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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. [ABSTRACT FROM AUTHOR]

Background: Stereotactic thrombolysis reduces intracerebral haemorrhage (ICH) volume in patients with spontaneous ICH. Whether intrahaematomal alteplase administration is associated with a change in intraventricular haemorrhage volume (deltaIVH) and functional outcomes is unknown., Methods: Post hoc secondary analysis of the Minimally Invasive Surgery plus Alteplase for Intracerebral Hemorrhage Evacuation Phase III (MISTIE-III) trial in patients with IVH on the stability CT scan. Exposure was minimally invasive surgery plus alteplase (MIS+alteplase). Primary outcome was deltaIVH defined as IVH volume on end-of-treatment CT minus IVH volume on stability CT scan. Secondary outcomes were favourable functional outcome (modified Rankin Scale 0-3) and mortality at 365 days. We assessed the relationship between MIS+alteplase and deltaIVH in the primary analysis using multivariable linear regression, and between deltaIVH and functional outcomes in secondary analyses using multiple logistic regression., Results: Of 499 patients in MISTIE-III, 310 (62.1%) had IVH on stability scans; mean age (SD) was 61.2±12.3 years. A total of 146 (47.1%) received the MISTIE procedure and 164 (52.9%) standard medical care (SMC) only. The MIS+alteplase group had a greater mean reduction in IVH volume compared with the SMC group (deltaIVH: -2.35 (5.30) mL vs -1.15 (2.96) mL, p=0.02). While IVH volume decreased significantly in both treatment groups, in the primary analysis, MIS+alteplase was associated with greater deltaIVH in multivariable linear regression analysis adjusted for potential confounders (β -0.80; 95% CI -1.37 to -0.22, p=0.007). Secondary analysis demonstrated no associations between IVH reduction and functional outcomes (adjusted OR (aOR) for poor outcome 1.02; 95% CI 0.96 to 1.08, p=0.61; aOR for mortality 0.99; 95% CI 0.92 to 1.06, p=0.77)., Conclusions: Alteplase delivered into the ICH in MISTIE-III subjects with IVH was associated with a small reduction in IVH volume. This reduction did not translate into a significant benefit in mortality or functional outcomes at 365 days., Trial Registration Number: NCT01827046., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Early diagnosis of acute brain injury (ABI) is critical for patients on veno-arterial extracorporeal membrane oxygenation (V-A ECMO) to guide anticoagulation strategy; however, neurological assessment in ECMO is often limited by patient sedation., Methods: In this pilot study of adults from June 2018 to May 2019, plasma samples of glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and tubulin associated unit (Tau) were collected daily after V-A ECMO cannulation and measured using a multiplex platform. Primary outcomes were occurrence of ABI, assessed clinically, and neurologic outcome, assessed by modified Rankin Scale (mRS)., Results: Of 20 consented patients (median age = 48.5°years; 55% female), 8 (40%) had ABI and 15 (75%) had unfavorable neurologic outcome at discharge. 10 (50%) patients were centrally cannulated. Median duration on ECMO was 4.5°days (IQR: 2.5-9.5). Peak GFAP, NFL, and Tau levels were higher in patients with ABI vs. without (AUC = 0.77; 0.85; 0.57, respectively) and in patients with unfavorable vs. favorable neurologic outcomes (AUC = 0.64; 0.59; 0.73, respectively). GFAP elevated first, NFL elevated to the highest degree, and Tau showed limited change regardless of ABI., Conclusion: Further studies are warranted to determine how plasma biomarkers may facilitate early detection of ABIs in V-A ECMO to assist timely clinical decision-making., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Intracerebral hemorrhage is the most serious type of stroke, leading to high rates of severe disability and mortality. Hematoma expansion is an independent predictor of poor functional outcome and is a compelling target for intervention. For decades, randomized trials aimed at decreasing hematoma expansion through single interventions have failed to meet their primary outcomes of statistically significant improvement in neurological outcomes. A wide range of evidence suggests that ultra-early bundled care, with multiple simultaneous interventions in the acute phase, offers the best hope of limiting hematoma expansion and improving functional recovery. Patients with intracerebral hemorrhage who fail to receive early aggressive care have worse outcomes, suggesting that an important treatment opportunity exists. This consensus statement puts forth a call to action to establish a protocol for Code ICH, similar to current strategies used for the management of acute ischemic stroke, through which early intervention, bundled care, and time-based metrics have substantially improved neurological outcomes. Based on current evidence, we advocate for the widespread adoption of an early bundle of care for patients with intracerebral hemorrhage focused on time-based metrics for blood pressure control and emergency reversal of anticoagulation, with the goal of optimizing the benefit of these already widely used interventions. We hope Code ICH will endure as a structural platform for continued innovation, standardization of best practices, and ongoing quality improvement for years to come., Competing Interests: Disclosures Dr Andrei Alexandrov has received consulting fees from AstraZeneca. Dr Anne Alexandrov has received speakers bureau honoraria and reimbursement for travel expenses via an unrestricted educational grant from AstraZeneca. Dr Anderson has received grants from the National Health and Medical Research Council of Australia, the Medical Research Council of the UK, Penumbra, and Takeda paid to his institution, and is Vice-President of the World Stroke Organisation and Editor-in-Chief of Cerebrovascular Disease. Dr Dowlatshahi has received consulting fees from Astra Zeneca, serves as Canadian national PI for the FASTEST trial (Factor VIIa for Acute Hemorrhagic Stroke Administered at Earliest Time; 5U01NS110772-02) and holds a patent for automatic detection of contrast extravasation (CARL). Dr Frontera is a site PI for the ANNEXA-I trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of fXa Inhibitors; funded by AstraZeneca), the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS)-funded ASPIRE (Anticoagulation in ICH Survivors for Stroke Prevention and Recovery) and SATURN (Statins in Intracerbral Hemorrhage) trials, has received consulting fees from Lusmosa, has received support for attending meetings and travel from Alexion, and was a member of the NIH/NINDS-funded SHINE (Stroke Hyperglycemia Insulin Network Effort) trials data safety monitoring board. Dr Ganti is a speaker bureau member and has received consulting fees from AstraZeneca and has received royalties from McGraw Hill and Springer for writing textbooks and review books. Dr Hemphill has played a leadership or fiduciary role in the 2022 AHA/ASA ICH guidelines and the 2023 AHA/ASA ICH performance measures and has received gifts from AstraZeneca. Dr Kellner is treasurer of the cerebrovascular section of the American Association of Neurological Surgeons/Congress of Neurological Surgeons; receives research grant support from Cerebrotech, Siemens, Penumbra, Medtronic, Minnetronix, vizAI, Integra, Longeviti, IRRAS, ICE Neurosystems, CVAid, Inc, and Endostream and has equity in Precision Recovery, Borealis, E8, Borvo, and Metis Innovative. Metis Innovative is an investment group that has coordinated investments in Synchron, Proprio, Fluid Biomed, Von Medical, and Precision Recovery. C. May has received consulting fees and travel support from AstraZeneca and speaking honoraria from Voxmedia LLC. Dr Morotti has received consulting fees and honoraria from EMG-REG international. A. Parry-Jones has received consulting fees and speaking honoraria from AstraZeneca. Dr Sheth is supported by the NIH (U24NS107136, U24NS107215, R01NR018335, R01NS107215, R01EB031114, R01MD016178, U01NS106513) and the American Heart Association (Bugher Grant AHA000BFCHS00199732). He has also received consulting fees from Astrocyte, Zoll, Certus, CSL Behring, Rhaeos, and Cerevasc, and equity from Alva. Dr Sheth reports stock holdings in AbbVie; stock options in BrainQ; stock holdings in verve therapeutics; service as President for Advanced Innovation in Medicine; a patent pending for stroke wearables licensed to Alva Health; and has received stock options from Astrocyte and Rhaeos, meeting and travel support from Biogen. He has participated in data and safety monitoring board or advisory boards for Zoll, Sense, and Philips; and has received ad hoc payment for legal testimony. Yale has received grants to support Dr Sheth’s research from Biogen, Hyperfine, Novartis, and Bard. Dr Steiner has received consulting and speaker fees from Bayer, Boehringer, BMS Pfizer, AtraZeneca, Daiichi Sankyo. Dr Ziai has received grants from the NIH, serves as the Associate Editor of Neurocritical Care, and reports consulting fees from C. R. Bard (data monitoring committee) and Lumosa Therapeutics. Dr Goldstein has received research support from the NIH, Pfizer, Octapharma, and Takeda and has received consulting fees from Astra Zeneca, CSL Behring, Prothya, nControl, Cayuga, and Lumosa. Dr Mayer has received consulting fees from CSL Behring, AstraZeneca, and MaxQ AI and grant support from the NIH (IMSM) for the FASTEST trial (5U01NS110772-02). The other authors report no conflicts.

Background: Children with moyamoya are at high risk for incident and recurrent stroke. Transcranial Doppler (TCD) ultrasound is an attractive option to screen high-risk populations for moyamoya and to provide stroke risk stratification information due to its safety and cost-effectiveness. We used TCD to evaluate cerebral blood flow velocities in children with presurgical moyamoya and to determine if velocities differ between children with stable and unstable disease., Methods: Fourteen participants aged ≤21 years with a radiographic diagnosis of moyamoya or moyamoya-like arteriopathy underwent a research TCD at a median age of 7.2 years. TCDs were performed outside of the setting of acute stroke and before surgical revascularization. Arteriopathy was classified as unstable if the participant had a stroke or transient ischemic attack within three months preceding the TCD., Results: Middle cerebral artery and internal carotid artery (ICA) blood flow velocities were elevated. The median M1 velocity was 138 cm/s (interquartile range [IQR] 106 to 168). Individual M1 flow velocities were a median of 5.0 S.D.s above age-based normative values. The median distal ICA velocity was 146 cm/s (IQR 124 to 163). Individual ICA flow velocities were a median of 5.9 S.D.s above normative values. Participants with unstable arteriopathy had higher M1 velocities compared with those with stable arteriopathy (170 vs 119 cm/s, P = 0.0003). We did not identify velocity differences based on comorbid conditions or age., Conclusions: These preliminary data suggest that TCD is a promising tool for screening for cerebral arteriopathies in high-risk pediatric populations and assessment for unstable disease., Competing Interests: Declaration of competing interest None, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Extracorporeal membrane oxygenation has a high risk of acute brain injury and resultant mortality. Transcranial Doppler characterizes cerebral hemodynamics in real time, but limited data exist on its interpretation in ECMO. Here, we report TCD mean flow velocity and pulsatility index in a large ECMO population., Methods: This was a prospective cohort study at a tertiary care center. The patients were adults on venoarterial ECMO or venovenous ECMO undergoing TCD studies., Results: A total of 135 patients underwent a total of 237 TCD studies while on VA-ECMO (n = 95, 70.3%) or VV-ECMO (n = 40, 29.6%). MFVs were captured reliably (approximately 90%) and were similar to a published healthy cohort in all vessels except the internal carotid artery. Presence of a recordable PI was strongly associated with ECMO mode (57% in VA vs. 95% in VV, p < 0.001). Absence of TCD pulsatility was associated with intraparenchymal hemorrhage (14.7 vs. 1.6%, p = 0.03) in VA-ECMO patients., Conclusions: Transcranial Doppler analysis in a single-center cohort of VA-ECMO and VV-ECMO patients demonstrates similar MFVs and PIs. Absence of PIs was associated with a higher frequency of intraparenchymal hemorrhage and a composite bleeding event. However, cautious interpretation and external validation is necessary for these findings with a multicenter study with a larger sample size., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Intracerebral haemorrhage (ICH) is a dramatic condition caused by the rupture of a cerebral vessel and the entry of blood into the brain parenchyma. ICH is a major contributor to stroke-related mortality and dependency: only half of patients survive for 1 year after ICH, and patients who survive have sequelae that affect their quality of life. The incidence of ICH has increased in the past few decades with shifts in the underlying vessel disease over time as vascular prevention has improved and use of antithrombotic agents has increased. The pathophysiology of ICH is complex and encompasses mechanical mass effect, haematoma expansion and secondary injury. Identifying the causes of ICH and predicting the vital and functional outcome of patients and their long-term vascular risk have improved in the past decade; however, no specific treatment is available for ICH. ICH remains a medical emergency, with prevention of haematoma expansion as the key therapeutic target. After discharge, secondary prevention and management of vascular risk factors in patients remains challenging and is based on an individual benefit-risk balance evaluation., (© 2023. Springer Nature Limited.)

Background: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes., Methods: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE)., Results: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome., Conclusions: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Objective: Extracorporeal membrane oxygenation (ECMO) carries a high morbidity of acute brain injury (ABI) with resultant mortality increase. Transcranial Doppler (TCD) allows real-time characterization of regional cerebral hemodynamics, but limited data exist on the interpretation of microembolic signals (MES) in ECMO., Methods: This prospective cohort study was conducted at a single tertiary care center, November 2017 through February 2022, and included all adult patients receiving venoarterial (VA) and venovenous (VV) ECMO undergoing TCD examinations, which all included MES monitoring., Results: Of 145 patients on ECMO who underwent at least 1 TCD examination, 100 (68.9%) patients on VA-ECMO received 187 examinations whereas 45 (31.1%) patients on VV-ECMO received 65 examinations ( P  = .81). MES were observed in 35 (35.0%) patients on VA-ECMO and 2 (4.7%) patients on VV-ECMO ( P  < .001), corresponding to 46 (24.6%) and 2 (3.1%) TCD examinations, respectively. MES were present in 29.4% of patients on VA-ECMO without additional cardiac support, compared with 38.1% with intra-aortic balloon pump and 57.1% with left ventricular assist device, but these differences were not statistically significant ( P  = .39; P  = .20, respectively). Presence or number of MES was not associated with VA-ECMO cannulation mode (23.4% MES presence in peripheral cannulation vs 25.8% in central cannulation, P  = .80). In both VA- and VV-ECMO, MES presence or number was not associated with presence of clot or fibrin in the ECMO circuit or with any studied hemodynamic, laboratory, or ECMO parameters at the time of TCD. ABI occurred in 38% and 31.1% of patients on VA- and VV-ECMO, respectively. In multivariable logistic regression analyses, neither ABI nor a composite outcome of arterial thromboembolic events was associated with presence or number of MES in VA- ECMO., Conclusions: TCD analysis in a large cohort of patients on ECMO demonstrates a significant number of MES, especially in patients on VA-ECMO with intra-aortic balloon pump, and/or left ventricular assist device. However, clinical associations and significance of TCD MES remain unresolved and warrant further correlation with systematic imaging and long-term neurologic follow-up., (© 2022 The Author(s).)

Background: Coronavirus disease (COVID-19) has led to changes in how healthcare is delivered. Here, through the administration of surveys, we evaluated telehealth use and views in US intensive care units (ICUs) during the pandemic., Methods: From June 2020 to July 2021, voluntary, electronic surveys were provided to ICU leaders of Johns Hopkins Medical Institution (JHMI) hospitals, members of the Neurocritical Care Society (NCS) who practice in the US, and Society of Critical Care Medicine (SCCM) members practicing adult medicine., Results: Response rates to our survey were as follows: 18 of 22 (81.8%) JHMI-based ICU leaders, 22 of 2218 (1.0%) NCS members practicing in the US, and 136 of 13,047 (1.0%) SCCM members. COVID-19 patients were among those cared for in the ICUs of 77.7, 86.4, and 93.4% of respondents, respectively, in April 2020 (defined as the peak of the pandemic). Telehealth technologies were used by 88.9, 77.3, and 75.6% of respondents, respectively, following the start of COVID-19 while only 22.2, 31.8, and 43.7% utilized them prior. The most common telehealth technologies were virtual meeting software and telephone (with no video component). Provider, nurse, and patient communications with the patient's family constituted the most frequent types of interactions utilizing telehealth. Most common reasons for telehealth use included providing an update on a patient's condition and conducting a goals of care discussion. 93.8-100.0% of respondents found telehealth technologies valuable in managing patients. Technical issues were noted by 66.7, 50.0, and 63.4% of respondents, respectively., Conclusions: Telehealth use increased greatly among respondents following the start of COVID-19. In US ICUs, telehealth technologies found diverse uses during the pandemic. Future studies are needed to confirm our findings., (© 2022. The Author(s).)

Recovery from coma or disordered consciousness is a central issue in patients with acute brain injuries such as stroke, trauma, cardiac arrest, and brain infections. Yet, major gaps remain in the scientific underpinnings of coma and this has led to inaccuracy in prognostication and limited interventions for coma recovery. Even so, recent studies have begun to elucidate mechanisms of consciousness early and prolonged after acute brain injury and some pilot interventions have begun to be tested. The importance and scope of this led in 2019 to the development of the Curing Coma Campaign, an initiative of the Neurocritical Care Society designed to provide a platform for scientific collaboration across the patient care continuum and to empower a community for purposes of research, education, implementation science, and advocacy. Seen as a "grand challenge," the Curing Coma Campaign has developed an infrastructure of scientific working groups and operational modules, along with a 10-year roadmap., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: We investigated the effect of hematoma volume reduction with minimally invasive surgery (MIS) on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with large spontaneous intracerebral hemorrhage (ICH). Methods: Post-hoc analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE III) study, a clinical trial with blinded outcome assessments. The primary outcome was the proportion of ICP readings ≥20 and 30 mmHg, and CPP readings <70 and 60 mm Hg. Secondary outcomes included major disability (modified Rankin scale >3) and mortality at 30 and 365 days. We assessed the relationship between proportion of high ICP and low CPP events and MIS using binomial generalized linear models, and outcomes using multiple logistic regression. Results: Of 499 patients enrolled in MISTIE III, 72 patients had guideline based ICP monitors placed, 34 in the MIS group and 38 in control (no surgery) group. Threshold ICP and CPP events ≥20/ <70 mmHg occurred in 31 (43.1%) and 52 (72.2%) patients respectively. On adjusted analyses, proportion of ICP readings ≥20 and 30 mmHg were significantly lower in the MIS group vs. control group [Odds Ratio (OR) 0.27, 95% Confidence Interval [CI] 0.11-0.63 ( p = 0.002); OR = 0.18, 0.04-0.75, p = 0.02], respectively. Proportion of CPP readings <70 and 60 mm Hg were also significantly lower in MIS patients [OR 0.31, 95% CI 0.15-0.63 ( p = 0.001); OR 0.30, 95% CI 0.11-0.83 ( p = 0.02)], respectively. Higher proportions of CPP readings <70 and 60 mm were significantly associated with short term mortality ( p = 0.04), and ( p = 0.006), respectively. Long term mortality was significantly associated with higher proportion of time with ICP ≥ 20 ( p = 0.04), ICP ≥ 30 ( p = 0.04), and CPP <70 mmHg ( p = 0.01). Conclusion: Our results are consistent with the hypothesis that surgical reduction of ICH volume decreases proportion of high ICP and low CPP events and that these variables are associated with short- and long-term mortality., Competing Interests: IA and DH were awarded significant research support for Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE) III by NIH/NINDS grant U01NS080824. WZ is supported by grants R01NS102583, R01AG06993, U01NS106513 and U01NS080824. AH reports investigator-initiated funding from Regeneron, Amgen, and AMAG pharmaceuticals. IA reports grants from NIH outside the submitted work. DH reports grants from NIH including BEACH (NIA): R01AG06993, TIC (NCATS): U24TR001609, and personal fees from BrainScope, Neurotrope, Op2Lysis, and Portola Pharmaceuticals, outside the submitted work. WZ is an associate editor for Neurocritical Care and an assistant editor for Stroke and has received data monitoring committee fees from C.R. Bard, Inc. outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Al-Kawaz, Li, Thompson, Avadhani, de Havenon, Gruber, Awad, Hanley and Ziai.)

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.

Background: The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure., Objective: To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials., Methods: Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n = 84) were compared to STICH II all lobar cases (n = 259) for volumetric analyses. All MISTIE III surgical patients (n = 240) were compared to both STICH I and II (n = 722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment., Results: End-of-treatment ICH volume ≤28.8 mL in MISTIE III and ≤30.0 mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180 d (P = .01 and P = .003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180 d with STICH I and II (P = .0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure., Conclusion: Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window., (© Congress of Neurological Surgeons 2021.)

Background: Mechanisms of chemotherapy-associated neurotoxicity are poorly understood, and therefore, prevention strategies have not been developed. We hypothesized that a subgroup of children receiving intrathecal cytarabine develops subclinical vasospasm, which may contribute to long-term neurocognitive sequelae of cancer., Methods: We used transcranial Doppler ultrasound to serially evaluate cerebral blood flow velocities in participants ≤25 years old receiving intrathecal cytarabine for hematologic malignancies., Results: Four of 18 participants (22%) met the criteria for subclinical vasospasm within 4 days of intrathecal cytarabine administration. The distribution of oncologic diagnoses differed between the vasospasm and non-vasospasm groups (p = 0.02). Acute myeloid leukemia was identified as a potential risk factor for vasospasm. Children with vasospasm were more likely to have received intravenous cytarabine (75% versus 0%, p = 0.01) and less likely to have received steroids (25% versus 100%, p = 0.01)., Conclusions: A subpopulation of children with hematologic malignancies develops subclinical vasospasm after intrathecal cytarabine treatment. Future research is needed to determine the long-term clinical consequences of cerebral vasospasm in this population., Impact: A subset of children with hematologic malignancies who receive intrathecal cytarabine experience subclinical cerebral vasospasm, as measured by transcranial Doppler ultrasound. Of children receiving intrathecal cytarabine, those who develop cerebral vasospasm are more likely to have diagnosis of acute myeloid leukemia, more likely to receive concurrent intravenous cytarabine, and less likely to receive steroids as part of their chemotherapy regimen, as compared with children without vasospasm. Future research is needed to determine if vasospasm during chemotherapy is associated with higher rates of neurocognitive dysfunction, and if so, to focus on prevention of these long-term sequelae of childhood cancer.

Objective: To determine the prevalence and associated mortality of well-defined neurologic diagnoses among patients with coronavirus disease 2019 (COVID-19), we prospectively followed hospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients and recorded new neurologic disorders and hospital outcomes., Methods: We conducted a prospective, multicenter, observational study of consecutive hospitalized adults in the New York City metropolitan area with laboratory-confirmed SARS-CoV-2 infection. The prevalence of new neurologic disorders (as diagnosed by a neurologist) was recorded and in-hospital mortality and discharge disposition were compared between patients with COVID-19 with and without neurologic disorders., Results: Of 4,491 patients with COVID-19 hospitalized during the study timeframe, 606 (13.5%) developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset. The most common diagnoses were toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). No patient had meningitis/encephalitis or myelopathy/myelitis referable to SARS-CoV-2 infection and 18/18 CSF specimens were reverse transcriptase PCR negative for SARS-CoV-2. Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment (SOFA) scores (all p < 0.05). After adjusting for age, sex, SOFA scores, intubation, history, medical complications, medications, and comfort care status, patients with COVID-19 with neurologic disorders had increased risk of in-hospital mortality (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.17-1.62, p < 0.001) and decreased likelihood of discharge home (HR 0.72, 95% CI 0.63-0.85, p < 0.001)., Conclusions: Neurologic disorders were detected in 13.5% of patients with COVID-19 and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness., (© 2020 American Academy of Neurology.)

Objectives: Stroke is commonly reported in patients receiving venovenous extracorporeal membrane oxygenation, but risk factors are not well described. We sought to determine preextracorporeal membrane oxygenation and on-extracorporeal membrane oxygenation risk factors for both ischemic and hemorrhagic strokes in patients with venovenous extracorporeal membrane oxygenation support., Design: Retrospective analysis., Setting: Data reported to the Extracorporeal Life Support Organization by 366 extracorporeal membrane oxygenation centers from 2013 to 2019., Patients: Patients older than 18 years supported with a single run of venovenous extracorporeal membrane oxygenation., Interventions: None., Measurements and Main Results: Of 15,872 venovenous extracorporeal membrane oxygenation patients, 812 (5.1%) had at least one type of acute brain injury, defined as ischemic stroke, hemorrhagic stroke, or brain death. Overall, 215 (1.4%) experienced ischemic stroke and 484 (3.1%) experienced hemorrhagic stroke. Overall inhospital mortality was 36%, but rates were higher in those with ischemic or hemorrhagic stroke (68% and 73%, respectively). In multivariable analysis, preextracorporeal membrane oxygenation pH (adjusted odds ratio = 0.10; 95% CI, 0.03-0.35; p < 0.001), hemolysis (adjusted odds ratio = 2.27; 95% CI, 1.22-4.24; p = 0.010), gastrointestinal hemorrhage (adjusted odds ratio = 2.01; 95% CI 1.12-3.59; p = 0.019), and disseminated intravascular coagulation (adjusted odds ratio = 3.61; 95% CI, 1.51-8.66; p = 0.004) were independently associated with ischemic stroke. Pre-extracorporeal membrane oxygenation pH (adjusted odds ratio = 0.28; 95% CI, 0.12-0.65; p = 0.003), preextracorporeal membrane oxygenation Po2 (adjusted odds ratio = 0.96; 95% CI, 0.93-0.99; p = 0.021), gastrointestinal hemorrhage (adjusted odds ratio = 1.70; 95% CI, 1.15-2.51; p = 0.008), and renal replacement therapy (adjusted odds ratio=1.57; 95% CI, 1.22-2.02; p < 0.001) were independently associated with hemorrhagic stroke., Conclusions: Among venovenous extracorporeal membrane oxygenation patients in the Extracorporeal Life Support Organization registry, approximately 5% had acute brain injury. Mortality rates increased two-fold when ischemic or hemorrhagic strokes occurred. Risk factors such as lower pH and hypoxemia during the pericannulation period and markers of coagulation disturbances were associated with acute brain injury. Further research on understanding preextracorporeal membrane oxygenation and on-extracorporeal membrane oxygenation risk factors and the timing of acute brain injury is necessary to develop appropriate prevention and management strategies., Competing Interests: Dr. Cho receives a grant from the Extracorporeal Life support Organization. Dr. Lorusso is a consultant for Medtronic and LivaNova and an advisory board member for EUROSETS. All honoraria are paid to Maastricht University for research funding. Dr. Geocadin is supported, in part, by the National Institute of Health (NIH) Grants UG3 HL145269 and R01 HL071568 and medico-legal consulting, and unrestricted fund from the Wenzel Family Foundation. He received support for article research from the NIH. Dr. Ziai is supported by the NIH and receives consulting fees from C. R. Bard and Portola outside of the area of work commented on here. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) procedure was recently tested in a large phase III randomized trial showing a significant probability of functional benefit in those cases that reached the goal hematoma evacuation of ≤15 mL residual (or ≥70% removal). Benefit of thrombolysis was also identified in cases with large intraventricular hemorrhage, and achieving at least 85% volume reduction in the Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial., Objective: To protocolize steps in the MISTIE and CLEAR procedures in order to maximize hematoma evacuation and minimize complications., Methods: We articulate data-driven lessons and expert opinions surrounding the factors of patient selection, catheter placement, and dosing, which impacted safety and surgical performance in the MISTIE and CLEAR trials., Results: Modifiable factors to maximize evacuation efficiency include optimizing catheter placement and pursuing aggressive dosing to achieve treatment goals, while strictly adhering to the safety steps as articulated in the respective trials. Prognostic factors that are viewed as nonmodifiable include greater initial intracerebral hemorrhage volume with irregular shape, smaller intraventricular bleeds, and the uncommon but consequential development of new bleeding during the dosing period despite strict protocol adherence., Conclusions: Surgeon education in this tutorial is aimed at maximizing the benefit of the MISTIE and CLEAR procedures by reviewing case selection, safety steps, treatment objectives, and technical nuances. Key lessons include stability imaging, etiology screening, and technical adherence to the protocol in order to achieve defined thresholds of evacuation., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Objectives: Although acute brain injury is common in patients receiving extracorporeal membrane oxygenation, little is known regarding the mechanism and predictors of ischemic and hemorrhagic stroke. We aimed to determine the risk factors and outcomes of each ischemic and hemorrhagic stroke in patients with venoarterial extracorporeal membrane oxygenation support., Design: Retrospective analysis., Setting: Data reported to the Extracorporeal Life Support Organization by 310 extracorporeal membrane oxygenation centers from 2013 to 2017., Patients: Patients more than 18 years old supported with a single run of venoarterial extracorporeal membrane oxygenation., Interventions: None., Measurements and Main Results: Of 10,342 venoarterial extracorporeal membrane oxygenation patients, 401 (3.9%) experienced ischemic stroke and 229 (2.2%) experienced hemorrhagic stroke. Reported acute brain injury during venoarterial extracorporeal membrane oxygenation decreased from 10% to 6% in 5 years. Overall in-hospital mortality was 56%, but rates were higher when ischemic stroke and hemorrhagic stroke were present (76% and 86%, respectively). In multivariable analysis, lower pre-extracorporeal membrane oxygenation pH (adjusted odds ratio, 0.21; 95% CI, 0.09-0.49; p < 0.001), higher PO2 on first day of extracorporeal membrane oxygenation (adjusted odds ratio, 1.01; 95% CI, 1.00-1.02; p = 0.009), higher rates of extracorporeal membrane oxygenation circuit mechanical failure (adjusted odds ratio, 1.33; 95% CI, 1.02-1.74; p = 0.03), and renal replacement therapy (adjusted odds ratio, 1.49; 95% CI, 1.14-1.94; p = 0.004) were independently associated with ischemic stroke. Female sex (adjusted odds ratio, 1.61; 95% CI, 1.16-2.22; p = 0.004), extracorporeal membrane oxygenation duration (adjusted odds ratio, 1.01; 95% CI, 1.00-1.03; p = 0.02), renal replacement therapy (adjusted odds ratio, 1.81; 95% CI, 1.30-2.52; p < 0.001), and hemolysis (adjusted odds ratio, 1.87; 95% CI, 1.11-3.16; p = 0.02) were independently associated with hemorrhagic stroke., Conclusions: Despite a decrease in the prevalence of acute brain injury in recent years, mortality rates remain high when ischemic and hemorrhagic strokes are present. Future research is necessary on understanding the timing of associated risk factors to promote prevention and management strategy.

Background: Early systolic blood pressure (SBP) reduction is believed to improve outcome after spontaneous intracerebral hemorrhage (ICH), but there has been a limited assessment of SBP trajectories in individual patients. We aimed to determine the prognostic significance of SBP trajectories in ICH., Methods: We collected routine data on spontaneous ICH patients from two healthcare systems over 10 years. Unsupervised functional principal components analysis (FPCA) was used to characterize SBP trajectories over first 24 h and their relationship to the primary outcome of unfavorable shift on modified Rankin scale (mRS) at hospital discharge, categorized as an ordinal trichotomous variable (mRS 0-2, 3-4, and 5-6 defined as good, poor, and severe, respectively). Ordinal logistic regression models adjusted for baseline SBP and ICH volume were used to determine the prognostic significance of SBP trajectories., Results: The 757 patients included in the study were 65 ± 23 years old, 56% were men, with a median (IQR) Glasgow come scale of 14 (8). FPCA revealed that mean SBP over 24 h and SBP reduction within the first 6 h accounted for 76.8% of the variation in SBP trajectories. An increase in SBP reduction (per 10 mmHg) was significantly associated with unfavorable outcomes defined as mRS > 2 (adjusted-OR = 1.134; 95% CI 1.044-1.233, P = 0.003). Compared with SBP reduction < 20 mmHg, worse outcomes were observed for SBP reduction = 40-60 mmHg (adjusted-OR = 1.940, 95% CI 1.129-3.353, P = 0.017) and > 60 mmHg, (adjusted-OR = 1.965, 95% CI 1.011, 3.846, P = 0.047). Furthermore, the association of SBP reduction and outcome varied according to initial hematoma volume. Smaller SBP reduction was associated with good outcome (mRS 0-2) in small (< 7.42 mL) and medium-size (≥ 7.42 and < 30.47 mL) hematomas. Furthermore, while the likelihood of good outcome was low in those with large hematomas (≥ 30.47 mL), smaller SBP reduction was associated with decreasing probability of severe outcome (mRS 5-6)., Conclusion: Our analyses suggest that in the first 6 h SBP reduction is significantly associated with the in-hospital outcome that varies with initial hematoma volume, and early SBP reduction > 40 mmHg may be harmful in ICH patients. For early SBP reduction to have an effective therapeutic effect, both target levels and optimum SBP reduction goals vis-à-vis hematoma volume should be considered.

Background: Intraventricular hemorrhage occurs due to intracerebral hemorrhage with intraventricular extension or without apparent parenchymal involvement, known as primary intraventricular hemorrhage., Aims: We evaluated the prognosis of primary intraventricular hemorrhage patients in the CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage)., Methods: In patients with primary intraventricular hemorrhage versus those with secondary intraventricular hemorrhage, we compared intraventricular alteplase response and outcomes including modified Rankin Scale, Barthel Index, National Institutes of Health Stroke Scale (NIHSS), and extended Glasgow Outcome Scale (eGOS) at 30, 180, and 365 days. Outcomes were also compared in primary intraventricular hemorrhage patients who received intraventricular alteplase versus placebo (normal saline) and in matched primary and secondary intraventricular hemorrhage patients using inverse-probability-weighted regression adjustment., Results: Of 500 patients enrolled in CLEAR III, 46 (9.2%) had primary intraventricular hemorrhage. Combining both treatment groups, primary intraventricular hemorrhage patients had larger intraventricular hemorrhage volumes (median: 34.2 mL vs. 20.8 mL, p  < 0.01) but similar intraventricular hemorrhage removal (51.0% vs. 59.0%, p  = 0.24) compared to secondary intraventricular hemorrhage patients, respectively. Confirming previous studies, primary intraventricular hemorrhage patients achieved better NIHSS, modified Rankin Scale, Barthel Index, and eGOS scores at days 30, 180, and 365, respectively (all p  < 0.01), although mortality was similar to secondary intraventricular hemorrhage patients; matching analysis yielded similar results. Primary intraventricular hemorrhage patients who received intraventricular alteplase ( n  = 19) and saline ( n  = 27) achieved similar outcomes., Conclusions: In CLEAR III, primary intraventricular hemorrhage patients who survived achieved better long-term outcomes than surviving secondary intraventricular hemorrhage patients with similar mortality. Outcomes and safety were similar between primary intraventricular hemorrhage patients receiving alteplase and those receiving saline.

Spontaneous intracerebral hemorrhage (ICH) results in high rates of morbidity and mortality, with intraventricular hemorrhage (IVH) being associated with even worse outcomes. Therapeutic interventions in acute ICH have continued to emerge with focus on arresting hemorrhage expansion, clot volume reduction of both intraventricular and parenchymal hematomas, and targeting perihematomal edema and inflammation. Large randomized controlled trials addressing the effectiveness of rapid blood pressure lowering, hemostatic therapy with platelet transfusion, and other clotting complexes and hematoma volume reduction using minimally invasive techniques have impacted clinical guidelines. We review the recent evolution in the management of acute spontaneous ICH, discussing which interventions have been shown to be safe and which may potentially improve outcomes.

Background: As the COVID-19 pandemic developed, reports of neurological dysfunctions spanning the central and peripheral nervous systems have emerged. The spectrum of acute neurological dysfunctions may implicate direct viral invasion, para-infectious complications, neurological manifestations of systemic diseases, or co-incident neurological dysfunction in the context of high SARS-CoV-2 prevalence. A rapid and pragmatic approach to understanding the prevalence, phenotypes, pathophysiology and prognostic implications of COVID-19 neurological syndromes is urgently needed., Methods: The Global Consortium to Study Neurological dysfunction in COVID-19 (GCS-NeuroCOVID), endorsed by the Neurocritical Care Society (NCS), was rapidly established to address this need in a tiered approach. Tier-1 consists of focused, pragmatic, low-cost, observational common data element (CDE) collection, which can be launched immediately at many sites in the first phase of this pandemic and is designed for expedited ethical board review with waiver-of-consent. Tier 2 consists of prospective functional and cognitive outcomes assessments with more detailed clinical, laboratory and radiographic data collection that would require informed consent. Tier 3 overlays Tiers 1 and 2 with experimental molecular, electrophysiology, pathology and imaging studies with longitudinal outcomes assessment and would require centers with specific resources. A multicenter pediatrics core has developed and launched a parallel study focusing on patients ages <18 years. Study sites are eligible for participation if they provide clinical care to COVID-19 patients and are able to conduct patient-oriented research under approval of an internal or global ethics committee. Hospitalized pediatric and adult patients with SARS-CoV-2 and with acute neurological signs or symptoms are eligible to participate. The primary study outcome is the overall prevalence of neurological complications among hospitalized COVID-19 patients, which will be calculated by pooled estimates of each neurological finding divided by the average census of COVID-19 positive patients over the study period. Secondary outcomes include: in-hospital, 30 and 90-day morality, discharge modified Rankin score, ventilator-free survival, ventilator days, discharge disposition, and hospital length of stay., Results: In a one-month period (3/27/20-4/27/20) the GCS-NeuroCOVID consortium was able to recruit 71 adult study sites, representing 17 countries and 5 continents and 34 pediatrics study sites., Conclusions: This is one of the first large-scale global research collaboratives urgently assembled to evaluate acute neurological events in the context of a pandemic. The innovative and pragmatic tiered study approach has allowed for rapid recruitment and activation of numerous sites across the world-an approach essential to capture real-time critical neurological data to inform treatment strategies in this pandemic crisis.

Objectives: Lateral displacement and impaired cerebral autoregulation are associated with worse outcomes following acute brain injury, but their effect on long-term clinical outcomes remains unclear. We assessed the relationship between lateral displacement, disturbances to cerebral autoregulation, and clinical outcomes in acutely comatose patients., Design: Retrospective analysis of prospectively collected data., Setting: Neurocritical care unit of the Johns Hopkins Hospital., Patients: Acutely comatose patients (Glasgow Coma Score ≤ 8)., Interventions: None., Measurements and Main Results: Cerebral oximetry index, derived from near-infrared spectroscopy multimodal monitoring, was used to evaluate cerebral autoregulation. Associations between lateral brain displacement, global cerebral autoregulation, and interhemispheric cerebral autoregulation asymmetry were assessed using mixed random effects models with random intercept. Patients were grouped by functional outcome, determined by the modified Rankin Scale. Associations between outcome group, lateral displacement, and cerebral oximetry index were assessed using multivariate linear regression. Increasing lateral brain displacement was associated with worsening global cerebral autoregulation (p = 0.01 septum; p = 0.05 pineal) and cerebral autoregulation asymmetry (both p < 0.001). Maximum lateral displacement during the first 3 days of coma was significantly different between functional outcome groups at hospital discharge (p = 0.019 pineal; p = 0.008 septum), 3 months (p = 0.026; p = 0.007), 6 months (p = 0.018; p = 0.010), and 12 months (p = 0.022; p = 0.012). Global cerebral oximetry index was associated with functional outcomes at 3 months (p = 0.019) and 6 months (p = 0.013)., Conclusions: During the first 3 days of acute coma, increasing lateral brain displacement is associated with worsening global cerebral autoregulation and cerebral autoregulation asymmetry, and poor long-term clinical outcomes in acutely comatose patients. The impact of acute interventions on outcome needs to be explored.

Optimal neurologic monitoring methods have not been characterized for patients on extracorporeal membrane oxygenation (ECMO). We assessed the feasibility of noninvasive multimodal neuromonitoring (NMN) to prognosticate outcome. In this prospective observational study, neurologic examinations, transcranial Doppler (TCD), electroencephalography (EEG), and somatosensory evoked potentials (SSEPs) were performed at prespecified intervals. Outcome at discharge was defined as favorable when modified Rankin Scale (mRS) 0-3; unfavorable when mRS >3. Of 20 patients (median age 60 years), 17 had TCDs, 13 had EEGs, and seven had SSEPs. With NMN, 17 (85%) were found to have neurologic complications. Fourteen (70%) had unfavorable outcomes. The unfavorable outcome was associated with absent EEG reactivity, coma, central cannulation, higher transfusion requirement, and higher Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores. Seven patients had both SSEPs and EEGs and exhibited intact N20 responses despite poor outcomes. Four of these seven showed absent EEG reactivity despite intact N20. Eighteen thromboembolic events were observed, 14 of which had positive microembolic signals (MESs) in TCD. All 10 patients with arterial-sided thrombotic events had positive MES. NMN caused no adverse effects. NMN during ECMO is feasible and found high neurologic complication rate. EEG and TCD showed potential for prognostication of neurologic outcome.

Background: Rapid diagnosis and proper management of intracerebral hemorrhage (ICH) play a crucial role in the outcome. Prediction of the outcome with a high degree of accuracy based on admission data including imaging information can potentially influence clinical decision-making practice., Methods: We conducted a retrospective multicenter study of consecutive ICH patients admitted between 2012-2017. Medical history, admission data, and initial head computed tomography (CT) scan were collected. CT scans were semiautomatically segmented for hematoma volume, hematoma density histograms, and sphericity index (SI). Discharge unfavorable outcomes were defined as death or severe disability (modified Rankin Scores 4-6). We compared (1) hematoma volume alone; (2) multiparameter imaging data including hematoma volume, location, density heterogeneity, SI, and midline shift; and (3) multiparameter imaging data with clinical information available on admission for ICH outcome prediction. Multivariate analysis and predictive modeling were used to determine the significance of hematoma characteristics on the outcome., Results: We included 430 subjects in this analysis. Models using automated hematoma segmentation showed incremental predictive accuracies for in-hospital mortality using hematoma volume only: area under the curve (AUC): 0.85 [0.76-0.93], multiparameter imaging data (hematoma volume, location, CT density, SI, and midline shift): AUC: 0.91 [0.86-0.97], and multiparameter imaging data plus clinical information on admission (Glasgow Coma Scale (GCS) score and age): AUC: 0.94 [0.89-0.99]. Similarly, severe disability predictive accuracy varied from AUC: 0.84 [0.76-0.93] for volume-only model to AUC: 0.88 [0.80-0.95] for imaging data models and AUC: 0.92 [0.86-0.98] for imaging plus clinical predictors., Conclusions: Multiparameter models combining imaging and admission clinical data show high accuracy for predicting discharge unfavorable outcome after ICH.

Background: The process of informed consent in National Institutes of Health randomized, placebo-controlled trials is poorly studied. There are several issues regarding informed consent in emergency neurologic trials, including a shared decision-making process with the patient or a legally authorized representative about overall risks, benefits, and alternative treatments., Methods: To evaluate the informed consent process, we collected best and worst informed consent practice information from a National Institutes of Health trial and used this in medical simulation videos to educate investigators at multiple sites to improve the consent process. Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) (clinicaltrials.gov, NCT00784134) studied the effect of intraventricular alteplase (n = 251) versus saline (placebo) injections (n = 249) for intraventricular hemorrhage reduction. Reasons for ineligibility (including refusing to consent) for all screen failures were analyzed. The broadcasted presentation outlined best practices for doctor-patient interactions during the consenting process, as well as anecdotal, study-specific reasons for consent refusal. Best and worst consent elements were then incorporated into a simulation video to enhance the informed consent process. This video was disseminated to trial sites as a webinar around the midpoint of the trial to improve the consent process. Pre- and post-intervention consent refusals were compared., Results: During the trial, 10,538 patients were screened for eligibility, of which only three were excluded due to trial timing. Pre-intervention, 77 of 5686 (1.40%) screen eligible patients or their proxies refused consent. Post-intervention, 55 of 4849 (1.10%) refused consent, which was not significantly different from pre-intervention (P = 0.312). The incidence of screen failures was significantly lower post-intervention (P = 0.006), possibly due to several factors for patient exclusion., Conclusion: The informed consent process for prospective randomized trials may be enhanced by studying and refining best practices based on trial-specific plans and patient concerns particular to a study.

Therapeutic hypothermia (TH) remains one of the few proven neuroprotective modalities available in clinical practice today. Although targeting lower temperatures during TH seems to benefit ischemic brain cells, systemic side effects associated with global hypothermia limit its clinical applicability. Therefore, the ability to selectively reduce the temperature of the brain while minimally impacting core temperature allows for maximizing neurological benefit over systemic complications. In that scenario, selective brain cooling (SBC) has emerged as a promising modality of TH. In this report, we reviewed the general concepts of TH, from systemic to selective brain hypothermia, and explored the different cooling strategies and respective evidence, including preclinical and clinical data. SBC has been investigated in different animal models with promising results, wherein organ-specific, rapid, and deep target brain temperature managements stand out as major advantages over systemic TH. Nevertheless, procedure-related complications and adverse events still remain a concern, limiting clinical translation. Different invasive and noninvasive methods for SBC have been clinically investigated with variable results, and although adverse effects were still reported in some studies, therapies rendered overall safe profiles. Further study is needed to define the optimal technique, timing of initiation, rate and length of cooling as well as target temperature and rewarming protocols for different indications., Competing Interests: Harikrishna Tandri is the founder of CoolTech Inc., which is developing a transnasal device for hypothermia., (Copyright: © 2019 Brain Circulation.)

Objectives: This study investigated whether comatose patients with greater duration and magnitude of clinically observed mean arterial pressure outside optimal mean arterial blood pressure have worse outcomes than those with mean arterial blood pressure closer to optimal mean arterial blood pressure calculated by bedside multimodal cerebral autoregulation monitoring using near-infrared spectroscopy., Design: Prospective observational study., Setting: Neurocritical Care Unit of the Johns Hopkins Hospital., Subjects: Acutely comatose patients secondary to brain injury., Interventions: None., Measurements and Main Results: The cerebral oximetry index was continuously monitored with near-infrared spectroscopy for up to 3 days. Optimal mean arterial blood pressure was defined as that mean arterial blood pressure at the lowest cerebral oximetry index (nadir index) for each 24-hour period of monitoring. Kaplan-Meier analysis and proportional hazard regression models were used to determine if survival at 3 months was associated with a shorter duration of mean arterial blood pressure outside optimal mean arterial blood pressure and the absolute difference between clinically observed mean arterial blood pressure and optimal mean arterial blood pressure. A total 91 comatose patients were enrolled in the study. The most common etiology was intracerebral hemorrhage. Optimal mean arterial blood pressure could be calculated in 89 patients (97%), and the median optimal mean arterial blood pressure was 89.7 mm Hg (84.6-100 mm Hg). In multivariate proportional hazard analysis, duration outside optimal mean arterial blood pressure of greater than 80% of monitoring time (adjusted hazard ratio, 2.13; 95% CI, 1.04-4.41; p = 0.04) and absolute difference between clinically observed mean arterial blood pressure and optimal mean arterial blood pressure of more than 10 mm Hg (adjusted hazard ratio, 2.44; 95% CI, 1.21-4.92; p = 0.013) were independently associated with mortality at 3 months, after adjusting for brain herniation, admission Glasgow Coma Scale, duration on vasopressors and midline shift at septum., Conclusions: Comatose neurocritically ill adults with an absolute difference between clinically observed mean arterial blood pressure and optimal mean arterial blood pressure greater than 10 mm Hg and duration outside optimal mean arterial blood pressure greater than 80% had increased mortality at 3 months. Noninvasive near-infrared spectroscopy-based bedside calculation of optimal mean arterial blood pressure is feasible and might be a promising tool for cerebral autoregulation oriented-therapy in neurocritical care patients.

Background and Purpose- There is increasing evidence that higher systolic blood pressure variability (SBPV) may be associated with poor outcome in patients with intracerebral hemorrhage (ICH). We explored the association between SBPV and in-hospital ICH outcome. Methods- We collected 10-years of consecutive data of spontaneous ICH patients at 2 healthcare systems. Demographics, medical history, laboratory tests, computed tomography scan data, in-hospital treatments, and neurological and functional assessments were recorded. Blood pressure recordings were extracted up to 24 hours postadmission. SBPV was measured using SD, coefficient of variation, successive variation (SV), range and 1 novel index termed functional SV. The effects of SBPV on the functional outcome at discharge were evaluated by multivariate logistic and ordinal regression analyses for dichotomous and trichotomous modified Rankin Scale categorizations, respectively. In secondary analyses, associations between SBPV, history of hypertension, and hematoma expansion were explored. Results- The analysis included 762 subjects. All 5 SBPV indices were significantly associated with the probability of unfavorable outcome (modified Rankin Scale score, 4-6) in logistic models. In ordinal models, SD, coefficient of variation, range, and functional SV were found to have a significant effect on the probabilities of poor (modified Rankin Scale score, 3-4) and severe/death (modified Rankin Scale score, 5-6) outcomes. Normotensive patients had significantly lower mean SBPV compared with the untreated-hypertension cohort for all SBPV indices and compared with treated-hypertension patients for 3 out of 5 SBPV indices. Lower mean SBPV of treated-hypertension subjects compared with untreated-hypertension subjects was only detected in the SV and functional SV indices (P=0.045). None of the SBPV indices were significantly associated with the probability of hematoma expansion. Conclusions- Higher SBPV in the first 24 hours of admission was associated with unfavorable in-hospital outcome among ICH patients. Further prospective studies are warranted to understand any cause-effect relationship and whether controlling for SBPV may improve the ICH outcome.

Background: The Glasgow Coma Scale (GCS) is an essential coma scale in critical care for determining the neurological status of patients and for estimating their long-term prognosis. Similarly, cerebral autoregulation (CA) monitoring has shown to be an accurate technique for predicting clinical outcomes. However, little is known about the relationship between CA measurements and GCS scores among neurological critically ill patients. This study aimed to explore the association between noninvasive CA multimodal monitoring measurements and GCS scores., Methods: Acutely comatose patients with a variety of neurological injuries admitted to a neurocritical care unit were monitored using near-infrared spectroscopy-based multimodal monitoring for up to 72 hours. Regional cerebral oxygen saturation (rScO2), cerebral oximetry index (COx), GCS, and GCS motor data were measured hourly. COx was calculated as a Pearson correlation coefficient between low-frequency changes in rScO2 and mean arterial pressure. Mixed random effects models with random intercept was used to determine the relationship between hourly near-infrared spectroscopy-based measurements and GCS or GCS motor scores., Results: A total of 871 observations (h) were analyzed from 57 patients with a variety of neurological conditions. Mean age was 58.7±14.2 years and the male to female ratio was 1:1.3. After adjusting for hemoglobin and partial pressure of carbon dioxide in arterial blood, COx was inversely associated with GCS (β=-1.12, 95% confidence interval [CI], -1.94 to -0.31, P=0.007) and GCS motor score (β=-1.06, 95% CI, -2.10 to -0.04, P=0.04). In contrast rScO2 was not associated with GCS (β=-0.002, 95% CI, -0.01 to 0.01, P=0.76) or GCS motor score (β=-0.001, 95% CI, -0.01 to 0.01, P=0.84)., Conclusions: This study showed that fluctuations in GCS scores are inversely associated with fluctuations in COx; as COx increases (impaired autoregulation), more severe neurological impairment is observed. However, the difference in COx between high and low GCS is small and warrants further studies investigating this association. CA multimodal monitoring with COx may have the potential to be used as a surrogate of neurological status when the neurological examination is not reliable (ie, sedation and paralytic drug administration).

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., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Background: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage., Methods: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046., Findings: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012)., Interpretation: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons., Funding: National Institute of Neurological Disorders and Stroke and Genentech., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: As intraventricular thrombolysis for intraventricular hemorrhage (IVH) has developed over the last 2 decades, hemorrhagic complications have remained a concern despite general validation of its safety in controlled trials in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-IVH) program., Objective: To analyze factors associated with symptomatic bleeding following IVH with and without thrombolysis in conjunction with the recently completed CLEAR III trial., Methods: We reviewed safety reports on symptomatic bleeding events reported during the first year after randomization among subjects enrolled in the CLEAR III trial. Clinical and imaging data were retrieved through the trial database as part of ongoing quality and safety monitoring. A posthoc root-cause analysis was performed to identify potential factors predisposing to rebleeding in each case. Cases were classified according to onset of rebleeding (during dosing, early after dosing and delayed), the pattern of bleeding, and treatment rendered (alteplase vs saline)., Results: Twenty subjects developed a secondary symptomatic intracranial hemorrhage constituting 4% of subjects. Symptomatic rebleeding events occurred during the dosing protocol (n = 9, 67% alteplase), early after the protocol (n = 5, 40% alteplase), and late (n = 6, 0% alteplase). Catheter-related hemorrhages were the most common (n = 7, 35%) followed by expansion or new intraventricular (n = 6, 30%) and intracerebral (n = 5, 25%) hemorrhages. Symptomatic hemorrhages during therapy resulted from a combination of treatment- and patient-related factors and were at most partially attributable to alteplase. Rebleeding after the dosing protocol primarily reflected patients' risk factors., Conclusion: Intraventricular thrombolysis marginally increases the overall risk of symptomatic hemorrhagic complications after IVH, and only during the treatment phase.

Acute spontaneous intracerebral haemorrhage is a life-threatening illness of global importance, with a poor prognosis and few proven treatments. As a heterogeneous disease, certain clinical and imaging features help identify the cause, prognosis, and how to manage the disease. Survival and recovery from intracerebral haemorrhage are related to the site, mass effect, and intracranial pressure from the underlying haematoma, and by subsequent cerebral oedema from perihaematomal neurotoxicity or inflammation and complications from prolonged neurological dysfunction. A moderate level of evidence supports there being beneficial effects of active management goals with avoidance of early palliative care orders, well-coordinated specialist stroke unit care, targeted neurointensive and surgical interventions, early control of elevated blood pressure, and rapid reversal of abnormal coagulation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)