other organs. SAH patients are routinely admitted to an intensive care unit and are cared for by a multidisciplinary team. A lack of high quality data has led to numerous approaches to management and limited guidance on choosing among them. Existing guidelines emphasize risk factors, prevention, natural history, and prevention of rebleeding, but provide limited discussion of the complex critical care issues involved in the care of SAH patients. The Neurocritical Care Society organized an international, multidisciplinary consensus conference on the critical care management of SAH to address this need. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. A jury of four experienced neurointensivists was selected for their experience in clinical investigations and development of practice guidelines. Recommendations were developed based on literature review using the GRADE system, discussion integrating the literature with the collective experience of the participants and critical review by an impartial jury. Recommendations were developed using the GRADE system. Emphasis was placed on the principle that recommendations should be based not only on the quality of the data but also tradeoffs and translation into practice. Strong consideration was given to providing guidance and recommendations for all issues faced in the daily management of SAH patients, even in the absence of high quality data.

Magnesium offers theoretic vascular and neuroprotective benefits for patients with subarachnoid hemorrhage. An electronic literature search was conducted to identify original research studies describing intravenous magnesium treatment in patients with SAH published in English between January 1990 and October 2010. Seventeen articles were identified and reviewed, including one phase III randomized-controlled clinical trial and six phase II randomized-controlled trials. Study quality was low for most of the included studies, with the phase III trial considered to be of moderate quality. Due to inconsistently reported benefits and the occurrence of side effects, phase II data suggested that intravenous magnesium for SAH provided either no overall net benefit or uncertain trade-offs. Benefit was likewise not supported in the single phase III clinical trial.

Introduction: Anemia is associated with poor outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). It remains unclear whether this association can be modified with more aggressive use of red blood cell (RBC) transfusions. The degree to which restrictive thresholds have been adopted in neurocritical care patients remains unknown., Methods: We performed a survey of North American academic neurointensivists, vascular neurosurgeons and multidisciplinary intensivists who regularly care for patients with SAH to determine hemoglobin (Hb) concentrations which commonly trigger a decision to initiate transfusion. We also assessed minimum and maximum acceptable Hb goals in the context of a clinical trial and how decision-making is influenced by advanced neurological monitoring, clinician characteristics and patient-specific factors., Results: The survey was sent to 531 clinicians, of whom 282 (53%) responded. In a hypothetical patient with high-grade SAH (WFNS 4), the mean Hb concentration at which clinicians administered RBCs was 8.19 g/dL (95% CI, 8.07 to 8.30 g/dL). Transfusion practices were comparatively more restrictive in patients with low-grade SAH (mean Hb 7.85 g/dL (95% CI, 7.73 to 7.97 g/dL)) (P < 0.0001) and more liberal in patients with delayed cerebral ischemia (DCI) (mean Hb 8.58 g/dL (95% CI, 8.45 to 8.72 g/dL)) (P < 0.0001). In each setting, there was a broad range of opinions. The majority of respondents expressed a willingness to study a restrictive threshold of ≤8 g/dL (92%) and a liberal goal of ≥10 g/dl (75%); in both cases, the preferred transfusion thresholds were significantly higher for patients with DCI (P < 0.0001). Neurosurgeons expressed higher minimum Hb goals than intensivists, especially for patients with high-grade SAH (β = 0.46, P = 0.003), and were more likely to administer two rather than one unit of RBCs (56% vs. 19%; P < 0.0001). Institutional use of transfusion protocols was associated with more restrictive practices. More senior clinicians preferred higher Hb goals in the context of a clinical trial. Respondents were more likely to transfuse patients with brain tissue oxygen tension values <15 mmHg and lactate-to-pyruvate ratios >40., Conclusions: There is widespread variation in the use of RBC transfusions in SAH patients. Practices are heavily influenced by the specific dynamic clinical characteristics of patients and may be further modified by clinician specialty and seniority, the use of protocols and advanced neurological monitoring.

The primary objective of this prospective dose-finding pilot study is to demonstrate the tolerability and safety of four dosages of 25% human albumin in patients with subarachnoid hemorrhage (SAH). For each dosage group, the study will enroll 20 patients who meet the eligibility criteria. The enrolled patients will undergo follow-up for 90 days post-treatment. The primary tolerability hypothesis is that intravenous 25% human albumin can be given without precipitating treatment related serious adverse events beyond expectations. The study will determine the maximum tolerated dosage of 25% human albumin therapy based on the rate of treatment related serious adverse events during treatment: severe or life-threatening heart failure. The secondary objectives are to obtain preliminary estimates of the albumin treatment effect using the incidence of neurological deterioration within 15 days after symptom onset. In addition, the incidence of rebleeding, hydrocephalus, seizures, delayed cerebral ischemia and the incidence of vasospasm (both symptomatic and by transcranial Doppler ultrasound criteria) within 15 days after symptom onset will be evaluated. Furthermore, the serum osmolality and serum albumin concentrations, serum magnesium concentration, blood pressure and heart rate within 15 days of symptom onset will also be observed. The Glasgow Outcome Scale, Barthel Index, modified Rankin Scale, NIH Stroke Scale, and Stroke Impact Scale will be performed 3 months after the onset of symptoms to assess residual neurological deficits.

Introduction: Subarachnoid hemorrhage is one of the most common entities encountered in neurocritical care units. Knowledge of disease sequelae and their management is paramount for all neurointensivists., Materials and Methods: This study relates the case of a 70-year-old woman with poor grade subarachnoid hemorrhage who underwent endovascular detachable coil embolization of a right internal carotid artery aneurysm. Her hospital course was subsequently complicated by symptomatic carotid stenosis and cerebral vasospasm requiring intervention., Discussion: The discussants present their views regarding five main questions pertaining to management of the patient regarding the choice of endovascular versus surgical aneurysm occlusion, stent-supported angioplasty in a patient with a recent subarachnoid hemorrhage, and treatment options for vasospasm.

Object: Human albumin is used to induce hypervolemia (central venous pressure [CVP] > 8 mm Hg) after subarachnoid hemorrhage (SAH). Unfortunately, human albumin may increase the mortality rate in critically ill patients; because of this, its use became restricted in the authors' hospital in May 1999. The goal of this study was to determine the effect of human albumin on outcome and cost in patients with SAH before and after this restriction was put into place., Methods: All patients with aneurysmal SAH who were admitted to the authors' institution between May 1998 and May 2000 were studied. Basic demographic information, dosage of human albumin given, length of stay, and the incidence of in-hospital deaths and complications were collected. The authors obtained Glasgow Outcome Scale (GOS) scores at 3 months after SAH (good outcome, GOS > or = 4). Data were analyzed using t-test and chi-square analysis. Logistic regression was used to identify independent associations between use of human albumin and outcome. The authors studied 140 patients: 63 who were admitted between May 1998 and May 1999 (Group 1) and 77 treated between June 1999 and May 2000 (Group 2). Two subgroups of patients were further analyzed. Group 1 patients who received human albumin (albumin subgroup, 37 patients) and Group 2 patients who would have received albumin under the old protocol (that is, those who failed to achieve CVP > 8 mm Hg after normal saline administration; nonalbumin subgroup, 47 patients). Patients in the nonalbumin subgroup were more likely to be male (38% compared with 16%), to experience hypertension (55% compared with 30%), to suffer from hypomagnesemia (49% compared with 5.4%), and to have hydrocephalus (47% compared with 27%). There was a trend for these patients to have more vasospasm (28% compared with 19%, p = 0.2). Patients in the albumin subgroup were more likely to have a good outcome at 3 months., Conclusions: Administration of human albumin after SAH may improve clinical outcome and reduce hospital cost.

Objective: To evaluate the reliability of transcranial Doppler ultrasound in detecting symptomatic vasospasm in patients after aneurysmal subarachnoid hemorrhage and monitoring response after hypertensive and endovascular treatments., Design: Retrospective chart review., Setting: Neurosciences critical care unit in a tertiary-care university hospital., Patients: All patients admitted to a neurosciences critical care unit with the diagnosis of subarachnoid hemorrhage between January 1990 and June 1997., Interventions: None, Measurements and Main Results: We reviewed transcranial Doppler ultrasound data of 199 patients; 55 had symptomatic vasospasm. Clinical symptoms and corresponding vascular distributions were identified, as was angiographic vasospasm (n = 35). The sensitivity and specificity of transcranial Doppler ultrasound for anterior circulation vessels were calculated by using a mean cerebral blood flow velocity criterion of >120 cm/sec. Clinical diagnosis of symptomatic vasospasm was used as the standard to determine sensitivity and specificity of transcranial Doppler ultrasound and cerebral angiography. The sensitivity of transcranial Doppler ultrasound for anterior circulation in patients with symptomatic vasospasm was 73% with a specificity of 80%. The sensitivity of cerebral angiography was 80%. For individual vessels, the sensitivity and specificity of transcranial Doppler ultrasound were middle cerebral artery, 64% and 78%; anterior cerebral artery, 45% and 84%; and internal carotid artery, 80% and 77%, respectively. The mean times for symptomatic and transcranial Doppler ultrasound signs of vasospasm presentation were 6.4 +/- 2 and 6.1 +/- 3 days, respectively. In patients without symptomatic vasospasm, the mean time for mean cerebral blood flow velocities >120 cm/sec was 7.0 +/- 3 days (p <.05). Symptomatic vasospasm also was associated with thickness of clot on head computed tomography scan and rapidly increasing mean cerebral blood flow velocities. Transcranial Doppler ultrasound signs of vasospasm improved after endovascular treatment in 30 patients., Conclusions: The reliability of transcranial Doppler ultrasound was better at detecting high mean cerebral blood flow velocities in patients with symptomatic vasospasm related to middle cerebral and internal carotid artery distributions than for anterior cerebral artery distribution. Transcranial Doppler ultrasound was as sensitive as cerebral angiography at detecting symptomatic vasospasm. High mean cerebral blood flow velocities can be apparent before the presence of symptomatic vasospasm. Daily transcranial Doppler ultrasound monitoring could provide early identification of patients with aneurysmal subarachnoid hemorrhage who are at high risk for symptomatic vasospasm and may be helpful at following success of endovascular treatment.

Objective: Cigarette smoking has been demonstrated to increase the risk of subarachnoid hemorrhage (SAH). Whether cessation of smoking decreases this risk remains unclear. We performed a case-control study to examine the effect of smoking and other known risk factors for cerebrovascular disease on the risk of SAH., Methods: We reviewed the medical records of all patients with a diagnosis of SAH (n = 323) admitted to Johns Hopkins Hospital between January 1990 and June 1997. Controls matched for age, sex, and ethnicity (n = 969) were selected from a nationally representative sample of the Third National Health and Nutrition Examination Survey. We determined the independent association between smoking (current and previous) and various cerebrovascular risk factors and SAH by use of multivariate logistic regression analysis. A separate analysis was performed to determine associated risk factors for aneurysmal SAH., Results: Of 323 patients admitted with SAH (mean age, 52.7+/-14 yr; 93 were men), 173 (54%) were hypertensive, 149 (46%) were currently smoking, and 125 (39%) were previous smokers. In the multivariate analysis, both previous smoking (odds ratio [OR], 4.5; 95% confidence interval [CI], 3.1-6.5) and current smoking (OR, 5.2; 95% CI, 3.6-7.5) were significantly associated with SAH. Hypertension was also significantly associated with SAH (OR, 2.4; 95% CI, 1.8-3.1). The risk factors for 290 patients with aneurysmal SAH were similar and included hypertension (OR, 2.4; 95% CI, 1.8-3.2), previous smoking (OR, 4.1; 95% CI, 2.7-6.0), and current smoking (OR, 5.4; 95% CI, 3.7-7.8)., Conclusion: Hypertension and cigarette smoking increase the risk for development of SAH, as found in previous studies. However, the increased risk persists even after cessation of cigarette smoking, which suggests the importance of early abstinence from smoking.

Objective: Symptomatic vasospasm after subarachnoid hemorrhage (SAH) is associated with a high incidence of permanent disability and death. For early identification of patients who are at risk for poor outcome, we determined the predictors of outcome in patients with symptomatic vasospasm after SAH., Design: We retrospectively determined the prognostic value of clinical characteristics and computed tomographic scan both at admission and at the time of initiation of hypervolemic and hypertensive therapy., Settings: Neurosciences critical care unit at a University hospital., Patients: A total of 70 consecutive patients who developed symptomatic vasospasm after SAH., Intervention: Treatment with oral nimodipine, hypervolemic therapy, and hypertensive therapy. Angioplasty and intra-arterial papaverine were used in patients with vasospasm resistant to standard treatment., Measurements and Main Results: Poor outcome, defined as Glasgow Outcome Scale Score of 3-5 at 2 months or discharge, was observed in 32 (46%) patients. In the logistic regression analysis, a Glasgow Coma Scale (GCS) score of < or =11 (odds ratio, 11.0; 95% confidence interval, 3.6-39.3) and hydrocephalus (odds ratio, 4.3; 95% confidence interval, 1.2-18.2) at the time of initiation of hypervolemic and hypertensive therapy were significantly associated with poor outcome. Poor outcome was observed in 91% of the patients who had both a GCS score of < or =11 and hydrocephalus compared with 15% of patients with a GCS score of >11 and no hydrocephalus at the time of initiation of hypervolemic and hypertensive therapy. A GCS score of < or =11 was also independently associated with length of intensive care unit stay (F ratio = 18.0; p = .0011) and hospital stay (F ratio = 9.2; p = .0034) after initiation of hypervolemic and hypertensive therapy., Conclusions: The results of this study suggest that outcome in patients with symptomatic vasospasm can be effectively predicted by routinely available information, including GCS score at the time of initiation of hypervolemic and hypertensive therapy. This information can be used for selection and stratification of patients in future treatment studies of patients with symptomatic vasospasm.

A retrospective study was carried out to evaluate the effect of hypertonic (3%) saline chloride/acetate on various hemodynamic parameters in mildly hyponatremic patients with symptomatic vasospasm following aneurysmal subarachnoid hemorrhage (SAH). We identified 29 hyponatremic (serum sodium < 135 mEq/L) patients who received hypertonic (3%) sodium chloride/acetate as a continuous infusion. Administration of hypertonic (3%) sodium chloride/acetate resulted in higher central venous pressures and positive fluid balance, with a concomitant increase in serum sodium and chloride concentrations without metabolic acidosis. There were no changes in mean cerebral blood flow velocities after infusion of hypertonic (3%) sodium chloride/acetate. We found no reports of congestive heart failure, pulmonary edema, metabolic acidosis, coagulopathy, intracranial hemorrhages, or central pontine myelinolysis in any of these patients. We conclude that hypertonic (3%) sodium chloride/acetate can be administered to patients with mild hyponatremia in the setting of symptomatic vasospasm following SAH without untoward effects. Sample size and limitations of a retrospective analysis preclude conclusions about safety and efficacy of hypertonic (3%) sodium chloride/acetate administration in this patient population. However, our results support justification for a prospective, randomized, double-blind trial of hypertonic (3%) sodium chloride/acetate versus normal saline in patients with symptomatic vasospasm following SAH.