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Background: Ischemic lesions on diffusion weighted imaging (DWI) are common after acute spontaneous intracerebral hemorrhage (ICH) but are poorly understood for large ICH volumes (> 30 mL). We hypothesized that large blood pressure drops and effect modification by cerebral small vessel disease markers on magnetic resonance imaging (MRI) are associated with DWI lesions., Methods: This was an exploratory analysis of participants in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial with protocolized brain MRI scans within 7 days from ICH. Multivariable logistic regression analysis was performed to assess biologically relevant factors associated with DWI lesions, and relationships between DWI lesions and favorable ICH outcomes (modified Rankin Scale 0-3)., Results: Of 499 enrolled patients, 300 had MRI at median 7.5 days (interquartile range 7-8), and 178 (59%) had DWI lesions. The incidence of DWI lesions was higher in patients with systolic blood pressure (SBP) reduction ≥ 80 mm Hg in first 24 h (76%). In adjusted models, factors associated with DWI lesions were as follows: admission intraventricular hematoma volume (p = 0.03), decrease in SBP ≥ 80 mm Hg from admission to day 1 (p = 0.03), and moderate-to-severe white matter disease (p = 0.01). Patients with DWI lesions had higher odds of severe disability at 1 month (p = 0.04), 6 months (p = 0.036), and 12 months (p < 0.01). No evidence of effect modification by cerebral small vessel disease on blood pressure was found., Conclusions: In patients with large hypertensive ICH, white matter disease, intraventricular hemorrhage volume, and large reductions in SBP over the first 24 h were independently associated with DWI lesions. Further investigation of potential hemodynamic mechanisms of ischemic injury after large ICH is warranted., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a "worst-case" safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury., (© 2023. The Author(s).)

Background: Serum neutrophil-lymphocyte ratio (NLR) is a surrogate marker for the inflammatory response after intracerebral hemorrhage (ICH) and is associated with perihematomal edema and long-term functional outcomes. Whether NLR is associated with short-term ICH complications is poorly understood. We hypothesized that NLR is associated with 30-day infection and thrombotic events after ICH., Methods: We performed a post hoc exploratory analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial. The study exposure was the serum NLR obtained at baseline and on days 3 and 5. The coprimary outcomes, ascertained at 30 days, were any infection and a thrombotic event, defined as composite of cerebral infarction, myocardial infarction, or venous thromboembolism; both infection and thrombotic event were determined through adjudicated adverse event reporting. Binary logistic regression was used to study the relationship between NLR and outcomes, after adjustment for demographics, ICH severity and location, and treatment randomization., Results: Among the 500 patients enrolled in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial, we included 303 (60.6%) without missing data on differential white blood cell counts at baseline. There were no differences in demographics, comorbidities, or ICH severity between patients with and without data on NLR. In adjusted logistic regression models, NLR ascertained at baseline (odds ratio [OR] 1.03; 95% confidence interval [CI] 1.01-1.07, p = 0.03) and NLR ascertained at day 3 were associated with infection (OR 1.15; 95% CI 1.05-1.20, p = 0.001) but not with thrombotic events. Conversely, NLR at day 5 was associated with thrombotic events (OR 1.07, 95% CI 1.01-1.13, p = 0.03) but not with infection (OR 1.13; 95% CI 0.76-1.70, p = 0.56). NLR at baseline was not associated with either outcome., Conclusions: Serum NLR ascertained at baseline and on day 3 after randomization was associated with 30-day infection, whereas NLR obtained on day 5 was associated with thrombotic events after ICH, suggesting that NLR could be a potential early biomarker for ICH-related complications., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC., Methods: The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC., Results: There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC., Conclusions: Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH)., Methods: We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders., Results: Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders., Conclusions: The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH., Clinical Trial Registration: ClinicalTrials.gov: NCT01176565., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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: Liver disease is associated with altered serum osmolality, increased thrombin generation, and systemic inflammation, all of which may contribute to perihematomal edema (PHE) after intracerebral hemorrhage (ICH). We evaluated the association between a validated liver fibrosis index and PHE growth in a cohort of patients with primary ICH., Methods: We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-ICH. We included adult patients with primary ICH presenting within 6 h of symptom onset. The exposure of interest was the Fibrosis-4 (FIB-4) score, a validated liver fibrosis index; this was modeled as a continuous variable. The primary outcome was absolute PHE growth over 96 h. Secondary outcomes were absolute admission and 96-h PHE volumes. We used multiple linear regression models adjusted for established determinants of PHE. In a secondary analysis, the FIB-4 score was modeled as a categorical variable to compare patients with versus without liver fibrosis., Results: Among 354 patients with ICH, 8% had evidence of liver fibrosis based on a validated cutoff. The FIB-4 score was not associated with PHE growth in unadjusted (β, 0.03; 95% CI, - 0.01 to 0.12) or adjusted models (β, 0.04; 95% CI, - 0.03 to 0.13). In a secondary analysis treating FIB-4 as a categorical variable, patients with liver fibrosis did not have greater PHE growth than those without liver fibrosis. FIB-4 score was also not associated with absolute admission or 96-h PHE volumes., Conclusions: In a multicenter cohort of patients with primary intracerebral hemorrhage, a liver fibrosis score was not associated with PHE volume or growth.

Background/objective: Intracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials., Methods: In ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0-4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint., Results: Of 635 patients, 55% had WML grade 1-4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54-6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors., Conclusions: Concomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome., Clinical Trial Registration: http://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.

Background: With increasing use of direct oral anticoagulants (DOACs) and availability of new reversal agents, the risk of traumatic intracranial hemorrhage (tICH) requires better understanding. We compared hemorrhage expansion rates, mortality, and morbidity following tICH in patients treated with vitamin k antagonists (VKA: warfarin) and DOACs (apixaban, rivaroxaban, dabigatran)., Methods: Retrospective chart review of patients from 2010 to 2017 was performed to identify patients with imaging diagnosis of acute traumatic intraparenchymal, subdural, subarachnoid, and epidural hemorrhage with preadmission use of DOACs or VKAs. We identified 39 patients on DOACs and 97 patients on VKAs. Demographic information, comorbidities, hemorrhage size, and expansion over time, as well as discharge disposition and Glasgow Outcome Scale (GOS) were collected. Primary outcome was development of new or enlargement of tICH within the first 48 h of initial CT imaging., Results: Of 136 patients with mean (SD) age 78.7 (13.2) years, most common tICH subtype was subdural hematoma (N = 102/136; 75%), and most common mechanism was a fall (N = 130/136; 95.6%). Majority of patients in the DOAC group did not receive reversal agents (66.7%). Hemorrhage expansion or new hemorrhage occurred in 11.1% in DOAC group vs. 14.6% in VKA group (p = 0.77) at a median of 8 and 11 h from initial ED admission, respectively (p = 0.82). Patients in the DOAC group compared to VKA group had higher median discharge GOS (4 vs. 3 respectively, p = 0.03), higher percentage of patients with good outcome (GOS 4-5, 66.7% vs. 40.2% respectively, p = 0.005), and higher rate of discharge to home or rehabilitation (p = 0.04)., Conclusions: We report anticoagulation-associated tICH outcomes predominantly due to fall-related subdural hematomas. Patients on DOACs had lower tICH expansion rates although not statistically significantly different from VKA-treated patients. DOAC-treated patients had favorable outcomes versus VKA group following tICH despite low use of reversal strategies. DOAC use may be a safer alternative to VKA in patients at risk of traumatic brain hemorrhage.

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.

Introduction: The Clot Lysis: Evaluating Accelerated Resolution of IVH trial examined whether irrigating the ventricular system with alteplase improved functional outcomes in patients with small intracerebral hemorrhage (ICH) and large intraventricular hemorrhage (IVH). Thalamic ICH location was common and was associated with poor outcome. One possible explanation is thalamic ICH-associated mass effect obstructing the third ventricle. We hypothesized that patients with thalamic ICH obstructing the third ventricle would have worse functional outcomes compared to patients without obstructing lesions., Methods: ICH obstruction of third ventricle was defined as third ventricle compression on 1 or more axial computed tomography slices visually impeding cerebral spinal fluid flow. If the third ventricle was casted with IVH, it was scored as such. Multivariable logistic regression analyses were used to determine whether obstruction of the third ventricle predicts poor functional outcomes defined as modified Rankin score (mRS) 4-6, higher mRS, and mortality at 180 days. Models were adjusted for thalamic ICH location, ICH volume, IVH volume, age, hydrocephalus, baseline Glasgow coma scale, and percentage of low cerebral perfusion pressures during treatment., Results: Among saline-treated patients, obstruction of the third ventricle by IVH was a significant predictor of higher mRS at 180 days (OR 1.87, CI 1.01-3.47) and mortality at 180 days (OR 2.73, CI 1.27-5.87) while obstruction by ICH was not. In contrast, among alteplase-treated patients, obstruction by ICH was a significant predictor of mRS 4-6 (OR 3.20, CI 1.30-7.88) and higher mRS at 180 days (OR 2.33, CI 1.24-4.35), while obstruction by IVH was not., Conclusions: Poor outcomes were associated with mass-related obstruction of the third ventricle from thalamic ICH in alteplase-treated patients and from IVH in saline-treated patients. Once the ventricular system is cleared with alteplase, obstruction of cerebral spinal fluid flow from thalamic ICH might become important in functional recovery.

Background: Concomitant acute ischemic lesions are detected in up to a quarter of patients with spontaneous intracerebral hemorrhage (ICH). Influence of bleeding pattern and intraventricular hemorrhage (IVH) on risk of ischemic lesions has not been investigated., Methods: Retrospective study of all 500 patients enrolled in the CLEAR III randomized controlled trial of thrombolytic removal of obstructive IVH using external ventricular drainage. The primary outcome measure was radiologically confirmed ischemic lesions, as reported by the Safety Event Committee and confirmed by two neurologists. We assessed predictors of ischemic lesions including analysis of bleeding patterns (ICH, IVH and subarachnoid hemorrhage) on computed tomography scans (CT). Secondary outcomes were blinded assessment of mortality and modified Rankin scale (mRS) at 30 and 180 days., Results: Ischemic lesions occurred in 23 (4.6%) during first 30 days after ICH. Independent risk factors associated with ischemic lesions in logistic regression models adjusted for confounders were higher IVH volume (p = 0.004) and persistent subarachnoid hemorrhage on CT scan (p = 0.03). Patients with initial IVH volume ≥ 15 ml had five times the odds of concomitant ischemic lesions compared to IVH volume < 15 ml. Patients with ischemic lesions had significantly higher odds of death at 1 and 6 months (but not poor outcome; mRS 4-6) compared to patients without concurrent ischemic lesions., Conclusions: Occurrence of ischemic lesions in the acute phase of IVH is not uncommon and is significantly associated with increased early and late mortality. Extra-parenchymal blood (larger IVH and visible subarachnoid hemorrhage) is a strong predictor for development of concomitant ischemic lesions after ICH.

Background: Infections after intracerebral hemorrhage (ICH) may be associated with worse outcomes. We aimed to evaluate the association between nosocomial infections (>48 h) and outcomes of ICH at a population level., Methods: We identified patients with ICH using ICD-9-CM codes in the 2002-2011 Nationwide Inpatient Sample. Demographics, comorbidities, surgical procedures, and hospital characteristics were compared between patients with and without concomitant nosocomial infections. Primary outcomes were in-hospital mortality and home discharge. Secondary outcome was permanent cerebrospinal shunt placement. Logistic regression analyses were used to analyze the association between infections and outcomes., Results: Among 509,516 ICH patients, infections occurred in 117,636 (23.1 %). Rates of infections gradually increased from 18.7 % in 2002-2003 to 24.1 % in 2010-2011. Pneumonia was the most common nosocomial infection (15.4 %) followed by urinary tract infection (UTI) (7.9 %). Patients with infections were older (p < 0.001), predominantly female (56.9 % vs. 47.9 %, p < 0.001), and more often black (15.0 % vs. 13.4 %, p < 0.001). Nosocomial infection was associated with longer hospital stay (11 vs. 5 days, p < 0.001) and a more than twofold higher cost of care (p < 0.001). In the adjusted regression analysis, patients with infection had higher odds of mortality [odds ratio (OR) 2.11, 95 % CI 2.08-2.14] and cerebrospinal shunt placement (OR 2.19, 95 % CI 2.06-2.33) and lower odds of home discharge (OR 0.49, 95 % CI 0.47-0.51). Similar results were observed in subgroup analyses of individual infections., Conclusions: In a nationally representative cohort of ICH patients, nosocomial infection was associated with worse outcomes and greater resource utilization.

Background: The impact of ventriculostomy-associated infections (VAI) on intracerebral hemorrhage (ICH) outcomes has not been clearly established, although prior studies have attempted to address the incidence and predictors of VAI. We aimed to explore VAI characteristics and its effect on ICH outcomes at a population level., Methods: ICH patients requiring ventriculostomy with and without VAI were identified from 2002 to 2011 Nationwide Inpatient Sample using ICD-9 codes. A retrospective cohort study was performed. Demographics, comorbidities, hospital characteristics, inpatient outcomes, and resource utilization measures were compared between the two groups. Pearson's Chi-square and Wilcoxon-Mann-Whitney tests were used for categorical and continuous variables, respectively. Logistic regression was used to analyze the predictors of VAI., Results: We included 34,238 patients in the analysis, of whom 1934 (5.6 %) had VAI. The rate of ventriculostomy utilization in ICH increased from 5.7 % in 2002-2003 to 7.0 % in 2010-2011 (trend p < 0.001) and the rate of VAI also showed a gradual upward trend from 6.1 to 7.0 % across the same interval (trend p < 0.001). The VAI group had significantly higher inpatient mortality (41.2 vs. 36.5 %, p < 0.001) and it remained higher after controlling for baseline demographics, hospital characteristics, comorbidity, and systemic infections (adjusted OR 1.38, 95 % CI 1.22-1.46, p < 0.001). The VAI group had longer length of hospital stay and higher inflation adjusted cost of care. Predictors of VAI included higher age, males, higher Charlson's comorbidity scores, longer length of stay, and presence of systemic infections mainly pneumonia and sepsis., Conclusion: VAI resulted in higher inpatient mortality, more unfavorable discharge disposition, and higher resource utilization measures in ICH patients. Steps to mitigate VAI may help improve ICH outcomes and decrease hospital costs.

Background: Outcome from spontaneous intracerebral hemorrhage (sICH) may depend on patient-care variability. We developed as ICH-specific therapy intensity level (TIL) metric using evidence-based elements in a high severity sICH cohort., Methods: This is a cohort study of 170 patients with sICH and any intraventricular hemorrhage treated in 2 academic neuroICUs. Pre-defined quality indicators were identified based on current guidelines, scientific evidence, and likelihood of care documentation in first 72 h of hospital admission. We assessed performance on each indicator and association with discharge mortality. Significant indicators were aggregated to develop a TIL score. The predictive validity of the best fit TIL score was tested with threefold cross-validation of multivariate logistic regression models of in-hospital survival and good outcome (modified Rankin score 0-3)., Results: Median ICH score was 3; discharge mortality was 51.2%. Five/19 tested variables were significantly associated with lower discharge mortality: no DNR/withdrawal of treatment within 24 h of admission, target glucose within 4 h of high glucose, no recurrent hyperpyrexia, clinical reversal of herniation/intracranial pressure >20 mmHg within 60 min of detection, and reversal of INR (<1.4) within 2 h of first elevation. One point was given for each or if not applicable. Median TIL score was significantly higher in survivors versus non-survivors (5[1] vs. 3[1]; P < 0.001). A 4-point aggregated TIL score was most predictive of discharge survival (area under receiving operating characteristic curve 0.85, 95% CI 0.80-0.90) and good outcome (AUC 0.84) and was an independent predictor of both (survival: OR 7.10; 95% CI 3.57-14.11; P < 0.001; good outcome: OR 3.10; 95% CI 1.06-8.79; P < 0.001)., Conclusion: A simplified TIL score using evidenced-based patient-care parameters within first 3 days of admission after sICH was significantly associated with early mortality and good outcome. The next step is prospective validation of the simplified TIL score in a large clinical trial.

Background: External ventricular drain (EVD) usage in patients with intraventricular hemorrhage (IVH) is variable in current practice and in clinical trials, and its impact on outcome remains controversial. The objective of this study was to identify the clinical predictors of EVD utilization, and associated outcome in adults with spontaneous IVH with or without intracerebral hemorrhage (ICH)., Methods: Retrospective review of 183 consecutive IVH patients admitted to a University Hospital between 2003 and 2010. Clinical and radiographic data were analyzed for associations between EVD placement and mortality, poor outcome, and improvement in Glasgow Coma Scale score (GCS) using multivariate logistic regression models., Results: Average age was 62 ± 15.6 years, and average ICH and IVH volumes were 35.8 ± 40.9 cc and 19.7 ± 25.3 cc, respectively. Independent predictors of EVD placement within first 5 days of admission were GCS ≤ 8 (OR 11.5; P < 0.001), Graeb score >5 (OR 4.6; P = 0.001), and non-lobar ICH ≤ 30 cc (OR 9.7; P < 0.001). Median GCS increased from 5 (IQR 3-7) 48 h post-EVD (P < 0.001). EVD placement was an independent predictor of reduced mortality (OR 0.31; P = 0.04) and modified Rankin score 0-3 (OR 15.7; P = 0.01) at hospital discharge. In patients with hydrocephalus on presentation, EVD was associated with reduced mortality for patients with GCS > 3 after controlling for ICH and IVH severity (OR 0.02; P = 0.01)., Conclusions: Patients with lower GCS, higher IVH severity, and lower ICH volume are more likely to have an EVD placed. EVD placement is associated with reduced mortality and improved short-term outcomes in patients with IVH after adjusting for known severity factors. EVD use should be protocolized in clinical trials of ICH management where IVH is included.

Background: The purpose of the study is to review the CT findings associated with ventriculostomy placement in regards to the safety of an EVD plus recombinant tissue plasminogen activator (rt-PA) for IVH., Methods: A retrospective review was conducted for patients receiving intraventricular rt-PA for IVH from January 2004 to September 2009. Safety was assessed by the presence of EVD tract hemorrhage by CT at baseline after EVD placement, worsening hemorrhage after rt-PA, and CSF infection. IVH volumetrics were assessed by the Le Roux score and outcomes by Glasgow Outcome Scale and modified Rankin Scale., Results: Twenty-seven patients received rt-PA for IVH. Median dose was 2 mg (range 0.3-8) and a median of two doses (range 1-17) were given. Worsening EVD catheter tract hemorrhage after rt-PA was 46.7 %, with a significantly higher incidence of worsening tract hemorrhage seen with incorrectly placed EVDs (p = 0.04). IVH hematoma burden decreased by a median Le Roux score of 10 (range 3-16) prior to rt-PA to 4 (range 0-16) after rt-PA. There were no central nervous system bacterial infections., Conclusion: Intraventricular rt-PA appears to be relatively safe especially when all EVD fenestrations are within the ventricle and reduces IVH burden similar to other studies. We describe a CT-based EVD tract hemorrhage grading scale to evaluate EVD tract hemorrhage before and after thrombolysis, and a bone-window technique to evaluate EVD fenestrations prior to IVH thrombolysis. Further research is needed evaluating these imaging techniques in regard to intraventricular thrombolytic safety and EVD tract hemorrhage.

Introduction: In severe spontaneous intraventricular hemorrhage (IVH), intraventricular (IVR) administration of tissue plasminogen activator (rtPA) clears blood from the ventricles more rapidly than with external ventricular drainage (EVD) alone. However, experimental studies suggest tPA may be neurotoxic in compromised brain tissue and may exacerbate perihematomal edema., Methods: We used computerized volumetrics to assess change in intracerebral hemorrhage (ICH), IVH, ventricular, and perihematomal edema (PHE) volumes at 2-4 (T1) and 5-9 (T2) days following diagnostic CT scans (T0) of 24 patients (12 tPA-treated; 12 controls) with IVH requiring EVD. Controls from a hospital registry were matched by IVH and ICH volume to tPA-treated patients who came from a multicenter trial involving 52 patients with IVH., Results: There were no significant differences between matched pairs in admission ICH and IVH volumes. IVR tPA resulted in more rapid clearance of IVH as determined by T2-T0 decrease in median IVH volume (tPA: -18.7 cc, iqr 14.9; control:-6.9 cc, iqr 6.4; P = 0.002). Median ratios of PHE to ICH volume were not significantly different in control versus tPA-treated patients at T1 and T2 [control:tPA = 0.55:0.56 (T1); P = 0.84 and 0.81:0.71 (T2); P = 1.00]. Total ventricular volume was significantly larger in the control group at T2 (mean: 57.57 ± 10.32 vs. tPA: 24.80 ± 2.67 cc; P = 0.01). Bacterial ventriculitis was more frequent in the control group (5 vs. 1 episodes; P = 0.06) as was shunt dependence (4 vs. 0 cases; P = 0.03)., Conclusions: For case matched large IVH with small ICH volume, IVR tPA enhances lysis of intraventricular blood clots and has no significant impact on PHE.

Objective: Detecting and treating elevated intracranial pressure (ICP) is a cornerstone of management in patients with severe traumatic brain injury. The aim of this study was to determine the association between area under the curve measurement of elevated ICP and clinical outcome., Methods: Single center observational study using prospectively collected data at a University hospital, level one-trauma center. Sixty prospective patients with severe traumatic brain injury were prospectively enrolled over a 2-year period. Intracranial pressure measurements were captured using a real-time automated, high resolution vital signs data recording system. Mortality and functional outcome were assessed at 30 days, 3 and 6 months using Extended Glasgow Outcome Scale., Results: Increasing elevated intracranial pressure time dose was associated with mortality (OR 1.08; 95 % confidence interval [CI], 1.01-1.15, p = 0.03) and poor functional outcome at 3 (OR 1.04; CI 1.00-1.07, p = 0.03) and 6 months (1.04; CI 1.01-1.08, p = 0.02). However, there was no association between episodic ICP data and outcome., Conclusions: These results suggest that pressure time dose measurement of intracranial pressure may be used to predict outcome in severe traumatic brain injury and may be a candidate biomarker in this disease.

Background: Little is known about the efficacy of single versus dual extraventricular drain (EVD) use in intraventricular hemorrhage (IVH), with and without thrombolytic therapy., Methods: Post-hoc analysis of seven patients with dual bilateral EVDs from two multicenter trials involving 100 patients with IVH, and spontaneous intracerebral hemorrhage (ICH) volume <30 ml requiring emergency external ventricular drainage. Seven "control" patients with single catheters were matched by IVH volume and distribution and treatment assignment. Head CT scans were obtained daily during intraventricular injections for quantitative determination of IVH volume., Results: Median [min-max] age of the 14 subjects was 56 [40-73] years. Median duration of EVD was 7.9 days (single catheter group) versus 12.2 days (dual catheter group) (P = 0.34). Baseline median IVH volume was not significantly different between groups (75.4 ml [22.4-105.1]--single EVD vs. 84.5 ml [42.0-132.0]--dual EVD; P = 0.28). Comparing the change in IVH volume on time-matched CT scans during dual EVD use, the median decrease in IVH volume in dual catheter patients was significantly larger (52.1 [31.7-81.1] ml) versus single catheter patients (34.5 [13.1-73.9] ml) (P = 0.004). There was a trend to greater decrease in IVH volume during dual EVD use in both rt-PA (P = 0.9) and placebo-treated (P = 0.11) subgroups., Conclusion: The decision to place dual EVDs is generally reserved for large IVH (>40 ml) with casting and mass effect. The use of dual simultaneous catheters may increase clot resolution with or without adjunctive thrombolytic therapy.

Background: Recent reports suggest that when thrombolytic agents are administered within the clot, lysis rate accelerates at the expense of increased risk of worsening edema. To test this hypothesis, we report on the volumetric analysis of (1) the intraparenchymal hematoma and, (2) perihematomal edema in a cohort of ICH patients treated with intraclot rtPA., Methods: A convenience sample of highly selected ICH patients underwent frameless stereotactic aspiration and thrombolysis (FAST) of the clot. Two milligrams of rtPA were administered every 12 h until ICH volume < or =10 cc, or catheter fenestrations were no longer in continuity with the clot. ICH and perihematomal edema volumes were calculated from CT scans. Using random effects linear regression we estimated the rate of hematoma and edema volume resolution as well as their relationship during the first 8 days of lytic therapy., Results: Fifteen patients were treated, mean age: 60.7 years, median time from ictus to FAST: 1 (range 0-3) day. Using a random effects model that considered volume resolution over the first 8 days following lytic therapy we found that the both percentage hematoma and percentage perihematoma edema resolution per day were quadratic with respect to time. Percentage residual hematoma volume on day K = 97.7% - [24.36%*K] + [1.89%*K (2)]; P < 0.001 for both terms. Percentage residual edema on day K = 97.4% - [13.94%*K] + [1.30%*K (2)]; P < 0.001 for K and P = 0.01 for K (2). Examination of each patient's volume data suggests that there exists a strong direct relationship between perihematoma edema volume and same day hematoma volume., Conclusions: In this cohort of ICH patients treated using FAST, volumetric analysis of ICH and perihematomal edema seems to suggest that local use of rtPA does not exacerbate brain edema formation. Furthermore, there seems to be a strong association between reduction in ICH volume and reduction in edema volume, as would be expected following the concept of "hemotoxicity" postulated by some investigators.

We describe a woman with congestive heart failure who presented with acute cardiac decompensation followed by ischemic stroke. The management of the patient posed unique challenges for thrombolytic treatment (due to existing coagulopathy) and subsequent optimization of hemodynamic status. Issues related to rethrombosis and use of platelet glycoprotein IIB/IIIA inhibitors are also discussed.