Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-ß0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

Does stereotactic thrombolysis with alteplase for intracerebral haemorrhage alter intraventricular haematoma volume? A secondary analysis of the MISTIE-III trial.

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 (ß -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.

Association Between Hematoma Volume and Risk of Subsequent Ischemic Stroke: A MISTIE III and ATACH-2 Analysis.

BACKGROUND: Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic risk has been studied, whether hematoma volume influences this risk is poorly understood. METHODS: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics. RESULTS: Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase [95% CI, 1.01-1.04]). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 [95% CI, 1.1-7.2]), compared with those with an ICH volume <17.3 mL. CONCLUSIONS: In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke.

Association Between Neutrophil-Lymphocyte Ratio and 30-Day Infection and Thrombotic Outcomes After Intraventricular Hemorrhage: A CLEAR III Analysis.

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.

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage.

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.

Catheter Tract Hemorrhages and Intracerebral Hemorrhage Outcomes in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Trial.

BACKGROUND AND OBJECTIVES: Factors associated with external ventricular catheter tract hemorrhage (CTH) are well studied; whether CTH adversely influence outcomes after intracerebral hemorrhage (sICH), however, is poorly understood. We therefore sought to evaluate the association between CTH and sICH outcomes. METHODS: We performed a post hoc analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial. The exposure was CTH and evaluated on serial computed tomography scans between admission and randomization (approximately 72 hours). The primary outcomes were a composite of death or major disability (modified Rankin Score >3) and mortality alone, both assessed at 6 months. Secondary outcomes were functional outcomes at 30 days, permanent cerebrospinal fluid (CSF) shunt placement, any infection, and ventriculitis. We performed logistic regression adjusted for demographics, comorbidities, sICH characteristics, and treatment assignment, for all analyses. RESULTS: Of the 500 patients included, the mean age was 59 (SD, ±11) years and 222 (44%) were female. CTH occurred in 112 (22.4%) patients and was more common in minority patients, those on prior antiplatelet therapy, and patients who had more than 1 external ventricular drain placed. The end of treatment intraventricular hemorrhage volume was higher among patients with CTH (11.7 vs 7.9 mL, P = .01), but there were no differences in other sICH characteristics or the total duration of external ventricular drain. In multivariable regression models, CTH was not associated with death or major disability (odds ratio, 0.7; 95% CI: 0.4-1.2) or death alone (odds ratio, 0.8; 95% CI, 0.5-1.4). There were no relationships between CTH and secondary outcomes including 30-day functional outcomes, permanent CSF shunt placement, any infection, or ventriculitis. CONCLUSION: Among patients with sICH and large intraventricular hemorrhage, CTH was not associated with poor sICH outcomes, permanent CSF shunt placement, or infections. A more detailed cognitive evaluation is needed to inform about the role of CTH in sICH prognosis.

Mechanistic Evaluation of Diffusion Weighted Hyperintense Lesions After Large Spontaneous Intracerebral Hemorrhage: A Subgroup Analysis of MISTIE III.

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.

Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial.

Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia. Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. Trial Registration: ClinicalTrials.gov Identifier: NCT03101891.

Cerebral small vessel disease modifies outcomes after minimally invasive surgery for intracerebral haemorrhage.

BACKGROUND: Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes. METHODS: Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models. RESULTS: Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all Pinteraction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); Pinteraction=0.006), absence of lacunes (OR, 0.37 (0.18-0.80); Pinteraction=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); Pinteraction=0.03). CONCLUSIONS: Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.

One-Year Outcome Trajectories and Factors Associated with Functional Recovery Among Survivors of Intracerebral and Intraventricular Hemorrhage With Initial Severe Disability.

Importance: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future recovery is limited. Objective: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery. Design, Setting, and Participants: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022. Exposures: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care. Main Outcomes and Measures: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort. Results: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio [aOR], 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99]), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.83-0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001). Conclusions and Relevance: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

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.

Intraventricular Hemorrhage Expansion in the CLEAR III Trial: A Post Hoc Exploratory Analysis.

BACKGROUND: The objective of this study was to evaluate factors associated with intraventricular hemorrhage (IVH) expansion and its association with long-term outcomes. METHODS: We performed a post hoc analysis of the international, multi-center CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) which enrolled IVH patients between September 1, 2009, and January 31, 2015. The exposure was IVH expansion, defined as >1 mL increase in volume between baseline and stability computed tomography scans, before treatment randomization. We assessed factors associated with IVH expansion and secondarily assessed the relationship of IVH expansion with clinical outcomes: composite of death or major disability (modified Rankin Scale score, >3), and mortality alone at 6 months. The relationship of IVH expansion on ventriculoperitoneal shunt placement was additionally explored. Multivariable logistic regression was used for all analyses. RESULTS: Of 500 IVH patients analyzed, the mean age was 59 (±11) years old, 44% were female and 135 (27%) had IVH expansion. In multivariable regression models, factors associated with IVH expansion were baseline parenchymal intracerebral hemorrhage (ICH) volume (adjusted odds ratio [OR], 1.04 per 1 mL increase [95% CI, 1.01-1.08]), presence of parenchymal hematoma expansion: >33% (adjusted OR, 6.63 [95% CI, 3.92-11.24]), time to stability head CT (adjusted OR, 0.71 per 1 hour increase [95% CI, 0.54-0.94]), and thalamic hematoma location (adjusted OR, 1.68 [95% CI, 1.01-2.79]) while additionally adjusting for age, sex, and race. In secondary analyses, IVH expansion was associated with higher odds of poor 6-month outcomes (adjusted OR, 1.84 [95% CI, 1.12-3.02]) but not mortality (OR, 1.40 [95% CI, 0.78-2.50]) after adjusting for baseline ICH volume, thalamic ICH location, age, anticoagulant use, Glasgow Coma Scale score, any withdrawal of care order, and treatment randomization arm. However, there were no relationships of IVH expansion on subsequent ventriculoperitoneal shunt placement (adjusted OR, 1.02 [95% CI, 0.58-1.80]) after adjusting for similar covariates. CONCLUSIONS: In a clinical trial cohort of patients with large IVH, acute hematoma characteristics, specifically larger parenchymal volume, hematoma expansion, and thalamic ICH location were associated with IVH expansion. Given that IVH expansion resulted in poor functional outcomes, exploration of treatment approaches to optimize hemostasis and prevent IVH expansion, particularly in patients with thalamic ICH, require further study. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00784134.

Cerebral Microbleeds and Acute Hematoma Characteristics in the ATACH-2 and MISTIE III Trials.

BACKGROUND AND OBJECTIVES: To study the relationship between the presence of cerebral microbleeds (CMBs) and acute hematoma characteristics among patients with primary intracerebral hemorrhage (ICH). METHODS: We pooled individual patient data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 (MISTIE III) trial. We included individuals with a brain MRI scan. Exposure was the presence of a CMB. The coprimary outcomes were admission ICH volume and hematoma expansion. Mixed-effects linear and logistic regression models were used, with demographics and comorbid conditions considered fixed effects and the study cohort treated as a random effect. Additional analyses assessed the relationship between CMB topography and number and hematoma characteristics. RESULTS: Of the 1,499 patients with ICH enrolled in the parent trials, 466 (31.1%) were included in this analysis, and 231 (49.6%) patients had CMBs. In adjusted models, presence of CMBs was associated with smaller ICH volume (ß = -0.26, 95% confidence interval [CI] -0.44 to -0.08) and lower odds of hematoma expansion (odds ratio 0.65, 95% CI 0.40-0.95; p = 0.04). The strength of association between CMBs and hematoma characteristics increased with increasing number of CMBs. The location of the CMBs and the severity of leukoaraiosis did not modify these results. DISCUSSION: In a pooled cohort of patients with ICH, our results are consistent with the hypothesis that more severe underlying small vessel disease, as represented by CMBs, leads to smaller baseline hematoma volumes and reduced hematoma expansion. Underlying cerebral small vessel disease may be of prognostic significance after ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01176565 and NCT01827046. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of microbleeds on MRI is associated with a smaller ICH volume at presentation and a lower rate of hematoma expansion on follow-up imaging.

Association Between Intraventricular Alteplase Use and Parenchymal Hematoma Volume in Patients With Spontaneous Intracerebral Hemorrhage and Intraventricular Hemorrhage.

Importance: Intraventricular thrombolysis reduces intraventricular hemorrhage (IVH) volume in patients with spontaneous intracerebral hemorrhage (ICH), but it is unclear if a similar association with parenchymal ICH volume exists. Objective: To evaluate the association between intraventricular alteplase use and ICH volume as well as the association between a change in parenchymal ICH volume and long-term functional outcomes. Design, Setting, and Participants: This cohort study was a post hoc exploratory analysis of data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 randomized clinical trial with blinded outcome assessments. Between September 1, 2009, and January 31, 2015, patients with ICH and IVH were randomized to receive either intraventricular alteplase or normal saline via an external ventricular drain. Participants with primary IVH were excluded. Data analyses were performed between January 1 and June 30, 2021. Exposure: Randomization to receive intraventricular alteplase. Main Outcomes and Measures: The primary outcome was the change in parenchymal ICH volume between the hematoma stability and end-of-treatment computed tomography scans. Secondary outcomes were a modified Rankin Scale score higher than 3 and mortality, both of which were assessed at 6 months. The association between alteplase and change in parenchymal ICH volume was assessed using multiple linear regression, whereas the associations between change in parenchymal ICH volume and 6-month outcomes were assessed using multiple logistic regression. Prespecified subgroup analyses were performed for baseline IVH volume, admission ICH volume, and ICH location. Results: A total of 454 patients (254 men [55.9%]; mean [SD] age, 59 [11] years) were included in the study. Of these patients, 230 (50.7%) were randomized to receive alteplase and 224 (49.3%) to receive normal saline. The alteplase group had a greater mean (SD) reduction in parenchymal ICH volume compared with the saline group (1.8 [0.2] mL vs 0.4 [0.1] mL; P < .001). In the primary analysis, alteplase use was associated with a change in the parenchymal ICH volume in the unadjusted analysis per 1-mL change (ß, 1.37; 95% CI, 0.92-1.81; P < .001) and in multivariable linear regression analysis that was adjusted for demographic characteristics, stability ICH and IVH volumes, ICH location, and time to first dose of study drug per 1-mL change (ß, 1.20; 95% CI, 0.79-1.62; P < .001). In the secondary analyses, no association was found between change in parenchymal ICH volume and poor outcome (odds ratio [OR], 0.97; 95% CI 0.87-1.10; P = .64) or mortality (OR, 0.97; 95% CI 0.99-1.08; P = .59). Similar results were observed in the subgroup analyses. Conclusions and Relevance: This study found that intraventricular alteplase use in patients with a large IVH was associated with a small reduction in parenchymal ICH volume, but this association did not translate into improved functional outcomes or mortality. Intraventricular thrombolysis should be examined in patients with moderate to large ICH with IVH, especially in a thalamic location.

Intracranial Pressure and Cerebral Perfusion Pressure in Large Spontaneous Intracranial Hemorrhage and Impact of Minimally Invasive Surgery.

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.

Post-Stroke Depression in Patients with Large Spontaneous Intracerebral Hemorrhage.

OBJECTIVES: To determine factors associated with post-stroke depression (PSD) and relationship between PSD and functional outcomes in spontaneous intracerebral hemorrhage (ICH) using prospective data from a large clinical trial. MATERIALS AND METHODS: MISTIE III, a randomized, multicenter, placebo-controlled trial, was conducted to determine if minimally invasive surgery with thrombolysis improves outcome compared to standard medical care. Our primary outcome was post-stroke depression at 180 days. Secondary outcomes were change in blinded assessment of modified Rankin Scale (mRS) from 30 to 180 days, and from 180 to 365 days. Logistic regression models were used to assess the relationship between PSD and outcomes. RESULTS: Among 379 survivors at day 180, 308 completed Center for Epidemiologic Studies Depression Scale, of which 111 (36%) were depressed. In the multivariable analysis, female sex (Adjusted Odds Ratio [AOR], 95% Confidence Interval [CI]: 1.93 [1.07-3.48]), Hispanic ethnicity (3.05 [1.19-7.85]), intraventricular hemorrhage (1.88 [1.02-3.45]), right-sided lesions (3.00 [1.43-6.29]), impaired mini mental state examination at day 30 (2.50 [1.13-5.54]), and not being at home at day 30 (3.17 [1.05-9.57]) were significantly associated with higher odds of PSD. Patients with PSD were significantly more likely to have unchanged or worsening mRS from day 30 to 180 (42.3% vs. 25.9%; p=0.004), but not from day 180 to 365. CONCLUSIONS: We report high burden of PSD in patients with large volume ICH. Impaired cognition and not living at home may be more important than physical limitations in predicting PSD. Increased screening of high-risk post-stroke patients for depression, especially females and Hispanics may be warranted.

CSF and serum inflammatory response and association with outcomes in spontaneous intracerebral hemorrhage with intraventricular extension: an analysis of the CLEAR-III Trial.

BACKGROUND: Intracerebral hemorrhage (ICH) results in a cascade of inflammatory cell activation with recruitment of peripheral leukocytes to the brain parenchyma and surrounding the hematoma. We hypothesized that in patients with ICH and intraventricular hemorrhage (IVH), a robust cerebrospinal fluid (CSF) inflammatory response occurs with leukocyte subtypes being affected by alteplase treatment and contributing to outcomes. METHODS: Serum and CSF cell counts from patients in the phase 3 Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial were analyzed. CSF leukocytes were corrected for the presence of red blood cells. Trends in cell counts were plotted chronologically. Associations were evaluated between serum and CSF leukocyte subtypes and adjudicated functional outcome (modified Rankin Scale; mRS) at 30 and 180 days and bacterial infection according to treatment with intraventricular alteplase versus saline. RESULTS: A total of 279 and 292 patients had ≥3 differential cell counts from serum and CSF, respectively. CSF leukocyte subtypes evolved during IVH resolution with a significantly augmented inflammatory response for all subtypes in alteplase- compared to saline-treated patients. CSF leukocyte subtypes were not associated with detrimental effect on functional outcomes in the full cohort, but all were associated with poor 30-day outcome in saline-treated patients with IVH volume ≥20 mL. Higher serum lymphocytes were associated with good functional outcomes (mRS 0-3) in the entire cohort and saline-treated but not alteplase-treated group. Conversely, increased serum neutrophil-to-lymphocyte ratio (NLR) in the entire cohort and saline group was associated with worse functional outcomes. Higher median serum lymphocytes were associated with the absence of infection at 7 days. CONCLUSIONS: Aseptic CSF inflammation after IVH involves all leukocyte subtypes. Serum lymphocytes may be associated with better outcomes by mitigating infection. Alteplase augments the inflammatory response without affecting outcomes.

Diffusion-Weighted Imaging Lesions After Intracerebral Hemorrhage and Risk of Stroke: A MISTIE III and ATACH-2 Analysis.

BACKGROUND AND PURPOSE: Punctate ischemic lesions noted on diffusion-weighted imaging (DWI) are associated with poor functional outcomes after intracerebral hemorrhage (ICH). Whether these lesions increase long-term risk of stroke is poorly understood. METHODS: We pooled individual patient data from the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage) and the MISTIE III trial (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3). We included subjects with a magnetic resonance imaging scan. The exposure was a DWI lesion. The primary outcome was any stroke, defined as a composite of ischemic stroke or recurrent ICH, whereas secondary outcomes were incident ischemic stroke and recurrent ICH. Using multivariate Cox regression analysis, we evaluated the risk of stroke. RESULTS: Of 505 patients with ICH with magnetic resonance imaging, 466 were included. DWI lesions were noted in 214 (45.9%) subjects, and 34 incident strokes (20 ischemic stroke and 14 recurrent ICH) were observed during a median follow-up of 324 days (interquartile range, 91-374). Presence of a DWI lesion was associated with a 6.9% (95% CI, 2.2-11.6) absolute increase in risk of all stroke (hazard ratio, 2.6 [95% CI, 1.2-5.7]). Covariate adjustment with Cox regression models also demonstrated this increased risk. In the secondary analyses, there was an increased risk of ischemic stroke (hazard ratio, 3.5 [95% CI, 1.1-11.0]) but not recurrent ICH (hazard ratio, 1.7 [95% CI, 0.6-5.1]). CONCLUSIONS: In a heterogeneous cohort of patients with ICH, presence of a DWI lesion was associated with a 2.5-fold heightened risk of stroke among ICH survivors. This elevated risk persisted for ischemic stroke but not for recurrent ICH.

A Pooled Analysis of Diffusion-Weighted Imaging Lesions in Patients With Acute Intracerebral Hemorrhage.

Importance: The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. Objective: To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes. Design, Setting, and Participants: This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019. Main Outcomes and Measures: The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed. Results: After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10-mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH. Conclusions and Relevance: In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.