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Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified. Supplementary Information The online version contains supplementary material available at 10.1007/s12028-021-01260-x.

Consciousness in patients with brain injury is traditionally assessed based on semiological evaluation at the bedside. This classification is limited because of low granularity, ill-defined and rigid nomenclatures incompatible with the highly fluctuating nature of consciousness, failure to identify specific brain states like cognitive motor dissociation, and neglect for underlying biological mechanisms. Here, the authors present a pragmatic framework based on consciousness endotypes that combines clinical phenomenology with all essential physiological and biological data, emphasizing recovery trajectories, therapeutic potentials and clinical feasibility. The Neurocritical Care Society’s Curing Coma Campaign identified an international group of experts who convened in a series of online meetings between May and November 2020 to discuss and propose a novel framework for classifying consciousness. The expert group proposes Advanced Classification of Consciousness Endotypes (ACCESS), a tiered multidimensional framework reflecting increasing complexity and an aspiration to consider emerging and future approaches. Tier 1 is based on clinical phenotypes and structural imaging. Tier 2 adds functional measures including EEG, PET and functional MRI, that can be summarized using the Arousal, Volition, Cognition and Mechanisms (AVCM) score (where “Volition” signifies volitional motor responses). Finally, Tier 3 reflects dynamic changes over time with a (theoretically infinite) number of physiologically distinct states to outline consciousness recovery and identify opportunities for therapeutic interventions. Whereas Tiers 1 and 2 propose an approach for low-resource settings and state-of-the-art expertise at leading academic centers, respectively, Tier 3 is a visionary multidimensional consciousness paradigm driven by continuous incorporation of new knowledge while addressing the Curing Coma Campaign’s aspirational goals.

Background Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. Aim To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. Methods A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. Results Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. Conclusion The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

OBJECTIVEThe objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH).METHODSPatients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2–4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100–1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration.RESULTSFifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2–3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations.CONCLUSIONSPlasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

OBJECTIVEDelayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) may result in focal neurological deficits and cerebral infarction, believed to result from critical regional rather than global impairments in cerebral blood flow (CBF). However, the burden of such regional hypoperfusion has not been evaluated by gold-standard voxel-by-voxel CBF measurements. Specifically, the authors sought to determine whether the proportion of brain affected by hypoperfusion was greater in patients with DCI than in SAH controls without DCI and whether the symptomatic hemisphere (in those with lateralizing deficits) exhibited a greater cerebral hypoperfusion burden.METHODSSixty-one patients with aneurysmal SAH underwent 15O PET to measure regional CBF during the period of risk for DCI (median 8 days after SAH, IQR 7–10 days). Regions of visibly abnormal brain on head CT studies, including areas of hemorrhage and infarction, were excluded. Burden of hypoperfusion was defined as the proportion of PET voxels in normal-appearing brain with CBF < 25 ml/100 g/min. Global CBF and hypoperfusion burden were compared between patients with and those without DCI at the time of PET. For patients with focal impairments from DCI, the authors also compared average CBF and hypoperfusion burden in symptomatic versus asymptomatic hemispheres.RESULTSTwenty-three patients (38%) had clinical DCI at the time of PET. Those with DCI had higher mean arterial pressure (MAP; 126 ± 14 vs 106 ± 12 mm Hg, p < 0.001) and 18 (78%) were on vasopressor therapy at the time of PET study. While global CBF was not significantly lower in patients with DCI (mean 39.4 ± 11.2 vs 43.0 ± 8.3 ml/100 g/min, p = 0.16), the burden of hypoperfusion was greater (20%, IQR 12%–23%, vs 12%, 9%–16%, p = 0.006). Burden of hypoperfusion performed better than global CBF as a predictor of DCI (area under the curve 0.71 vs 0.65, p = 0.044). Neither global CBF nor hypoperfusion burden differed in patients who responded to therapy compared to those who had not improved by the time of PET. Although hemispheric CBF was not lower in the symptomatic versus contralateral hemisphere in the 13 patients with focal deficits, there was a trend toward greater burden of hypoperfusion in the symptomatic hemisphere (21% vs 18%, p = 0.049).CONCLUSIONSThe burden of hypoperfusion was greater in patients with DCI, despite hemodynamic therapies, higher MAP, and equivalent global CBF. Similarly, hypoperfusion burden was greater in the symptomatic hemisphere of DCI patients with focal deficits even though the average CBF was similar to that in the contralateral hemisphere. Evaluating the proportion of the brain with critical hypoperfusion after SAH may better capture the extent of DCI than averaging CBF across heterogenous brain regions.

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: The current state of the science regarding the care and prognosis of patients with disorders of consciousness is limited. Scientific advances are needed to improve the accuracy, relevance, and approach to prognostication, thereby providing the foundation to develop meaningful and effective interventions. METHODS: To address this need, an interdisciplinary expert panel was created as part of the Coma Science Working Group of the Neurocritical Care Society Curing Coma Campaign. RESULTS: The panel performed a gap analysis which identified seven research needs for prognostic modeling and trajectory analysis (“recovery science”) in patients with disorders of consciousness: (1) to define the variables that predict outcomes; (2) to define meaningful intermediate outcomes at specific time points for different endotypes; (3) to describe recovery trajectories in the absence of limitations to care; (4) to harness big data and develop analytic methods to prognosticate more accurately; (5) to identify key elements and processes for communicating prognostic uncertainty over time; (6) to identify health care delivery models that facilitate recovery and recovery science; and (7) to advocate for changes in the health care delivery system needed to advance recovery science and implement already-known best practices. CONCLUSION: This report summarizes the current research available to inform the proposed research needs, articulates key elements within each area, and discusses the goals and advances in recovery science and care anticipated by successfully addressing these needs.

Funder: Tiny Blue Dot Foundation, Funder: Templeton World Charity Foundation; doi: http://dx.doi.org/10.13039/501100011730, Funder: Cambridge Commonwealth, European and International Trust; doi: http://dx.doi.org/10.13039/501100003343, Funder: Gates Cambridge Trust; doi: http://dx.doi.org/10.13039/501100005370, AIM: In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. METHODS: To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. RESULTS: We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. CONCLUSION: In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a "virtuous cycle," leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice., This work was supported by the Tiny Blue Dot Foundation; the Templeton World Charity Foundation, Inc.; grant NInDS K23NS112473; NIH-NIGMS Grant R01GM135420; the National Institute of General Medical Sciences (1K08GM121961); The Johns Hopkins University Discovery Award, Stimulating and Advancing ACCM Research Award; the European Union���s Horizon 2020 Framework Program for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3); the Canadian Institute for Advanced Research (CIFAR) (RCZB/072 RG93193); the Stephen Erskine Fellowship (Queens��� College, Cambridge, UK); the Cambridge European Trust; the Gates Cambridge Trust.

The Fifth Neurocritical Care Research Network (NCRN) Conference held in Boca Raton, Florida, in September of 2018 was devoted to challenging the current status quo and examining the role of the Neurocritical Care Society (NCS) in driving the science and research of neurocritical care. The aim of this in-person meeting was to set the agenda for the NCS’s Neurocritical Care Research Central, which is the overall research arm of the society. Prior to the meeting, all 103 participants received educational content (book and seminar) on the ‘Blue Ocean Strategy®,’ a concept from the business world which aims to identify undiscovered and uncontested market space, and to brainstorm innovative ideas and methods with which to address current challenges in neurocritical care research. Three five-member working groups met at least four times by teleconference prior to the in-person meeting to prepare answers to a set of questions using the Blue Ocean Strategy concept as a platform. At the Fifth NCRN Conference, these groups presented to a five-member jury and all attendees for open discussion. The jury then developed a set of recommendations for NCS to consider in order to move neurocritical care research forward. We have summarized the topics discussed at the conference and put forward recommendations for the future direction of the NCRN and neurocritical care research in general.

Background Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). Objective To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. Methods Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. Results Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. Conclusion This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.

Background Hypothermia is neuroprotective in some ischemia–reperfusion injuries. Ischemia–reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia–reperfusion injury and improve global neurologic outcome. Methods This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. Results Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. Conclusions This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Background and Purpose: This study aimed to determine the maximum tolerated dose and to evaluate the overall safety and tolerability of single doses of PF-05230907 in subjects with acute intracerebral hemorrhage. Methods: Individuals presenting with intracerebral hemorrhage were enrolled in a phase 1, multicenter, open-label clinical trial. A Bayesian modified continual reassessment method design based on treatment-emergent thromboembolic or ischemic events was adopted. Sequential dosing, an external data monitoring committee, and prespecified stopping rules were incorporated as safeguards. Results: Twenty-one subjects received PF-05230907. The mean (±SD) age in years and intracerebral hemorrhage volume in mL at baseline were 62 (±9) and 18 (±11), respectively. Two treatment-emergent thromboembolic or ischemic events occurred (deep vein thrombosis and cerebral ischemia), in the 30 μg/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 μg/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 μg/kg, with a mean fitted dose-toxicity estimate of 11.9% (95% CI, 1.2%–27.4%). Conclusions: Single doses of PF-05230907 appeared to be tolerated across a range of doses in the intracerebral hemorrhage population, with thrombotic events observed only at the highest dose level tested. Recruitment within the recommended therapeutic window of opportunity remains a challenge. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02687191.

Consciousness in patients with brain injury is traditionally assessed based on semiological evaluation at the bedside. This classification is limited because of low granularity, ill-defined and rigid nomenclatures incompatible with the highly fluctuating nature of consciousness, failure to identify specific brain states like cognitive motor dissociation, and neglect for underlying biological mechanisms. Here, the authors present a pragmatic framework based on consciousness endotypes that combines clinical phenomenology with all essential physiological and biological data, emphasizing recovery trajectories, therapeutic potentials and clinical feasibility.The Neurocritical Care Society's Curing Coma Campaign identified an international group of experts who convened in a series of online meetings between May and November 2020 to discuss and propose a novel framework for classifying consciousness.The expert group proposes Advanced Classification of Consciousness Endotypes (ACCESS), a tiered multidimensional framework reflecting increasing complexity and an aspiration to consider emerging and future approaches. Tier 1 is based on clinical phenotypes and structural imaging. Tier 2 adds functional measures including EEG, PET and functional MRI, that can be summarized using the Arousal, Volition, Cognition and Mechanisms (AVCM) score (where "Volition" signifies volitional motor responses). Finally, Tier 3 reflects dynamic changes over time with a (theoretically infinite) number of physiologically distinct states to outline consciousness recovery and identify opportunities for therapeutic interventions.Whereas Tiers 1 and 2 propose an approach for low-resource settings and state-of-the-art expertise at leading academic centers, respectively, Tier 3 is a visionary multidimensional consciousness paradigm driven by continuous incorporation of new knowledge while addressing the Curing Coma Campaign's aspirational goals.

Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients. ispartof: NEUROCRITICAL CARE vol:33 issue:1 pages:1-12 ispartof: location:United States status: published

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.

Background Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. Methods Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. Results We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. Conclusions These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference. Electronic supplementary material The online version of this article (10.1007/s00134-019-05900-x) contains supplementary material, which is available to authorized users.

Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2–4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral nimodipine. The primary endpoint is the proportion of subjects with favorable outcome (6–8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.

OBJECTIVES Impaired oxygen delivery due to reduced cerebral blood flow is the hallmark of delayed cerebral ischemia following subarachnoid hemorrhage. Since anemia reduces arterial oxygen content, it further threatens oxygen delivery increasing the risk of cerebral infarction. Thus, subarachnoid hemorrhage may constitute an important exception to current restrictive transfusion practices, wherein raising hemoglobin could reduce the risk of ischemia in a critically hypoperfused organ. In this physiologic proof-of-principle study, we determined whether transfusion could augment cerebral oxygen delivery, particularly in vulnerable brain regions, across a broad range of hemoglobin values. DESIGN Prospective study measuring cerebral blood flow and oxygen extraction fraction using O-PET. Vulnerable brain regions were defined as those with baseline oxygen delivery less than 4.5 mL/100 g/min. SETTING PET facility located within the Neurology/Neurosurgery ICU. PATIENTS Fifty-two patients at risk for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage with hemoglobin 7-13 g/dL. INTERVENTIONS Transfusion of one unit of RBCs over 1 hour. MEASUREMENTS AND MAIN RESULTS Baseline hemoglobin was 9.7 g/dL (range, 6.9-12.9), and cerebral blood flow was 43 ± 11 mL/100 g/min. After transfusion, hemoglobin rose from 9.6 ± 1.4 to 10.8 ± 1.4 g/dL (12%; p < 0.001) and oxygen delivery from 5.0 (interquartile range, 4.4-6.6) to 5.5 mL/100 g/min (interquartile range, 4.8-7.0) (10%; p = 0.001); the response was comparable across the range of hemoglobin values. In vulnerable brain regions, transfusion resulted in a greater (16%) rise in oxygen delivery associated with reduction in oxygen extraction fraction, independent of Hgb level (p = 0.002 vs normal regions). CONCLUSIONS This study demonstrates that RBC transfusion improves cerebral oxygen delivery globally and particularly to vulnerable regions in subarachnoid hemorrhage patients at risk for delayed cerebral ischemia across a wide range of hemoglobin values and suggests that restrictive transfusion practices may not be appropriate in this population. Large prospective trials are necessary to determine if these physiologic benefits translate into clinical improvement and outweigh the risk of transfusion.

Supplemental Digital Content is available in the text., Background and Purpose— We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. Methods— Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. Results— Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). Conclusions— EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190.

Brain injury; Head trauma; Algorithm Daño cerebral; Trauma en la cabeza; Algoritmo Lesió cerebral; Trauma al cap; Algoritme Background: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation’s sTBI Management Guidelines, as they were not evidence-based. Methods: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists’ decision tendencies were the focus of recommendations. Results: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination. Conclusions: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management. We thank our financial supporters who include Adler/Geirsch Attorney at Law, the American Association of Neurological Surgeons/Congress of Neurological Surgeons Section on Neurotrauma and Critical Care, Bard, the Brain Trauma Foundation, DePuy, Hemedex, Integra, the Neurointensive Care Section of the European Society of Intensive Care Medicine, Neurosurgical Society of Australasia, Medtronic, Moberg Research, Natus, Neuroptics, Raumedic, Sophysa, Stryker, and Zoll.

The phosphodiesterase-5 inhibitor sildenafil has been shown to attenuate delayed cerebral ischemia (DCI) and improve neurologic function in experimental subarachnoid hemorrhage (SAH). We recently demonstrated that it could improve cerebral vasospasm (CVS) in humans after SAH. However, successful therapies for DCI must also restore cerebral blood flow (CBF) and/or autoregulatory capacity. In this study, we tested the effects of sildenafil on CBF in SAH patients at-risk for DCI. Six subjects with angiographically confirmed CVS received 30-mg of intravenous sildenafil (mean 9 ± 2 days after aneurysmal SAH). Each underwent 15O-PET imaging to measure global and regional CBF at baseline and post-sildenafil. Mean arterial pressure declined by 10 mm Hg on average post-sildenafil (8 %, p = 0.01), while ICP was unchanged. There was no change in global CBF (mean 34.5 ± 7 ml/100g/min at baseline vs. 33.9 ± 8.0 ml/100g/min post-sildenafil, p = 0.84). The proportion of brain regions with low CBF (

Seizures occur in 10–20% of patients with subarachnoid hemorrhage (SAH), predominantly in the acute phase. However, anticonvulsant prophylaxis remains controversial, with studies suggesting a brief course may be adequate and longer exposure may be associated with worse outcomes. Nonetheless, in the absence of controlled trials to inform practice, patients continue to receive variable chemoprophylaxis. The objective of this study was to compare brief versus extended seizure prophylaxis after aneurysmal SAH. We performed a prospective, single-center, randomized, open-label trial of a brief (3-day) course of levetiracetam (LEV) versus extended treatment (until hospital discharge). The primary outcome was in-hospital seizure. Secondary outcomes included drug discontinuation and functional outcome. Eighty-four SAH patients had been randomized when the trial was terminated due to slow enrollment. In-hospital seizures occurred in three (9%) of 35 in the brief LEV group versus one (2%) of 49 in the extended group (p = 0.2). Ten (20%) of the extended group discontinued LEV prematurely, primarily due to sedation. Four of five seizures (including one pre-randomization) occurred in patients with early brain injury (EBI) on computed tomography (CT) scans (adjusted OR 12.5, 95% CI 1.2–122, p = 0.03). Good functional outcome (mRS 0–2) was more likely in the brief LEV group (83 vs. 61%, p = 0.04). This study was underpowered to demonstrate superiority of extended LEV for seizure prophylaxis, although a trend to benefit was seen. Seizures primarily occurred in those with radiographic EBI, suggesting targeted prophylaxis may be preferable. Larger trials are required to evaluate optimal chemoprophylaxis in SAH, especially in light of worse outcomes in those receiving extended treatment.

This article addresses the intensive care unit (ICU) management of patients with aneurysmal subarachnoid hemorrhage (SAH), with an emphasis on the prevention of cerebral vasospasm and delayed cerebral ischemia (DCI), which are major contributors to morbidity and mortality. Interventions addressing various steps in the development of vasospasm have been attempted, with variable success. Enteral nimodipine remains the only approved measure to potentially prevent DCI. Since oral and intravenous administrations are limited by hypotension, direct administration via sustained-release pellets and intraventricular administration of sustained-release microparticles are being investigated. Studies of other calcium channel blockers have been disappointing. Efforts to remove blood from the subarachnoid space via cisternal irrigation, cisternal or ventricular thrombolysis, and lumbar cerebrospinal fluid drainage have met with limited and variable success, and they remain an area of active investigation. Several interventions that had early promise have failed to show benefit when studied in large trials; these include tirilazad, magnesium, statins, clazosentan, transluminal angioplasty, and hypervolemia.

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. EG-1962 is a sustained-release microparticle formulation of nimodipine that has shown preclinical efficacy when administered intraventricularly or intracisternally to dogs with SAH, without evidence of toxicity at doses in the anticipated therapeutic range. Thus, we propose to administer EG-1962 to humans in order to assess safety and tolerability and determine a dose to investigate efficacy in subsequent clinical studies. We describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of EG-1962 in patients with aSAH. The study will comprise two parts: a dose escalation period (Part 1) to determine the MTD of EG-1962 and a treatment period (Part 2) to assess the safety and tolerability of the selected dose of EG-1962. Patients with a ruptured saccular aneurysm treated by neurosurgical clipping or endovascular coiling will be considered for enrollment. Patients will be randomized to receive either EG-1962 (study drug: nimodipine microparticles) or oral nimodipine in the approved dose regimen (active control) within 60 h of aSAH. Primary objectives are to determine the MTD and the safety and tolerability of the selected dose of intraventricular EG-1962 as compared to enteral nimodipine. The secondary objective is to determine release and distribution by measuring plasma and CSF concentrations of nimodipine. Exploratory objectives are to determine the incidence of delayed cerebral infarction on computed tomography, clinical features of delayed cerebral ischemia, angiographic vasospasm, and incidence of rescue therapy and clinical outcome. Clinical outcome will be determined at 90 days after aSAH using the extended Glasgow outcome scale, modified Rankin scale, Montreal cognitive assessment, telephone interview of cognitive status, and Barthel index. Here, we describe a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the MTD and assess the safety and tolerability of EG-1962 in patients with aSAH.

A variety of technologies have been developed to assist decision-making during the management of patients with acute brain injury who require intensive care. A large body of research has been generated describing these various technologies. The Neurocritical Care Society (NCS) in collaboration with the European Society of Intensive Care Medicine (ESICM), the Society for Critical Care Medicine (SCCM), and the Latin America Brain Injury Consortium (LABIC) organized an international, multidisciplinary consensus conference to perform a systematic review of the published literature to help develop evidence-based practice recommendations on bedside physiologic monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews on physiologic processes important in the care of acute brain injury. In this article we provide the evidentiary tables for select topics including systemic hemodynamics, intracranial pressure, brain and systemic oxygenation, EEG, brain metabolism, biomarkers, processes of care and monitoring in emerging economies to provide the clinician ready access to evidence that supports recommendations about neuromonitoring.

Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been linked to focal reductions in cerebral blood flow (CBF) and microvascular impairments in oxygen delivery. Effective therapies that restore flow and oxygen transport to vulnerable brain regions are currently lacking. SANGUINATE is a dual-action carbon monoxide-releasing and hemoglobin-based oxygen transfer agent with efficacy in animal models of focal brain ischemia and tolerability in patients with sickle cell disease. We performed a safety and proof-of-principle study in 12 SAH patients at risk of DCI across three escalating doses (160, 240, and 320 mg/kg). We used 15O-PET (performed at baseline, after SANGUINATE and at 24 h) to evaluate efficacy for improving CBF and restoring flow–metabolism balance (assessed by oxygen extraction fraction [OEF]) to vulnerable regions (defined as baseline OEF ≥ 0.50). SANGUINATE resulted in a transient rise in mean arterial pressure (116 ± 15–127 ± 13 mm Hg, p = 0.001) that normalized by 24 h and allowed three patients with DCI to be weaned off vasopressors. No adverse events were noted during infusion. Global CBF did not rise (43 ± 8–46 ± 9 ml/100 g/min) although a trend was seen at the highest dose (45 ± 7–51 ± 9, p = 0.044). However, a significant 16% rise in regional CBF associated with reduction in OEF was seen in vulnerable regions, but did not persist at 24 h. We demonstrated that this novel agent can improve regional CBF and may improve oxygen supply–demand balance. Clinical studies (likely with repeat dosing) are required to evaluate whether this effect can prevent DCI or cerebral infarction.

Introduction: Impaired oxygen delivery (DO 2 ), as a result of reduced cerebral blood flow (CBF), is the hallmark of delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). Anemia further contributes to reductions in DO 2 and places the brain at risk for infarction. Transfusion, by raising hemoglobin (Hgb) and oxygen content of arterial blood, may be able to reduce the risk of ischemia. However, it is unknown whether an Hgb threshold exists above which CBF will fall sufficient to negate any benefit of transfusion on DO 2 . In this physiologic proof-of-principle study we evaluated whether transfusion improves DO 2 and reduces brain vulnerable to ischemia across a broad range of Hgb values. Methods: 47 SAH patients with/at-risk for DCI with Hgb 7-13 g/dl were transfused 1 unit of red blood cells (RBCs). 15 O-PET imaging was used to measure CBF, DO 2 , and oxygen extraction fraction (OEF) before and after transfusion. Vulnerable brain regions were defined as those with baseline DO 2 < 4.5 ml/100g/min (equivalent to CBF of 25 ml/100g/min at low-normal Hgb). Results: Baseline Hgb was 9.7 g/dl (range 6.9-12.5) and CBF was 43±11 ml/100g/min. After transfusion, Hgb rose by 12% and global DO 2 by 10% (from 5.0 to 5.5 ml/100g/min, p=0.001), with CBF only marginally lower; response to transfusion was not dependent on Hgb level. Transfusion resulted in a greater (16%) rise in DO 2 , associated with a larger reduction in OEF, in vulnerable brain regions (p=0.005 for low vs. normal regions), even after adjusting for Hgb. Number of vulnerable regions was reduced from median 9 to 4 per patient (p=0.005). Conclusions: Transfusion of RBCs to patients at-risk for DCI improves cerebral oxygen delivery, preferentially to vulnerable regions and reduces brain at-risk for ischemia. This physiologic benefit does not appear limited to those with severe anemia but persists to Hgb as high as 13 g/dl. Our findings suggest that restrictive transfusion practices may not be appropriate in this population. Prospective trials are needed to determine if these physiologic benefits outweigh risks of transfusion and translate into clinical prevention of DCI.

Few treatments for aneurysmal subarachnoid hemorrhage (aSAH) have been effective in randomized clinical studies. One reason may be that the outcome measures used are not sensitive enough to detect efficacy of treatments in this disease. This hypothesis was examined by comparing 6 outcome measures for 72 patients with aSAH. Patients with aSAH who were World Federation of Neurological Surgeons grades 2 to 4 with an external ventricular drain inserted as part of standard of care were entered in a Phase 1/2a multicenter, controlled, randomized, open-label, dose escalation study to determine the maximum tolerated dose and safety and tolerability of a sustained release formulation of nimodipine (EG-1962, NEWTON study) in patients with aSAH. Clinical outcome was assessed at 90 days after aSAH using the extended Glasgow outcome scale (eGOS), modified Rankin scale (mRS), Montreal cognitive assessment (MoCA), telephone interview of cognitive status (TICS), NIHSS and Barthel index. The relationship between each outcome measure and the eGOS was plotted on arithmetic graphs (Figure). The eGOS and mRS gave very similar results. More detailed cognitive assessments (MoCA, TICS) were more exponential in shape with more variability. The NIHSS and Barthel had outcomes clustered towards the highest ends of the scales with distributions that did not discriminate as much as the eGOS or mRS. The MoCA and TICS gave similar results. It was concluded that the eGOS or mRS produce a similar and varying range of outcomes after aSAH, whereas cognitive assessments like the MoCA and TICS and scales designed for ischemic stroke like the NIHSS and BI are less discriminatory of outcomes after aSAH.

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data.

Widely-varying published and presented analyses of the Benchmark Evidence From South American Trials: Treatment of Intracranial Pressure (BEST TRIP) randomized controlled trial of intracranial pressure (ICP) monitoring have suggested denying trial generalizability, questioning the need for ICP monitoring in severe traumatic brain injury (sTBI), re-assessing current clinical approaches to monitored ICP, and initiating a general ICP-monitoring moratorium. In response to this dissonance, 23 clinically-active, international opinion leaders in acute-care sTBI management met to draft a consensus statement to interpret this study. A Delphi method-based approach employed iterative pre-meeting polling to codify the group's general opinions, followed by an in-person meeting wherein individual statements were refined. Statements required an agreement threshold of more than 70% by blinded voting for approval. Seven precisely-worded statements resulted, with agreement levels of 83% to 100%. These statements, which should be read in toto to properly reflect the group's consensus positions, conclude that the BEST TRIP trial: 1) studied protocols, not ICP-monitoring per se; 2) applies only to those protocols and specific study groups and should not be generalized to other treatment approaches or patient groups; 3) strongly calls for further research on ICP interpretation and use; 4) should be applied cautiously to regions with much different treatment milieu; 5) did not investigate the utility of treating monitored ICP in the specific patient group with established intracranial hypertension; 6) should not change the practice of those currently monitoring ICP; and 7) provided a protocol, used in non-monitored study patients, that should be considered when treating without ICP monitoring. Consideration of these statements can clarify study interpretation.

Background Cerebral infarction is a major contributor to poor outcome after subarachnoid hemorrhage (SAH). Although usually considered a complication of delayed cerebral ischemia, infarcts may also occur early, in relation to initial brain injury or aneurysm-securing procedures. Objective We analyzed the relative frequency and volume of early vs delayed infarcts after SAH and their relationship to hospital outcome. Methods Retrospective review of consecutive patients admitted with aneurysmal SAH over 4 years who had follow-up brain imaging 7 days or later after admission. Imaging 24 to 48-hours after aneurysm-securing procedures was reviewed to classify infarcts seen on final imaging as early or delayed. Infarct volumes were measured by perimeter tracing and infarct burden calculated for each patient. Results Of 250 eligible patients, 205 had follow-up imaging; infarcts were present in 61 patients. Of these, 29 had early infarcts, 16 had delayed infarcts, and 5 had both early and delayed infarcts. Eleven patients with infarcts did not undergo postprocedure computed tomography; these were presumptively classified as having late infarcts. Early and delayed infarcts contributed equally to infarct burden. Early infarcts were associated with aneurysm clipping (odds ratio: 4.2, 95% confidence interval: 1.8-9.5 compared with coiling), whereas delayed infarcts were almost always seen in association with angiographic vasospasm (odds ratio: 3.3, 95% confidence interval: 1.5-7.3). Patients with early as well as late infarcts, especially those with infarct burden more than 30 cm had worse hospital discharge disposition. Conclusion Early infarction occurs frequently after SAH and contributes as much as delayed cerebral ischemia to infarct burden and hospital outcome. Efforts to better understand and modify contributors to early infarction appear warranted.

To discuss trends in the use of osmotic therapy.Use of osmotic therapy has evolved from bolus administration of mannitol to routine use of hypertonic saline as a bolus as well as in continuous infusions to creating a sustained hyperosmolar state.In a survey of neurointensivists 55% favored hypertonic saline over mannitol. Retrospective studies suggest better intracranial pressure (ICP) control with hypertonic saline. Whereas a prospective study in adults with head injury compared alternating doses of mannitol and hypertonic saline and found no difference in change in ICP control or outcome, two meta-analyses, which did not include this study, favored hypertonic saline for ICP control (although the absolute difference of 2 mmHg is of little clinical value) with no difference in outcome.Hypertonic saline has also been administered by infusions to creating a sustained stable hyperosmolar state. Two studies, using historical controls, suggested benefit of hypertonic saline infusions. In a prospective, randomized study, in children with severe head injury Lactated Ringer's solution was compared to hypertonic saline. Although ICP control was similar, the hypertonic saline group required fewer other interventions.The existing data do not support favoring boluses of hypertonic saline over mannitol in terms of ICP control, let alone outcome. The rationale for continuous infusions to create a sustained hyperosmolar state is open to discussion and use of this approach should be curtailed pending further research.

Neurologists are often asked to define prognosis in comatose patients. However, comatose patients following cardiac arrest are usually cared for by cardiologists or intensivists, and it is their approach that will influence decisions regarding withdrawal of life-sustaining interventions (WLSI). We observed that factors leading to these decisions vary across specialties and considered whether they could result in self-fulfilling prophecies and early WLSI. We conducted a hypothesis-generating qualitative study to identify factors used by non-neurologists to define prognosis in these patients and construct an explanatory model for how early WLSI might occur. This was a single-center qualitative study of intensivists caring for cardiac arrest patients with hypoxic-ischemic coma. Thirty attending physicians (n = 16) and fellows (n = 14) from cardiac (n = 8), medical (n = 6), surgical (n = 10), and neuro (n = 6) intensive care units underwent semi-structured interviews. Interview transcripts were analyzed using grounded theory techniques. We found three components of early WLSI among non-neurointensivists: (1) development of fixed negative opinions; (2) early framing of poor clinical pictures to families; and (3) shortened windows for judging recovery potential. In contrast to neurointensivists, non-neurointensivists’ negative opinions were frequently driven by patients’ lack of consciousness and cardiopulmonary resuscitation circumstances. Both groups were influenced by age and comorbidities. The results demonstrate that factors influencing prognostication differ across specialties. Some differ from those recommended by published guidelines and may lead to self-fulfilling prophecies and early WLSI. Better understanding of this framework would facilitate educational interventions to mitigate this phenomenon and its implications on patient care.

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. EG-1962 is a sustained release formulation of nimodipine for intraventricular delivery into the subarachnoid space while avoiding dose-limiting hypotension common with systemic administration. We conducted a phase 1/2a multicenter, controlled, randomized, open label, dose escalation study to determine the maximum tolerated dose (MTD) and assess safety, tolerability, pharmacokinetics and clinical outcome at 90 days on the extended Glasgow outcome scale (GOSE) of a single intraventricular dose of EG-1962 (www.clinicaltrials.gov Identifier: NCT01893190). Subjects with aSAH repaired by clipping or coiling were randomized within 60 hours of aSAH to EG-1962 or oral nimodipine if they were World Federation of Neurological Surgeons grade 2 to 4 and had a ventricular catheter. Cohorts of 12 subjects received 100, 200, 400, 600, 800 or 1200 mg EG-1962 (9 per cohort) or oral nimodipine (3 per cohort). The MTD was 800 mg EG-1962. Plasma nimodipine concentrations after administration of EG-1962 were sustained for 21 days and increased in a dose-dependent fashion. Cerebrospinal fluid nimodipine concentrations with EG-1962 were orders of magnitude higher than in plasma and with oral nimodipine. There was one serious adverse event (possible allergic reaction) related to EG-1962 (400 mg) and two EG-1962 dose limiting toxicities (increased intracranial pressure, 400 and 800 mg); all were without clinical sequelae. There was no EG-1962-related hypotension as compared to hypotension in 17% (3/18) with oral nimodipine. Favorable outcome (GOSE 6-8) was achieved in 27 of 45 (60%) EG-1962 subjects (5 of 9 with 100, 6 of 9 with 200, 7 of 9 with 400, 4 of 9 with 600 and 5 of 9 with 800 mg) and 5 of 18 (28%) oral nimodipine subjects. Improved efficacy was supported by reduction in delayed cerebral ischemia (15/45 [33%] EG-1962 versus 11/18 [61%] oral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]) in EG-1962 subjects. Intraventricular EG-1962 was safe and tolerable to 800 mg, associated with sustained and dose-dependent nimodipine plasma concentrations,improved clinical outcome and reduced delayed cerebral ischemia and use of rescue therapy after aSAH.

Statins may promote vasodilation following subarachnoid hemorrhage (SAH) and improve the response to blood pressure elevation. We sought to determine whether simvastatin increases cerebral blood flow (CBF) and alters the response to induced hypertension after SAH. Statin-naive patients admitted

For almost a century, it has been known that hypertonic solutions shrink cerebral tissue. Early attempts used hypertonic solutions of ions (sodium, magnesium) and sugars (glucose, dextrose, sucrose), concentrated albumin, and, later, urea. These early attempts were largely abandoned because the effect was short lived and often followed by a period of rebound edema. This was a result, to a great extent, of the osmotic agent either being metabolized or crossing the cell membrane.Renewed interest in osmotic therapy came in the 1960s, with the introduction of intracranial pressure monitoring in head injury and the use of mannitol as an osmotic agent. In the 1990s, use of hypertonic saline was reintroduced as an alternative to address concerns about mannitol. More recently, administration of hypertonic saline has transitioned from boluses to continuous infusions. The rationale for and data supporting the use of continuous infusions are presented.

Object The yield of CT angiography (CTA) and MR angiography (MRA) in patients with subarachnoid hemorrhage (SAH) who have a negative initial catheter angiogram is currently not well understood. This study aims to determine the yield of CTA and MRA in a prospective cohort of patients with SAH and a negative initial catheter angiogram. Methods From January 1, 2005, until September 1, 2010, the authors instituted a prospective protocol in which patients with SAH—as documented by noncontrast CT or CSF xanthochromia and a negative initial catheter angiogram— were evaluated using CTA and MRA to assess for causative cerebral aneurysms. Two neuroradiologists independently evaluated the noncontrast CT scans to determine the SAH pattern (perimesencephalic or not) and the CT and MR angiograms to assess for causative cerebral aneurysms. Results Seventy-seven patients were included, with a mean age of 52.8 years (median 54 years, range 19–88 years). Fifty patients were female (64.9%) and 27 male (35.1%). Forty-three patients had nonperimesencephalic SAH (55.8%), 29 patients had perimesencephalic SAH (37.7%), and 5 patients had CSF xanthochromia (6.5%). Computed tomography angiography demonstrated a causative cerebral aneurysm in 4 patients (5.2% yield), all of whom had nonperimesencephalic SAH (9.3% yield). Mean aneurysm size was 2.6 mm (range 2.1–3.3 mm). Magnetic resonance angiography demonstrated only 1 of these aneurysms. No causative cerebral aneurysms were found in patients with perimesencephalic SAH or CSF xanthochromia. Conclusions Computed tomography angiography is a valuable adjunct in the evaluation of patients with nonperimesencephalic SAH who have a negative initial catheter angiogram, demonstrating a causative cerebral aneurysm in 9.3% of patients.

Object Critical reductions in oxygen delivery (DO2) underlie the development of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). If DO2 is not promptly restored, then irreversible injury (that is, cerebral infarction) may result. Hemodynamic therapies for DCI (that is, induced hypertension [IH] and hypervolemia) aim to improve DO2 by raising cerebral blood flow (CBF). Red blood cell (RBC) transfusion may be an alternate strategy that augments DO2 by improving arterial O2 content. The authors compared the relative ability of these 3 interventions to improve cerebral DO2, specifically their ability to restore DO2 to regions where it is impaired. Methods The authors compared 3 prospective physiological studies in which PET imaging was used to measure global and regional CBF and DO2 before and after the following treatments: 1) fluid bolus of 15 ml/kg normal saline (9 patients); 2) raising mean arterial pressure 25% (12 patients); and 3) transfusing 1 U of RBCs (17 patients) in 38 individuals with aneurysmal SAH at risk for DCI. Response between groups in regions with low DO2 (< 4.5 ml/100 g/min) was compared using repeated-measures ANOVA. Results Groups were similar except that the fluid bolus cohort had more patients with symptoms of DCI and lower baseline CBF. Global CBF or DO2 did not rise significantly after any of the interventions, except after transfusion in patients with hemoglobin levels < 9 g/dl. All 3 treatments improved CBF and DO2 to regions with impaired baseline DO2, with a greater improvement after transfusion (23%) than hypertension (14%) or volume loading (10%); p < 0.001. Transfusion also resulted in a nonsignificantly greater (47%) reduction in the number of brain regions with low DO2 when compared with fluid bolus (7%) and hypertension (12%) (p = 0.33). Conclusions The IH, fluid bolus, and blood transfusion interventions all improve DO2 to vulnerable brain regions at risk for ischemia after SAH. Transfusion appeared to provide a physiological benefit at least comparable to IH, especially among patients with anemia, but transfusion is associated with risks. The clinical significance of these findings remains to be established in controlled clinical trials.