Abstract T P322: Risk Factors for Vascular Lesions as Etiology of Intraventricular Hemorrhage in Prospectively Screened Cases

Introduction: Previous studies have used inconsistent screening thresholds and modalities for detecting vascular lesions as the cause of intraventricular hemorrhage (IVH). We aimed to characterize demographic and ethnicity risks of harboring vascular lesions in a cohort of prospectively identified IVH cases with systematic screening for underlying vascular etiology. Methods: Patients with IVH were identified from the database of Clot Lysis: Evaluation Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) clinical trial. It included patients age 18-80 years with obstructive IVH with or without associated intracerebral hemorrhage (ICH) less than 30 ml in volume. This cohort study compared 447 patients enrolled in CLEAR, who were screened negative for underlying vascular lesion (no lesion), and 1276 patients with IVH concurrently screened and excluded from CLEAR because of underlying lesion (vascular lesion). Results: Mean age was lower in patients with vascular lesion (55 vs. 59; p&lt;.001), with a greater difference in patients with vascular malformations (47 versus 58, p&lt;.001) and Moyamoya disease (45 versus 58, p&lt;.001), and there was no difference in age of patients with aneurysms versus no lesion (mean age 59 in both groups). Male prevalence was lower (lesion: 42%, no lesion: 55%; p&lt;.001), with a higher prevalence in those with vascular malformations than those with aneurysm (56% versus 35%, p&lt;.001) and Moyamoya disease (56% versus 39%, p=0.074). The prevalence of Whites was higher (lesion: 60%, no lesion: 51%; p&lt;.001) and that of African-Americans lower (lesion: 11%, no lesion: 33%; p&lt;.001). The prevalence of patients with primary IVH as opposed to IVH with intracerebral hemorrhage (ICH) was higher among patients with lesions (lesion: 21%, no lesion: 15%; p=.003). Conclusion: IVH patients with an underlying vascular lesion tend to be significantly younger, more likely female, White, and harbor primary IVH. The younger age is attributed to vascular malformations or Moyamoya disease, rather than aneurysm. Patients with lesion may have exhibited other characteristic features of hemorrhage not addressed in this study. </jats:p

Abstract T P316: Occurrence of Intracranial Hypertension in the First 400 Patients Enrolled in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Trial (CLEAR III)

Background: Elevated intracranial pressure (ICP) is one proposed mechanism leading to poor outcomes in patients with spontaneous intraventricular hemorrhage (IVH). We characterized occurrence and significance of intracranial hypertension in severe IVH requiring extraventricular drainage (EVD). Methods: Prospective analysis of ICP in the first 400 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing EVD plus intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD plus placebo for treatment of IVH in patients with obstructive IVH and intracerebral hemorrhage (ICH) volume &lt;30cc. Maximum and minimum ICP was recorded every 4 hours in all patients until 7 days post randomization. ICP readings were analyzed at pre-defined thresholds and proportion of high ICP events compared by clinical/radiological variables. Impact on 30 day mortality was assessed. Results: of 17,593 ICP readings, maximum ICP ranged from -4 to 115 mm Hg (median, interquartile range; 11,8); 90.2% (15,861) were ≤ 20 mm Hg, 2.0% were &gt;30, 0.5% were &gt;40, and 0.2% were &gt; 50 mm Hg. Proportion of threshold events &gt; 20 and &gt; 30 mm Hg were more frequent in patients with persistent closure of the lower ventricular system after day 3 (p=0.047 and p=0.04, respectively), but were not correlated with initial or end of treatment (72 hours after last dose of study agent) ICH or IVH volumes. ICP elevation &gt; 20 mm Hg occurred during a required 1 hr EVD closure time after study agent injection in 507/3364 (15.1%) injections although early re-opening of EVDs occurred in only 3.9%. Shunting for hydrocephalus was required in 18% of patients over 1 yr follow-up and was not associated with high ICP events. Percentage of ICP readings per patient &gt; 30 mmHg and ICH/IVH volumes were independent predictors of 30 day mortality after adjustment for other outcome predictors (p=0.01; p=0.04; p&lt;0.001, respectively). Conclusions: ICP is not frequently elevated during monitoring and drainage with an EVD in patients with severe IVH. ICP &gt; 30 mm Hg predicts higher short-term mortality. Early opening of the lower ventricular system may reduce frequency of high ICP events. Injection of thrombolytics can be performed without additional ICP management in the majority of patients. </jats:p

Abstract WMP86: Evaluation of Cerebrospinal Fluid Dynamics and External Ventricular Drain Management in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial (CLEAR III)

Background: Acute obstructive hydrocephalus secondary to spontaneous intracerebral/intraventricular hemorrhage (ICH/IVH) requires early cerebrospinal fluid (CSF) drainage to reduce intracranial pressure (ICP). Extensive CSF drainage may reduce IVH clot burden. We characterize CSF dynamics, strategies and impact on end of treatment (EOT) IVH volume (72 hours post randomization [Rand]) in the CLEAR III trial. Methods: Prospective analysis of CSF output in all 500 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing EVD + intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD + placebo for treatment of obstructive IVH and intracerebral hemorrhage (ICH) volume &lt;30cc. CSF output was recorded every 4 hours until 7 days post Rand, and compared by clinical and radiological variables. Results: Daily median CSF output in the first week was 188cc (IQR: 125, 252). Maximum daily EVD drip settings were &lt;10mmHg in 27.8%, =10 in 44.1% and &gt;10 in 28.1%. Independent predictors of higher daily CSF output after adjustment for initial IVH volume (p=0.04) were lower drip setting (p&lt;0.001), lower age (p&lt;0.001), male sex (p=0.03), dual EVD (p=0.005), CSF protein (p&lt;0.001) and ICP&gt;20mmHg (P=0.007). Both EOT IVH volume and change in IVH volume (ChgIVH) (over 1 st week) were independently associated with total CSF output (P=0.004/&lt;0.001, respectively), and initial IVH volume (P&lt;0.001/&lt;0.001)). Early opening of 3 rd and 4 th ventricle (P=0.03) was associated with lower EOT volumes, while CSF protein (P=0.02), and side of EVD ipsilateral to largest IVH (P=0.04) were associated with ChgIVH. Shunting for hydrocephalus was performed in 18.6% over 1 year follow-up and was associated with higher total CSF output over first week (P&lt;0.001). Conclusions: CSF circulation in severe IVH can be assessed by CSF output which is associated with EVD drip management and other clinical variables. EOT IVH volume and IVH volume reduction are important surrogate endpoints which are related to CSF dynamics. VP shunt requirement in spontaneous IVH is associated with early CSF output levels. These results permit future correlation of CSF output with treatment rendered (thrombolysis versus placebo) with upcoming unblinding of the trial. </jats:p

Primary intraventricular hemorrhage outcomes in the CLEAR III trial

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

Abstract 217: Venous Thromboembolism in Patients With Spontaneous Intraventricular Hemorrhage- Results From the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III Trial

Introduction: Intraventricular hemorrhage (IVH) occurs in about 40% of patients with intracerebral hemorrhage (ICH) and is associated with higher mortality and worse outcomes than ICH patients without IVH. Venous thromboembolism (VTE) is common in ICH patients but data in IVH patients are limited. Methods: Prospective analysis of adjudicated adverse event reporting of VTE (deep venous thrombosis (DVT) and pulmonary embolism (PE)) during first 180 days in 500 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing external ventricular drain (EVD) + intraventricular recombinant tissue plasminogen activator (rtPA) vs EVD + placebo for treatment of obstructive IVH and intracerebral hemorrhage (ICH) volume &lt;30cc. Outcome measures were 90-day and 180-day mortality, ICU and hospital length of stay (LOS), catheter tract hemorrhage as well as predictors of VTE. Results: VTE was reported in 63 patients (13%); 46 (9%), 11 (2%) and 6 (1%) patients had DVT, PE or both, respectively. VTE occurred between 4 and 209 days from ICH onset. VTE pharmacologic prophylaxis was initiated in 404 (81%) patients, at median of 4 days [range:1-48] from ICH onset. Unfractionated and low molecular weight heparin were used in 71% and 29% patients, respectively. These patients had similar rates of VTE but showed a trend towards higher catheter tract hemorrhages (25 vs 15%, p=0.056) as compared to those who did not receive VTE prophylaxis. Patients who developed VTE had similar 90-d and 180-d mortality and ICU LOS but had prolonged hospital LOS (p=0.012) as compared to those who did not develop VTE. On multivariable analysis, ICH volume was a significant predictor of development of VTE (OR 1.04, 95% CI: 1.01-1.07, p=0.024). Conclusions: The association of IVH with VTE is important but complex, in spite of consideration of early VTE prophylaxis. There was trend towards higher catheter tract hemorrhages in patients receiving VTE prophylaxis. ICH volume was a significant predictor of VTE development. However, mortality and ICU LOS were not affected by VTE development. These results form a basis for future correlation of VTE complications with treatment rendered (thrombolysis versus placebo), with upcoming unblinding of the trial. </jats:p

Abstract TP376: Infections in Patients With Spontaneous Intraventricular Hemorrhage- Results From the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III Trial

Introduction: Intraventricular hemorrhage (IVH) occurs in about 40% of patients with intracerebral hemorrhage (ICH) and is associated with higher mortality and worse outcomes than ICH patients without IVH. Infections are common in ICH patients but data in IVH patients are limited. Methods: Prospective analysis of adjudicated adverse event infection reporting during first 180 days in 500 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing external ventricular drain (EVD) + intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD + placebo for treatment of obstructive IVH and intracerebral hemorrhage (ICH) volume &lt;30cc. Primary outcome measures were 90-day and 180-day mortality. Secondary outcome measures were hospital length of stay (LOS). We constructed binary logistic and linear regression models for multivariable analysis. Results: Infection was reported in 269 patients (53.8%). Pneumonia was the most common infection (33%), followed by UTI (16%), and bacterial ventriculitis (4.4%). Overall 180-day mortality was 20%. Patients with infection were more likely to have older age (p=0.012), lower admission GCS (p=0.007), higher ICH volume (8.8 vs 6.7ml, p=0.001), and higher ICH+IVH volume (37.7 vs 31.7 ml, p=0.002). In the regression model, IVH volume was associated with higher odds of 90-day or 180-day mortality, but presence of any infection was not a significant predictor of mortality. Infection was however associated with longer length of stay (26 vs 22 days, p&lt;0.001). Subgroup analysis of individual infections, showed only bacterial ventriculitis to be associated with 90-day (OR: 3.84, CI: 1.36-10.82), and 180-day mortality (OR: 2.9, CI: 1.05-8.06), while pneumonia and UTI were not. Conclusion: Patients with IVH have a high incidence of infections, which is associated with longer hospitalization but does not appear to influence mortality. Of the infections, bacterial ventriculitis is a significant predictor of mortality in our 7-factor model. IVH volume did not predict infections but predicted mortality.These results form a basis for future correlation of infectious complications with treatment rendered (thrombolysis versus placebo), with upcoming unblinding of the trial. </jats:p

Abstract 148: Evaluation of Sex, Racial and Geographic Demographics and Outcomes in Clinical Trials of Spontaneous Intracerebral Hemorrhage

Introduction: As large clinical trials for spontaneous intracerebral hemorrhage (ICH) increasingly influence management, recruitment of diverse populations must be ensured to fully understand the disease process and benefit of interventions to the general public. There is little data on sex, race and outcomes in ICH trials. We hypothesize that women and geographic minorities are underrepresented in ICH clinical trials and that there exist population specific differences in mortality, functional outcomes and response to interventions. Methods: Pooled analysis of 5456 subjects from the following clinical trials: VISTA (985), INTERACT I (404) and II (2829), STICH II (597), MISTIE II (141) and CLEAR III (500). Patients were grouped by sex, race, and geographic location. Modified Rankin Scale [mRS] was obtained at 30 days and 3 months. Results: More men than women participated in ICH trials (61.9% vs. 38.1%); women were older and more likely to have hypertension; men had more coronary artery disease. Women presented with lower Glasgow Coma scale, higher ICH score and more intraventricular hemorrhage. Day 90 mortality was 13.9% in women and 16.6 % in men (p=0.01); 90 day poor outcome (mRS 3-5) was 57.2% in women and 51.0% in men (p&lt;0.001). Only mortality was significantly different between sexes after adjustment for ICH score. Race representation varied in these clinical trials: 1.5% Hispanic; 6.6% black; 14% Arabic; 31% white and 43.4% Asian. Day 90 mortality and mRS 3-5 were highest in Hispanics (22.1%, 78.3%, respectively) and lowest in Asians (9.5%, 43.8%). Hispanics had higher ICH score, but blacks and Hispanics had lower day 90 mortality compared to whites in adjusted models. Asians had both lower mortality and less day 90 mRS 3-5 vs. whites while Arabics and blacks were more likely to have day 90 mRS 3-5. Study interventions were well balanced by sex and race. Conclusions: Sex and race representation in ICH clinical trials only partially equate to current understanding of epidemiology of ICH. There is a lack of trial evidence from Africa and South America and under-representation of women, Hispanics and blacks. Despite higher ICH severity, Hispanics had lower adjusted mortality risk while males had higher risk and Arabics and blacks had worse adjusted poor outcomes. </jats:p