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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 (β -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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) procedure was recently tested in a large phase III randomized trial showing a significant probability of functional benefit in those cases that reached the goal hematoma evacuation of ≤15 mL residual (or ≥70% removal). Benefit of thrombolysis was also identified in cases with large intraventricular hemorrhage, and achieving at least 85% volume reduction in the Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial., Objective: To protocolize steps in the MISTIE and CLEAR procedures in order to maximize hematoma evacuation and minimize complications., Methods: We articulate data-driven lessons and expert opinions surrounding the factors of patient selection, catheter placement, and dosing, which impacted safety and surgical performance in the MISTIE and CLEAR trials., Results: Modifiable factors to maximize evacuation efficiency include optimizing catheter placement and pursuing aggressive dosing to achieve treatment goals, while strictly adhering to the safety steps as articulated in the respective trials. Prognostic factors that are viewed as nonmodifiable include greater initial intracerebral hemorrhage volume with irregular shape, smaller intraventricular bleeds, and the uncommon but consequential development of new bleeding during the dosing period despite strict protocol adherence., Conclusions: Surgeon education in this tutorial is aimed at maximizing the benefit of the MISTIE and CLEAR procedures by reviewing case selection, safety steps, treatment objectives, and technical nuances. Key lessons include stability imaging, etiology screening, and technical adherence to the protocol in order to achieve defined thresholds of evacuation., (Copyright © 2020 by the Congress of Neurological Surgeons.)

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  < 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  < 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.

Background: Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr)., Objective: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes., Methods: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial., Results: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation., Conclusion: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Background: As intraventricular thrombolysis for intraventricular hemorrhage (IVH) has developed over the last 2 decades, hemorrhagic complications have remained a concern despite general validation of its safety in controlled trials in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-IVH) program., Objective: To analyze factors associated with symptomatic bleeding following IVH with and without thrombolysis in conjunction with the recently completed CLEAR III trial., Methods: We reviewed safety reports on symptomatic bleeding events reported during the first year after randomization among subjects enrolled in the CLEAR III trial. Clinical and imaging data were retrieved through the trial database as part of ongoing quality and safety monitoring. A posthoc root-cause analysis was performed to identify potential factors predisposing to rebleeding in each case. Cases were classified according to onset of rebleeding (during dosing, early after dosing and delayed), the pattern of bleeding, and treatment rendered (alteplase vs saline)., Results: Twenty subjects developed a secondary symptomatic intracranial hemorrhage constituting 4% of subjects. Symptomatic rebleeding events occurred during the dosing protocol (n = 9, 67% alteplase), early after the protocol (n = 5, 40% alteplase), and late (n = 6, 0% alteplase). Catheter-related hemorrhages were the most common (n = 7, 35%) followed by expansion or new intraventricular (n = 6, 30%) and intracerebral (n = 5, 25%) hemorrhages. Symptomatic hemorrhages during therapy resulted from a combination of treatment- and patient-related factors and were at most partially attributable to alteplase. Rebleeding after the dosing protocol primarily reflected patients' risk factors., Conclusion: Intraventricular thrombolysis marginally increases the overall risk of symptomatic hemorrhagic complications after IVH, and only during the treatment phase.

Background Intraventricular hemorrhage is a significant cause of mortality and morbidity worldwide. Treating intraventricular hemorrhage with intraventricular fibrinolytic therapy via a catheter is becoming an increasingly utilized intervention. Aims This meta-analysis aimed to investigate the role of intraventricular fibrinolytic treatment in hypertensive intraventricular hemorrhage patients and evaluate the effect sizes for survival as well as level of function at differing time points. Summary of review PubMed, CNKI, VIP, and Wanfang were searched using the terms "IVH" and "IVH and ICH" for human studies with adult patients published between January 1950 and July 2016. Seventeen publications were selected. Data analysis showed lower rates of mortality in the treatment group at 30 days ( P < 0.001), 180 days ( P = 0.001), 365 days ( P = 0.40), and overall ( P < 0.001). Pooling modified Rankin Scale and Glasgow outcome scale data, the treatment group had more good functional outcomes at 30 days ( P = 0.38), 90 days ( P = 0.04), 180 days ( P = 0.31), 365 days ( P = 0.76), and overall ( P = 0.02). Good functional outcome was defined as modified Rankin Scale score of 0 to 3 or a Glasgow outcome scale score of 3 to 5. Conclusions Intraventricular fibrinolytic for treatment of hypertensive intraventricular hemorrhage reduces mortality and potentially leads to an increased number of good functional outcomes. Different functional outcome scales (modified Rankin Scale or Glasgow outcome scale) produce different effect sizes. Intraventricular fibrinolytic treatment may offer intraventricular hemorrhage patients a targeted therapy that produces meaningful mortality benefit and possible functional outcome benefits.

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., Funding: National Institute of Neurological Disorders and Stroke., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage., Methods: MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770., Findings: Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051)., Interpretation: MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage., Funding: National Institute of Neurological Disorders and Stroke, Genentech, and Codman., Competing Interests: Declaration of Interests. IA, DFH, SWM, NU, KL, NMc, WAM, MR (R01NS046309 and U01NS062851), CBT, and PV report grants from the National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. DFH reports non-financial support from Genentech and Johnson& Johnson (Codman) during the conduct of the study, grants from NINDS outside the submitted work, and expert testimony. SWM reports personal fees from Johns Hopkins University outside the submitted work. JM reports grants from the National Institutes of Health during the conduct of the study and has a patent (C13388—primary intracerebral haemorrhage prediction employing logistic regression and features extracted from CT) pending for Johns Hopkins. ADM reports grants from the National Institutes of Health during the conduct of the study, non-financial support as the Director of the Newcastle Neurosurgery Foundation, and personal fees from Advisor to Stryker and Draeger outside the submitted work. BG reports grants from Johns Hopkins University (MISTIE National Institutes of Health grant) during the conduct of the study and grants from the National Institutes of Health Research (UK) Health Technology Assessment Programme outside the submitted work. All other authors declare no competing interests., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Retrospective series report varied rates of bleeding and infection with external ventricular drainage (EVD). There have been no prospective studies of these risks with systematic surveillance, threshold definitions, or independent adjudication., Objective: To analyze the rate of complications in the ongoing Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) trial, providing a comparison with a systematic review of complications of EVD in the literature., Methods: Patients were prospectively enrolled in the CLEAR III trial after placement of an EVD for obstructive intraventricular hemorrhage and randomized to receive recombinant tissue-type plasminogen activator or placebo. We counted any detected new hemorrhage (catheter tract hemorrhage or any other distant hemorrhage) on computed tomography scan within 30 days from the randomization. Meta-analysis of published series of EVD placement was compiled with STATA software., Results: Growing or unstable hemorrhage was reported as a cause of exclusion from the trial in 74 of 5707 cases (1.3%) screened for CLEAR III. The first 250 patients enrolled have completed adjudication of adverse events. Forty-two subjects (16.8%) experienced ≥1 new bleeds or expansions, and 6 of 250 subjects (2.4%) suffered symptomatic hemorrhages. Eleven cases (4.4%) had culture-proven bacterial meningitis or ventriculitis., Conclusion: Risks of bleeding and infection in the ongoing CLEAR III trial are comparable to those previously reported in EVD case series. In the present study, rates of new bleeds and bacterial meningitis/ventriculitis are very low despite multiple daily injections, blood in the ventricles, the use of thrombolysis in half the cases, and generalization to >60 trial sites.

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.