Neurocritical Care

Enterally-administered nimodipine is the only approved drug formulation available in the United States for treatment of patients with aneurysmal subarachnoid hemorrhage. Intravenous nimodipine is available in other countries but it contains a high concentration of ethanol that is irritating to the vasculature, can alter the effects of other medications, impair neurological assessments and is potentially harmful to the liver. We developed a sterile aqueous solution of nimodipine solubilized in polysorbate 80 micelles (GTX-104) that circumvents these problems. GTX-104 has been administered to 168 healthy human volunteers in 2 studies. We report the second study here, a phase 1, single center, randomized, 2-period cross over study that assessed the pharmacokinetics of GTX-104 and oral nimodipine capsules, which is the reference standard, in 58 healthy human volunteers. GTX-104 was administered for 72 hours as a continuous infusion of 0.15 mg/hour with a 30 minute bolus infusion of 4 mg every 4 hours. Nimodipine capsules were administered orally at a dose of 60 mg every 4 hours for 72 hours. The maximum plasma concentrations after the first dose of each formulation were similar (GTX-104: 63 ng/mL, n=57 versus nimodipine capsules: 69 ng/mL, n=56, ratio and 90% confidence interval [CI] of geometric means: 92% [90% CI: 82-104%]). The areas under the concentration-time curves on the 3rd day at steady state also were the same (GTX-104: 497 ng*h/mL, n=55 versus nimodipine capsules: 495 ng*h/mL, n=56, ratio and 90% CI of geometric means: 106% [90% CI: 99-114%]). The secondary pharmacokinetic parameters (daily maximum concentration at steady-state and time to maximum concentration) were also similar for the 2 formulations. The variability in PK parameters was less for GTX-104 compared to oral nimodipine. The average oral bioavailability for nimodipine capsules was 7%. These results enabled a Phase 3 safety study of GTX-104 in humans with aneurysmal subarachnoid hemorrhage.

Oral nimodipine is the only drug approved in North America for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is variable and frequently poor, leading to fluctuations in peak plasma concentrations that cause dose-limiting hypotension. Furthermore, administration is problematic in patients who cannot swallow capsules. An oral liquid formulation exists but causes gastrointestinal complications. An intravenous nimodipine formulation (GTX-104) has been developed that has bioavailability approaching 100% and is not affected by feeding or gastointestinal absorption. GTX-104 causes less hypotension and has more consistent peak plasma concentrations than oral nimodipine in healthy human volunteers. Herein we describe the protocol of a prospective, randomized, open-label safety and tolerability study of GTX-104 compared to oral nimodipine in patients with aSAH (STRIVE-ON, NCT05995405). Inclusion and exclusion criteria match the prescribing information for oral nimodipine and include adult patients with aSAH of all Hunt and Hess grades who can receive investigational product within 96 hours of aSAH. Subjects at imminent risk of death are excluded. Subjects are randomized 1:1 to GTX-104 or oral nimodipine for up to 21 days. The primary endpoint is the proportion of subjects in each group with clinically significant hypotension, defined as hypotension requiring any medical treatment, with a reasonable likelihood of being due to investigational product as determined by an independent, blinded endpoint adjudication committee. No statistical analysis of the endpoint is planned. Secondary endpoints include all episodes of hypotension, all adverse events, delayed cerebral ischemia, rescue therapy and suicidal ideation. Clinical and health economic outcomes include quality of life using the EQ-5D-3L, modified Rankin scale at 30 and 90 days after aSAH and hospital resource use. The planned sample size is 100 subjects across 25 sites in the United States and Canada. DETAILS PAGEO_LIWe confirm that manuscript complies with all instructions to authors. C_LIO_LIWe confirm that authorship requirements have been met and the final manuscript is approved by all authors. C_LIO_LIWe confirm that this manuscript has not been published elsewhere and is not under consideration by another journal. It is planned to post it on C_LIO_LIWe confirm adherence to ethical guidelines and indicate ethical approvals and use of informed consent. C_LIO_LIAll conflicts of Interest for all authors are disclosed. C_LIO_LIWe confirm the use of the Standard Protocol Items: Recommended for Interventional Trials (SPIRIT) checklist. C_LIO_LIThe source of funding for the study is disclosed. It is Acasti Pharma. C_LI

The SAFE MRI ECMO (NCT05469139) study established the safety of ultra-low-field 64mT MRI in patients receiving extracorporeal membrane oxygenation (ECMO) in the setting of intensive care and demonstrated that these images were highly sensitive in detecting acquired brain injuries. This retrospective analysis of prospectively collected observational data sought to expand on these findings in light of the crucial need for neurological monitoring while patients receive ECMO by evaluating the feasibility of volumetric analyses derived from ultra-low-field MR images. T2-weighted scans from thirty patients who received ultra-low-field MRI while undergoing ECMO at Johns Hopkins Hospital were analyzed using a volumetric pipeline to determine whole brain volume and volumes of total grey matter, total white matter, subcortical grey matter, ventricles, left hemisphere, right hemisphere, telencephalon, left and right lateral ventricles, the total intracranial volume, and the cerebellum. Segmented brain volumes in patients undergoing ECMO were comparable to measurements obtained using conventional field and ultra-low-field MRI in the absence of ECMO instrumentation. The subgroup analysis demonstrated subtle volumetric differences between patients supported with venoarterial ECMO and those receiving venovenous ECMO. These data provide the first evidence that ultra-low-field MRI provides volumetric measurements comparable to conventional field-strength MRI, even in the presence of ECMO circuitry, supporting its feasibility for neuroimaging in critically ill patients.

BackgroundInflammation contributes to morbidity following subarachnoid hemorrhage (SAH). Transauricular vagus nerve stimulation (taVNS) offers a noninvasive approach to target the inflammatory response following SAH. MethodsIn this prospective, triple-blinded, randomized, controlled trial, twenty-seven patients were randomized to taVNS or sham stimulation. Blood and cerebrospinal fluid (CSF) were collected to quantify inflammatory markers. Cerebral vasospasm severity and functional outcomes (modified Rankin Scale, mRS) were analyzed. ResultsNo adverse events occurred. Radiographic vasospasm was significantly reduced (p = 0.018), with serial vessel caliber measurements demonstrating a more rapid return to normal than sham (p < 0.001). In the taVNS group, TNF- was significantly reduced in both plasma (days 7 and 10) and CSF (day 13); IL-6 was also significantly reduced in plasma (day 4) and CSF (day 13) (p < 0.05). Patients receiving taVNS had higher rates of favorable outcomes at discharge (38.4% vs 21.4%) and first follow-up (76.9% vs 57.1%), with significant improvement from admission to first follow-up (p = 0.014), unlike the sham group (p = 0.18). The taVNS group had a significantly lower rate of discharge to skilled nursing facility or hospice (p = 0.04). ConclusiontaVNS is a non-invasive method of neuro- and systemic immunomodulation. This trial supports that taVNS following SAH can mitigate the inflammatory response, reduce radiographic vasospasm, and potentially improve functional and neurological outcomes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04557618

BACKGROUNDEarly brain injury attributable to initial or recurrent bleeding is the leading cause of poor outcomes in patients with subarachnoid hemorrhage (SAH). This study investigated rebleeding immediately after SAH ictus, focusing on its timing and associated blood pressure (BP). METHODSConsecutive patients with spontaneous SAH treated from January 1999 to June 2022 were reviewed. Rebleeding was defined as a sudden decline in consciousness to a coma, sudden pupillary dilation with elevated BP, or increased SAH on head computed tomography (CT). The rebleeding timing was examined during each management phase. Demographic, radiological, and initial evaluation data were assessed for rebleeding and outcomes. RESULTSAmong 940 patients (64% women, mean age 63.6 {+/-} 13.2, 73% with a World Federation of Neurological Societies grade [&ge;]4), rebleeding occurred in 221 cases (23.5%); 139 episodes in 121 patients (13.7%) before and 134 episodes in 112 patients after hospitalization (11.9%), and 19 patients (2.0%) in both. Rebleeding occurred more frequently in patients with worse neurological state, higher CT grades, and earlier arrivals. Systolic BP (SBP) was higher in patients with rebleeding (178 mmHg, IQR 140-204 mmHg) than in those without rebleeding (148 mmHg, IQR 100-180 mmHg) (P<0.001). Higher SBP was associated with increased rebleeding (OR 9.843; P<0.0001) and lower mortality (OR 0.0281; P=0.0084) but not with favorable outcomes (OR 1.686; P=0.22). When comparing the groups divided into 20 mmHg increments, the incidence of rebleeding, unfavorable outcomes, and mortality increased in the groups with SBP [&ge;]181 mmHg, SBP [&le;]100 mmHg and >160 mmHg, and SBP [&le;]100 mmHg, respectively. CONCLUSIONSRebleeding occurred in 23.5% of patients with SAH in the hyperacute phase, primarily before hospital arrival. Higher SBP was associated with rebleeding, and SBP of 101-160 mmHg was associated with favorable outcomes.

BackgroundHyperglycemia after intracerebral hemorrhage (ICH) may be associated with worse outcomes. In this study, we evaluated the association of early post-ICH glucose trajectories and clinical outcomes. MethodsWe performed a secondary analysis of the ATACH-2 trial dataset. Hyperglycemia was defined as a blood glucose of [&ge;]140 mg/dl. Glucose levels at 0h, 24h, 48h, and 72h were analyzed using a linear mixed effects model, with fixed effects for time and random intercept/slopes. Patient-specific estimates were used to predict glucose values at 0h and 72h, informed by all four timepoints, to classify patients into the following glycemic trajectory groups: (1) early hyperglycemia, (2) late hyperglycemia, (3) persistent hyperglycemia, and (4) persistent normoglycemia. Outcomes were compared using univariate analysis and log-rank test survival analysis. Good outcomes were defined as a modified Rankin Score of 0 to 2. The association between glycemic trajectories and functional outcomes was tested using logistic regression models adjusted for patient demographics and clinical variables. ResultsOf 1000 patients (median age 62 [IQR 52-71]; 38% female) in the study, 81 (8.1%) had early hyperglycemia, 59 (5.9%) late hyperglycemia, 225 (22.5%) persistent hyperglycemia, and 635 (63.5%) persistent normoglycemia. On univariate analysis, 45.8% of patients with persistent normoglycemia had favorable 90-day functional outcomes compared to 30.9% in early, 30.5% in late, and 32.0% in persistent hyperglycemia patients (p<0.001). The late hyperglycemia patients had the highest rate of hematoma expansion (35.3%, p=0.029) and the lowest Kaplan Meier-estimated survival (86%, p=0.015). In adjusted multivariable regression models, early hyperglycemia was significantly associated with a poor functional outcome (OR 2.27, 95% CI 1.10-4.68, p=0.026). ConclusionEarly hyperglycemia was associated with worse functional outcomes, while late and persistent hyperglycemia were associated with worse survival rates. These findings suggest that glycemic trajectories may affect or predict prognosis. This highlights the importance of continuous glucose monitoring and glycemic control strategies after ICH.

BACKGROUNDBrain injury is the major reason for patient deaths in victims who survive after cardiac arrest. Clinical studies have shown that the presence of hypoxic hepatitis and pre-cardiac arrest liver disease is associated with increased mortality and inferior neurological recovery. However, how the liver might impact the pathogenesis of post-cardiac arrest is still unknown. METHODSAn in vivo global cerebral ischemia model was established to assess how simultaneous liver ischemia affected the recovery of brain ischemic injury. In addition, an ex vivo brain normothermic machine perfusion (NMP) model was established to evaluate how addition of a functioning liver might impact the circulation, cytoarchitecture, neuron viability and electrocortical activity of the reperfused brain post-cardiac arrest. RESULTSIn the in vivo model, we observed a larger infarct area in the frontal lobe, elevated tissue injury scores in the CA1 region, as well as increased intravascular immune cell adhesion in the reperfused brains with hepatic ischemia, compared to those without simultaneous hepatic ischemia. The results of the ex vivo model demonstrated that the addition of a functioning liver to the brain NMP circuit significantly reduced post-cardiac arrest brain injury, increased neuronal viability and improved electrocortical activity. Furthermore, we observed significant alterations in gene expressions and metabolites in the presence or absence of hepatic ischemia. CONCLUSIONSOur research highlights the crucial role of the liver in the pathogenesis of post-cardiac arrest brain injury. These findings shed lights on a cardio-pulmonary-hepatic brain resuscitation strategy for patients with cardiac arrest.

BackgroundSpontaneous intracerebral haemorrhage (ICH) has high rates of death and disability, and no proven haemostatic treatment. Tranexamic acid might limit haematoma expansion and improve outcomes. We conducted the first individual patient data meta-analysis to evaluate the effect of tranexamic acid on functional outcomes in spontaneous ICH. MethodsThis systematic review and individual patient data meta-analysis included randomised controlled trials comparing intravenous tranexamic acid to placebo in adults with spontaneous ICH treated within 12 hours of onset. MEDLINE, EMBASE, CENTRAL, Web of Science, and WHO ICTRP were searched to November 2024. The primary outcome was functional status at 90 days after randomisation, measured by the modified Rankin Scale. Adverse events (seizures, thromboembolic events) were also summarised. Analyses used generalised linear mixed models with random intercepts for trial. Risk of bias was assessed using the Cochrane RoB 2 tool. The study was registered with PROSPERO (CRD42022345775). ResultsWe identified 1,131 records; nine trials (3,194 participants) were eligible for inclusion and five trials (2860 participants; 90% of those available) provided individual patient data for the primary analysis. Risk of bias was low across all included trials. At 90 days, 757/1423 (53.2%) patients assigned to tranexamic acid had a worse functional outcome compared with 759/1415 (53.6%) assigned to placebo, the difference was not statistically significant (adjusted common odds ratio 0.93 (95% CI 0.81 to 1.07; p = 0.30). Serious adverse events were similar between the groups, with no significant differences observed. There was no evidence of between-trial heterogeneity based on model fit (likelihood ratio test). DiscussionCompleted clinical trials provide no evidence that tranexamic acid improves functional outcome after spontaneous ICH. However, given the reduction in hematoma expansion and early mortality it remains to be seen if this translates to improved functional outcome in larger ongoing clinical trials. Even a small beneficial effect could have potential for global impact given the burden of ICH. FundingNo funding source.

BackgroundIntracerebral hemorrhage (ICH) is a leading cause of disability and mortality, accounting for 20-30% of acute cerebrovascular events. Resting heart rate (RHR) is an important vital sign linked to prognosis, particularly in cardiovascular diseases. This study investigates the association between RHR and all-cause mortality (ACM) in intensive care unit (ICU) patients with ICH. MethodsData were extracted from the MIMIC-IV database. Patients were divided into quartiles (Q1-Q4) based on RHR. ACM at 30 days, 90 days, and one year was assessed. Kaplan-Meier curves, multivariate Cox regression, and restricted cubic splines were used to analyze the relationship between RHR and ACM, with receiver operating characteristic curves evaluating the predictive value of RHR >90.3 beats per minute (bpm). ResultsA total of 1,918 patients were included. Survival curves showed significantly higher mortality in higher RHR quartiles (Q3 and Q4) compared to Q1 and Q2. Multivariate Cox regression confirmed that RHR above the second quartile (RHR=78.5 bpm) was linked to higher mortality. Restricted cubic splines revealed a nonlinear relationship between elevated RHR and increased mortality. ConclusionsA resting heart rate below 90.3 bpm may serve as an independent protective factor against all-cause mortality in patients with intracerebral hemorrhage in the intensive care unit. In contrast, an elevated resting heart rate exceeding 90.3 bpm may be independently associated with an increased risk of all-cause mortality in this population.

ObjectiveIntraventricular hemorrhage (IVH) is a severe condition with poor outcome and high mortality. New treatments are warranted to facilitate clot removal and accelerate recovery of IVH patients. We examined the effect to intraventricular lavage on IVH resolution, clearance and kinectics. The study is a post-hoc study on a recently performed randomized study, where intraventricular lavage using controlled irrigation and aspiration was tested against passive drainage. The present study describe post hoc analysis of the Active Study to determine the effect of intraventricular lavage on IVH resolution clearance and kinetics. MethodpostPost-hoc analysis using data from the multi-center, randomized, controlled clinical safety/feasibility trial (Active Study, NCT05204849) including 21 patients with IVH. IVH clearance was assessed using volume segmentation of serial CT scans. Clot resolution kinetics were determined and correlated with irrigation rates. ResultsThe data set consisted of 77 sequential CT scans from 18 patients (3 of the 21 patients included in the Active study were excluded due to rebleeding or only one CT scan performed). Baseline characteristics were equal in the two groups. Clot resolution followed 0-order kinetics. The clot half-life was 3.9 days in the group treated with intraventricular lavage compared to 5.3 days in the control group treated with passive drainage (p = 0.6). We did not observe accelerated clot resolution in the ventricles containing the catheter tip (3.9 days vs 3.6 days, p = 0.9). In the intervention group, clot resolution was increased by 0.05% per ml increase in irrigation (slope 1.576 ml/cm3 (95%CI 0.55-2.6) p=0.03) ConclusionWe found that IVH clot resolution followed 0-order kinetics. No significant differences in clot half-life were observed between the two groups. However, the clot resolution rate was positively correlated with the irrigation rates.

BackgroundNeonatal global hypoxic-ischemic cerebral injury is a leading cause of infant mortality and lifelong disability. Current rodent models do not replicate neonatal global cerebral ischemia (nGCI) and reperfusion injury. Here, we developed and characterized a rodent model of cardiac arrest and cardiopulmonary reperfusion (CA/CPR) to induce nGCI, producing acute systemic ischemia, mild neuronal injury, white matter alterations, and motor and memory deficits. MethodsRat pups underwent CA/CPR or sham procedure on postnatal day 9-11. CA/CPR in rat pups was performed under anesthesia while intubated. Asystole was induced with intravenous (IV) KCl and maintained for 10-14 minutes. Resuscitation included oxygen ventilation, chest compressions, and IV epinephrine. ResultsTwelve minutes of asystole provided an optimal balance between survival and systemic injury. Behavioral testing on postoperative day (POD) 7 revealed memory impairments. Despite the absence of overt neuronal death in the hippocampus or cerebellum, we observed evidence of glial activation and white matter alterations. ConclusionThis novel rodent model of nGCI addresses limitations in existing models while offering clinically relevant features to support future mechanistic and translational research. ImpactO_LIThis study validates cardiac arrest and cardiopulmonary resuscitation (CA/CPR) as a novel model for neonatal global cerebral ischemia (nGCI), complementing existing rodent models of unilateral and permanent injury by enabling investigation of both global ischemia and reperfusion injury. C_LIO_LInGCI results in memory impairment in the absence of overt neuronal cell death. Functional deficits are associated with neuroinflammatory responses in the hippocampus, white matter, and cerebellum. C_LIO_LINeonatal CA/CPR induces global cerebral ischemia which uniquely allows investigation of hindbrain structures, such as cerebellum, which are typically spared in existing rodent models of neonatal hypoxia-ischemia. C_LI

ObjectiveDespite substantial variability in the severity of post-anoxic encephalopathy, all comatose patients after cardiac arrest are usually treated according to the same standardized intensive care protocol, including sedation, mechanical ventilation, and targeted temperature management (TTM). We hypothesize that patients with a favourable EEG pattern (continuous EEG within 12 hours after cardiac arrest) may not benefit from prolonged sedation and TTM. We studied the feasibility and safety of early cessation of sedation and TTM in this subgroup. MethodsWe conducted a non-randomized, controlled intervention study including 40 adult patients admitted to the ICU with postanoxic encephalopathy after cardiac arrest and an early (< 12 hours) favourable EEG pattern. The control group received standard care with sedation and TTM for at least 24-48 hours, whereas the intervention group underwent early cessation of sedation and TTM as soon as possible after establishing a favourable EEG, followed by weaning from mechanical ventilation. The primary outcome was duration of mechanical ventilation. Secondary outcomes included ICU length of stay, total sedation time, number of ICU complications, and neurological outcomes at 3 and 6 months. ResultsDuration of mechanical ventilation was significantly shorter in the intervention than in the control group (median 12 vs 28 h, p < 0.001). Median ICU length of stay and median total sedation time were also reduced by more than 50% in the intervention group, from respectively 2.5 to 1.2 days (p = 0.001) and 27 to 12 h (p < 0.001). There was no increase in ICU complications in the intervention group. No statistically significant differences in neurological outcomes at 3 or 6 months were observed. ConclusionEarly withdrawal of sedation is feasible and safe in patients with an early favourable EEG following cardiac arrest. The study was underpowered to detect possible differences in long-term neurological recovery. SignificanceShortening sedation and mechanical ventilation is likely to result in direct reductions in healthcare costs and contribute to more appropriate care. Larger studies are needed to evaluate the impact on long-term neurological outcomes.

Background and PurposeThe intracerebral hemorrhage (ICH) score was created as a tool improve communication and consistency among providers, and authors initially cautioned against its use as a predictor of outcomes. We aimed to investigate the association of ICH score with mortality and withdrawal of life-sustaining treatment (WLST). MethodsPatients with a diagnosis of ICH were identified using data from Florida Stroke Registry (FSR) hospitals participating in the American Heart Association (AHA) Get with the Guidelines-Stroke (GWTG-S) from 2013-2022. Outcomes of WLST and in-hospital mortality were collected. ICH score was stratified into three groups: ICH score 0-2; 3-4; 5-6. Importance plots were generated to identify the most predictive factors associated with WLST. AUC-ROC curves were generated for logistic regression (LR) and random forest (RF) models, adjusted for relevant confounders. Secondary outcome analyses were performed using stratified univariate logistic regression to assess changes between 2015-2018 and 2019-2022. ResultsA total of 12,426 (26%) patients had documented ICH scores (mean age 69, 55% male, 56% white). The most predictive factors associated with WLST were ICH score, age, state region, presenting level of consciousness, insurance status and race (RF AUC=.94, LR AUC=.82). Mortality was 6.6%, 41.5% and 66% for ICH score 0-2, 3-4 and 5-6. Decision to WLST occurred more for ICH scores 3-4 (OR 9.35, 95% CI: 8.5-10.3) and ICH scores 5-6 (15.43, 95% CI: 15.28-22.74). Early WLST (< 2 days) was more likely for ICH score 3-4 (OR 2.97, 95% CI: 2.48-3.55) and score 5-6 groups (OR 9.51, 95% CI: 7.33-12.35). ConclusionAmong ICH patients admitted across Florida, we noted a significant association between ICH score and likelihood of mortality, decision to WLST, and specifically WLST within two days of presentation. We identified the most predictive variable associated with WLST to be the ICH score. These findings suggest a continued influence of the self-fulfilling prophecy in ICH.

ObjectiveTo develop a harmonized multicenter clinical and electroencephalography (EEG) database for acute hypoxic-ischemic brain injury research involving patients with cardiac arrest. DesignMulticenter cohort, partly prospective and partly retrospective. SettingSeven academic or teaching hospitals from the U.S. and Europe. PatientsIndividuals aged 16 or older who were comatose after return of spontaneous circulation following a cardiac arrest who had continuous EEG monitoring were included. Interventionsnot applicable. Measurements and Main ResultsClinical and EEG data were harmonized and stored in a common Waveform Database (WFDB)-compatible format. Automated spike frequency, background continuity, and artifact detection on EEG were calculated with 10 second resolution and summarized hourly. Neurological outcome was determined at 3-6 months using the best Cerebral Performance Category (CPC) scale. This database includes clinical and 56,676 hours (3.9 TB) of continuous EEG data for 1,020 patients. Most patients died (N=603, 59%), 48 (5%) had severe neurological disability (CPC 3 or 4), and 369 (36%) had good functional recovery (CPC 1-2). There is significant variability in mean EEG recording duration depending on the neurological outcome (range 53-102h for CPC 1 and CPC 4, respectively). Epileptiform activity averaging 1 Hz or more in frequency for at least one hour was seen in 258 (25%) patients (19% for CPC 1-2 and 29% for CPC 3-5). Burst suppression was observed for at least one hour in 207 (56%) and 635 (97%) patients with CPC 1-2 and CPC 3-5, respectively. ConclusionsThe International Cardiac Arrest Research (I-CARE) consortium database provides a comprehensive real-world clinical and EEG dataset for neurophysiology research of comatose patients after cardiac arrest. This dataset covers the spectrum of abnormal EEG patterns after cardiac arrest, including epileptiform patterns and those in the ictal-interictal continuum.

The Optimising Blood Pressure in acute intracerebral hemorrhage (ICH) study aims to conduct an IPDMA of pooling the four INTERACT trial to provide reliable information on the optimal blood pressure (BP) treatment target for patients with acute ICH. This protocol outlines the methods for the systematic review, research questions, and the approach to statistical analysis. An intention-to-treat principle (ITT) will be applied in all analyses. Baseline characteristics will be summarised by treatment group. BP lowering treatment effect on the outcomes will be analysed by means of an ordinal logistic regression, and on the secondary and safety outcomes will be analysed by means of a binary logistic regression. Primary outcome is an ordinal distribution of modified Rankin Scale (mRS) scores at 90 days; secondary outcomes include change (absolute and relative, defined as an increase by >33%) in hematoma volume from the baseline and 24 hours CT scans and safety events within 90 days. Publication policyThis policy is to be inclusive and follows that outlined for a prospective meta-analysis.1 This policy requires the identification of the lead investigator responsible for each randomized controlled trial (RCT) - known as a Principle Investigator (PI)- as well as up to four additional investigators from each RCT, members of the Trial Management Group or Trial Steering Committee for each RCT, and the methodologists/statisticians involved in the meta-analysis. ProtocolUp to five investigators from each INTERACT trial may be included as co-authors of this protocol if they fulfil the ICMJE criteria of contributing authors, and they will be listed alphabetically by surname. The methodologists and statisticians involved in the design of INTERACT individual participant data meta-analysis will be co-authors. Each RCT may provide an unlimited number of non-author contributors, who are most likely to be members of each RCTs Trial Management Group or Trial Steering Committee. The criteria for determining who is a contributing author or a non-author contributor follow ICMJE definitions: www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html. All publications will name contributing authors as well as the attribution, "on behalf of the INTERACT collaborators." Any report of the INTERACT IPDMA will be circulated to co-authors for comment and approval before submission for publication. All co-authors must have participated fully in manuscript preparation and editing.

BackgroundAneurysmal subarachnoid hemorrhage (aSAH) causes systemic changes that contribute to delayed cerebral ischemia (DCI) and morbidity. Circulating metabolites reflecting underlying pathophysiological mechanisms warrant investigation as biomarker candidates. MethodsBlood samples, prospectively collected within 24 hours (T1) of admission and 7-days (T2) post ictus, from patients with acute aSAH from two tertiary care centers were retrospectively analyzed. Samples from healthy subjects and patients with non-neurologic critical illness served as controls. A validated external analysis platform was used to perform untargeted metabolomics. Bioinformatics analyses were conducted to identify metabolomic profiles defining each group and delineate metabolic pathways altered in each group. Machine learning (ML) models were developed incorporating key metabolites to improve DCI prediction. ResultsAmong 70 aSAH, 30 healthy control, and 17 sick control subjects, a total of 1,117 metabolites were detected. Groups were matched among key clinical variables. DCI occurred in 36% of aSAH subjects, and poor functional outcome was observed in 70% at discharge. Metabolomic profiles readily discriminated the groups. aSAH subjects demonstrated a robust mobilization of lipid metabolites, with increased levels of free fatty acids (FFAs), mono- and diacylglycerols (MAG, DAG) compared with both control groups. aSAH subjects also had decreased circulating amino acid derived metabolites, consistent with increased catabolism. DCI was associated with increased sphingolipids (sphingosine and sphinganine) and decreased acylcarnitines and S- adenosylhomocysteine at T1. Decreased lysophospholipids and acylcarnitines were associated with poor outcomes. Incorporating metabolites into ML models improved prediction of DCI compared with clinical variables alone. ConclusionsProfound metabolic shifts occur after aSAH with characteristic increases in lipid and decreases in amino acid metabolites. Key lipid metabolites associated with outcomes (sphingolipids, lysophospholipids, and acylcarnitines) provide insight into systemic changes driving secondary complications. These metabolites may also prove to be useful biomarkers to improve prognostication and personalize aSAH care.

BackgroundBrain injury is pathophysiologically diverse, with many cases presenting with mixed pathologies. Utilizing objective measures to investigate the pathophysiology of injury would aid in understanding prognosis and targeting therapeutics. ObjectiveThe goal of this study is to develop a traumatic brain injury classification scheme based on open source deep learning computer tomography (CT) analysis and the two serum biomarkers, glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal L1 (UCH-L1). MethodsMachine learning was utilized to develop a novel algorithm capable of classifying the type of brain injury based on a CT scan analysis algorithm and GFAP and UCH-L1 concentrations. Injury was stratified into one of four groups: spontaneous hemorrhage, oxygen deprivation, trauma resulting in vascular injury or high-velocity trauma with negative CT scan. Outcomes100 research subjects were enrolled. Using a combination of CT analysis and serum markers, the subjects with CT positive trauma were distinguishable from those with spontaneous hemorrhage, ischemic injury, CT negative trauma and controls with AUCs of 0.96, 0.99., 0.98 and 1.00 respectively. Ischemic injury was distinguishable from CT positive trauma with an AUC of 0.98. All forms of brain injury could be distinguished from controls with AUC = 1.00. DiscussionAn open source algorithmic CT scan analysis algorithm and serum biomarkers accurately classified the nature of brain injury across major etiologies. Further implementation of such algorithms and addition of other objective measures will enable better prognostication of injury and improved development of therapeutics.

Background and aimsPerihematomal hypoperfusion may lead to ischemic damage during intraparenchymal cerebral hemorrhage (ICH), resulting in worse prognosis. We aimed to (1) investigate the relationship between serum biomarkers related to oxidative stress and vasoactive substances and the occurrence of hypoperfusion and ischemic perihematomal lesions in ICH, (2) to evaluate their correlation with the volumetric evolution of the hematoma and perihematomal edema. MethodsWe enrolled 28 patients affected by ICH. Blood samples were collected at timepoint T0 (admission to Emergency-Room), T1 (12-24hs from symptoms onset), T2 (48- 72hs from onset), to measure Endothelin-1 (ET-1), nitrites/nitrates (NO), NADPH oxidase-2 (NOX-2), metalloproteinase-12 (MMP12) and asymmetric dimethylarginine (ADMA). Patients underwent brain MRI with perfusion study at T1 and MRI without perfusion at T2. Results12 patients had ischemic perihematomal lesions at T1. A higher NOX-2 concentration at T0 was observed in patients with ischemic perihematomal lesions compared to those without, (34.9 pg/ml vs 22.4 pg/ml, p=0.051) and with a more severe perihematomal edema at T2 (37.99 pg/ml vs. 19.17 pg/ml, p=0.011). The ischemic perihematomal lesions development was also associated with an increased hematoma volume (p<0.005), perilesional edema (p=0.046), greater midline shift (p=0.036). ET-1 values at T1 inversely correlated with hemorrhage volume at T2 ({rho}=-0.717, p=0.030). ConclusionsNOX-2 seems to have a role in the development of ischemic perihematomal lesions. The association between higher ET-1 values and a lower hemorrhage volume could be related to the ET-1 vasoconstriction action on the ruptured vessel wall.

ObjectivesTo automate subarachnoid hemorrhage volume (SAHV) calculation (SAHVAI-SAHV Artificial Intelligence) and create 3D volumetric images (SAHVAI-3D) using non-contrast head CT (NCCT) imaging data in aneurysmal subarachnoid hemorrhage (SAH) patients. We also defined SAHVAI-4D, representing SAHV over time. The aim was to compare automated SAHVAI volumes to manual SAHV methods and computation times, explore these imaging biomarkers potential in identifying at-risk brain regions for delayed cerebral ischemia (DCI), and explore potential insights in future neurotherapeutic interventions for SAH patient recovery. MethodsA training set of 10 consecutive aneurysmal SAH cases was used to manually compute SAHV, SAHVAI-3D, and SAHVAI-4D, involving 92 non-contrast CT scans (182 slices each). The SAHVAI deep learning (DL) algorithm generated automated SAHV values in cubic centimeters (cc). For both SAHVAI and manual evaluations, a 3D SAH brain map was created for each patient. Blood volumetric outputs were analyzed and compared to neurological outcomes at discharge, including DCI events, symptomatic vasospasm (sVSP), and areas with the thickest SAH blood concentration. ResultsSAHVAI quantified SAH blood volume (SAHV) in average of 6.7 seconds per scan, significantly faster than the manual method, which took over 60 minutes per scan (Fishers exact test, P value <0.001). SAHVAI demonstrated an accuracy of 99.8%, a Dice score of 0.701, a false positive rate of 0.0005, and a negative predictive value of 0.999. The mean absolute error between SAHVAI and manual methods was 5.67 ml. The SAHVAI-3D brain map and total SAHV at admission were strongly associated with neurological outcomes, inversely with Glasgow coma scale (R2=0.23, p=0.017) and directly with length of hospital stay (R2=0.175, p=0.004), especially in regions with dense blood concentration. ConclusionSAHVAI-3D and SAHVAI-4D brain mapping techniques represent innovative imaging biomarkers for SAH. These advancements enable rapid evaluation and targeted interventions, potentially improving patient care in SAH management.

Background and ObjectivesAccurate assessment of level of consciousness and potential to recover in severe brain injury patients underpins crucial decisions in the intensive care unit but remains a major challenge for the clinical team. The neurological wake-up test (NWT) is a widely used assessment tool, but many patients behavioral response during a short interruption of sedation is ambiguous or absent, with little prognostic value. This study assesses the brains electroencephalogram response during an interruption of propofol sedation to complement behavioral assessment during the NWT to predict survival, recovery of consciousness, and long-term functional outcome in acute severe brain injury patients. MethodsWe recorded 128-channel EEG of 41 severely brain-injured patients during a clinically indicated NWT. The Glasgow Coma Scale (GCS) was used to assess behavioral responsiveness before and after interruption of sedation (GCSobserved). During the NWT, nine patients regained responsiveness, 13 patients showed ambiguous responsiveness and 19 patients were not responsive. Brain response to sedation interruption was quantified using EEG power, spatial ratios and the spectral exponent. We trained a linear regression model to identify brain patterns related to regaining behavioral responsiveness. We then applied this model to patients whose behavioral responses were ambiguous or absent, using their NWT brain responses to predict a change in behavioral response ({Delta}GCSpredicted). Prognostic value of the {Delta}GCSpredicted was assessed using the Mann-Whitney-U test and group-separability. The patients survival, recovery of responsiveness, and functional outcomes were assessed up to 12 months post-recording. ResultsEEG patterns during interruption of sedation reliably predicted the GCSobserved in patients who regained responsiveness during the NWT. Electrophysiological patterns of waking-up were observed in some patients whose behavioral response was ambiguous or absent. Compared to the GCSobserved, the {Delta}GCSpredicted improved separability of prognostic groups and significantly distinguished patients according to survival (U = 87, p<0.05). The EEG-trained model outperformed outcome predictions of the patients attending physician and predictions based on the patients APACHE score. DiscussionEEG can complement behavioral assessment during the NWT to improve prognostication, inform clinicians, family members and caregivers, and to set realistic goals for treatment and therapy.