Oedema extension distance in intracerebral haemorrhage: Association with baseline characteristics and long-term outcome

Introduction: Oedema extension distance is a derived parameter that may reduce sample size requirements to demonstrate reduction in perihaematomal oedema in early phase acute intracerebral haemorrhage trials. We aimed to identify baseline predictors of oedema extension distance and its association with clinical outcomes. Patients and methods: Using Virtual International Stroke Trials Archive-Intracerebral Haemorrhage, first Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial, and Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation II datasets, we calculated oedema extension distance at baseline and at 72 h measured using computed tomography. Using linear regression, we tested for associations between baseline characteristics and oedema extension distance at 72 h. Ordinal regression (underlying assumptions validated) was used to test for associations between oedema extension distance at baseline and 72 h and oedema extension distance change between baseline and 72 h, and modified Rankin scale scores at 90 days, adjusted for baseline and 72 h prognostic factors. Results: There were 1028 intracerebral haemorrhage cases with outcome data for analyses. Mean (standard deviation, SD) oedema extension distance at 72 h was 0.54 (0.26) cm, and mean oedema extension distance difference from baseline (EED72–0) was 0.24 (0.18) cm. Oedema extension distance at 72 h was greater with increasing baseline haematoma volume and baseline oedema extension distance. Increasing age, lobar haemorrhage, and intraventricular haemorrhage were independently associated with EED72–0. In multifactorial ordinal regression analysis, EED72–0 was associated with worse modified Rankin scale scores at 90 days (odds ratio 1.96, 95% confidence interval 1.00–3.82). Discussion: Increase in oedema extension distance over 72 h is independently associated with decreasing functional outcome at 90 days. Oedema extension distance may be a useful surrogate outcome measure in early phase trials of anti-oedema or anti-inflammatory treatments in intracerebral haemorrhage

Early inflammatory cytokine expression in cerebrospinal fluid of patients with spontaneous intraventricular hemorrhage

We investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8–48.8] and 14.3 [5.3–38] mL respectively. Mean levels of IL-1β, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9–10 (p < 0.05) and decreased across subsequent time periods. Levels of IL-1β, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3–8 whereas positive correlations with ICH volume occurred earlier at day 1–2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1–2 and with relative PHE at days 7–8 or 9–10 for IL-1β, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage

From MDPI via Jisc Publications RouterHistory: accepted 2021-07-13, pub-electronic 2021-07-30Publication status: PublishedWe investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8–48.8] and 14.3 [5.3–38] mL respectively. Mean levels of IL-1β, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9–10 (p 0.05) and decreased across subsequent time periods. Levels of IL-1β, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3–8 whereas positive correlations with ICH volume occurred earlier at day 1–2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1–2 and with relative PHE at days 7–8 or 9–10 for IL-1β, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial

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

Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage

We investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8–48.8] and 14.3 [5.3–38] mL respectively. Mean levels of IL-1β, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9–10 (p &lt; 0.05) and decreased across subsequent time periods. Levels of IL-1β, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3–8 whereas positive correlations with ICH volume occurred earlier at day 1–2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1–2 and with relative PHE at days 7–8 or 9–10 for IL-1β, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction