Thrombolysis for Evacuation of Intracerebral and Intraventricular Hemorrhage: A Guide to Surgical Protocols With Practical Lessons Learned From the MISTIE and CLEAR Trials.
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ABSTRACT: 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.
SUBMITTER: Polster SP
PROVIDER: S-EPMC7891242 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND: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. METHODS: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. FINDINGS: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). INTERPRETATION: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. FUNDING:National Institute of Neurological Disorders and Stroke and Genentech.
| S-EPMC6894906 | biostudies-literature
Project description:Background and purposeIntraventricular thrombolysis (IVT) is a promising treatment in facilitating intraventricular clot resolution after intraventricular hemorrhage. We examined in-hospital outcomes and resource utilization after thrombolysis in patients with intraventricular hemorrhage requiring ventriculostomy in a real-world setting.MethodsWe identified adult patients with primary diagnosis of nontraumatic intracerebral hemorrhage requiring ventriculostomy from the Nationwide Inpatient Sample from 2002 to 2011. We compared demographic and hospital characteristics, comorbidities, inpatient outcomes, and resource utilization measures between patients treated with IVT and those managed with ventriculostomy, but without IVT. Population estimates were extrapolated using standard Nationwide Inpatient Sample weighting algorithms.ResultsWe included 34 044 patients in the analysis, of whom 1133 (3.3%) received IVT. The thrombolysis group had significantly lower inpatient mortality (32.4% versus 41.6%; P=0.001) and it remained lower after controlling for baseline demographics, hospital characteristics, comorbidity, case severity, and withdrawal of care status (adjusted odds ratio, 0.670; 95% confidence interval, 0.520-0.865; P=0.002). There was a trend toward favorable discharge (home or rehabilitation) among the thrombolysis cohort (adjusted odds ratio, 1.335; 95% confidence interval, 0.983-1.812; P=0.064). The adjusted rates of bacterial meningitis and ventricular shunt placement were similar between groups. The thrombolysis group had longer length of stay and higher inflation-adjusted cost of care, but cost of care per day length of stay was similar to the non-IVT group.ConclusionsIVT for intracerebral hemorrhage requiring ventriculostomy resulted in lower inpatient mortality and a trend toward favorable discharge outcome with similar rates of inpatient complications compared with the non-IVT group.
| S-EPMC4525480 | biostudies-literature
Project description:Background and purposeThe ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography-based planimetry (CTP).MethodsIn Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression.ResultsIn 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots.ConclusionsABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.
| S-EPMC4550520 | biostudies-literature
Project description:BackgroundIntraventricular hemorrhage (IVH) is often caused by irruption of intracerebral hemorrhage (ICH) of basal ganglia or thalamus into the ventricular system. Instillation of recombinant tissue plasminogen activator (rtPA) via an external ventricular drainage (EVD) has been shown to effectively decrease IVH volumes while the impact of rtPA instillation on ICH volumes remains unclear. In this series, we analyzed volumetric changes of ICH in patients with and without intrathecal lysis therapy.MethodsBetween 01/2013 and 01/2019, 36 patients with IVH caused by hemorrhage of basal ganglia, thalamus or brain stem were treated with rtPA via an EVD (Group A). Initial volumes were determined in the first available computed tomography (CT) scan, final volumes in the last CT scan before discharge. During the same period, 41 patients with ICH without relevant IVH were treated without intrathecal lysis therapy at our neurocritical care unit (Group B). Serial CT scans were evaluated separately for changes in ICH volumes for both cohorts using OsiriX DICOM viewer. The Wilcoxon signed-rank test was performed for statistical analysis in not normally distributed variables.ResultsMedian initial volume of ICH for treatment Group A was 6.5 ml and was reduced to 5.0 ml after first instillation of rtPA (p < 0.01). Twenty-six patients received a second treatment with rtPA (ICH volume reduction 4.5 to 3.3 ml, p < 0.01) and of this cohort further 16 patients underwent a third treatment (ICH volume reduction 3.0 ml to 1.5 ml, p < 0.01). Comparison of first and last CT scan in Group A confirmed an overall median percentage reduction of 91.7% (n = 36, p < 0.01) of ICH volumes and hematoma resolution in Group A was significantly more effective compared to non-rtPA group, Group B (percentage reduction = 68%) independent of initial hematoma volume in the regression analysis (p = 0.07, mean 11.1, 95%CI 7.7-14.5). There were no adverse events in Group A related to rtPA instillation.ConclusionIntrathecal lysis therapy leads to a significant reduction in the intraparenchymal hematoma volume with faster clot resolution compared to the spontaneous hematoma resorption. Furthermore, intrathecal rtPA application had no adverse effect on ICH volume.
| S-EPMC8128818 | biostudies-literature
Project description:Background/objectiveIntracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials.MethodsIn ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0-4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint.ResultsOf 635 patients, 55% had WML grade 1-4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54-6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors.ConclusionsConcomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome.Clinical trial registrationhttp://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.
| S-EPMC7416541 | biostudies-literature
Project description:Non-invasive cross-sectional imaging techniques play a crucial role in the assessment of the varied manifestations of vascular disease. Vascular imaging encompasses a wide variety of pathology. Designing vascular imaging protocols can be challenging owing to the non-uniform velocity of blood in the aorta, differences in cardiac output between patients, and the effect of different disease states on blood flow. In this review, we provide the rationale behind-and a practical guide to-designing and implementing straightforward vascular computed tomography (CT) and magnetic resonance imaging (MRI) protocols.Teaching Points • There is a wide range of vascular pathologies requiring bespoke imaging protocols. • Variations in cardiac output and non-uniform blood velocity complicate vascular imaging. • Contrast media dose, injection rate and duration affect arterial enhancement in CTA. • Iterative CT reconstruction can improve image quality and reduce radiation dose. • MRA is of particular value when imaging small arteries and venous studies.
| S-EPMC5893493 | biostudies-literature
Project description: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.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.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).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.National Institute of Neurological Disorders and Stroke, Genentech, and Codman.
| S-EPMC5154627 | biostudies-literature
Project description:RATIONALE AND HYPOTHESIS:Surgical removal of spontaneous intracerebral hemorrhage may reduce secondary destruction of brain tissue. However, large surgical trials of craniotomy have not demonstrated definitive improvement in clinical outcomes. Minimally invasive surgery may limit surgical tissue injury, and recent evidence supports testing these approaches in large clinical trials. METHODS AND DESIGN:MISTIE III is an investigator-initiated multicenter, randomized, open-label phase 3 study investigating whether minimally invasive clot evacuation with thrombolysis improves functional outcomes at 365 days compared to conservative management. Patients with supratentorial intracerebral hemorrhage clot volume ??30 mL, confirmed by imaging within 24 h ofknown symptom onset,and intact brainstem reflexes were screened with a stability computed tomography scan at least 6 h after diagnostic scan. Patients who met clinical and imaging criteria (no ongoing coagulopathy; no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly; and stable hematoma size on consecutive scans) were randomized to either minimally invasive surgery plus thrombolysis or medical therapy. The sample size of 500 was based on findings of a phase 2 study. STUDY OUTCOMES:The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 365 days adjusting for severity variables. Clinical secondary outcomes include dichotomized extended Glasgow Outcome Scale and all-cause mortality at 365 days; rate and extent of parenchymal blood clot removal; patient disposition at 365 days; efficacy at 180 days; type and intensity of ICU management; and quality of life measures. Safety was assessed at 30 days and throughout the study.
| S-EPMC6706298 | biostudies-literature
Project description:BackgroundMinimally 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).ObjectiveTo assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes.MethodsUnivariate 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.ResultsGreater 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.ConclusionThis 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.
| S-EPMC6537634 | biostudies-literature
Project description:ObjectiveTo evaluate whether delayed appearance of intraventricular hemorrhage (dIVH) represents an independent entity from intraventricular hemorrhage (IVH) present on admission CT or is primarily related to the time interval between symptom onset and admission CT.MethodsA total of 282 spontaneous intracerebral hemorrhage (ICH) patients, admitted February 2009-March 2014 to the neurological intensive care unit of a tertiary care university hospital, were prospectively enrolled in the ICH Outcomes Project. Multivariate logistic regression was used to determine associations with acute mortality and functional long-term outcome (modified Rankin Scale).ResultsA cohort of 282 ICH patients was retrospectively studied: 151 (53.5%) had intraventricular hemorrhage on initial CT scan (iIVH). Of the remaining 131 patients, 19 (14.5%) developed IVH after the initial CT scan (dIVH). The median times from symptom onset to admission CT were 1.1, 6.0, and 7.4 hours for the dIVH, iIVH, and no IVH groups (Mann-Whitney U test, dIVH vs iIVH, p < 0.001) and median time from onset to dIVH detection was 7.2 hours. The increase in ICH volume following hospital admission was larger in dIVH than in iIVH and no IVH patients (mean 17.6, 0.2, and 0.4 mL). After controlling for components of the ICH score and hematoma expansion, presence of IVH on initial CT was associated with discharge mortality and poor outcome at 3, 6, and 12 months, but dIVH was not associated with any of the outcome measures.ConclusionsIn ICH patients, associated IVH on admission imaging is commonly encountered and is associated with poor long-term outcome. In contrast, dIVH on subsequent scans is far less common and does not appear to portend worse outcome.
| S-EPMC4352099 | biostudies-literature