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.

Abstract P447: Intracranial Pressure and Cerebral Perfusion Pressure Monitoring in Spontaneous Intracranial Hemorrhage: A Secondary Analysis of the Mistie III Trial

Introduction: Intracerebral hemorrhage (ICH) management guidelines recommend maintaining intracranial pressure (ICP) &lt;20 and cerebral perfusion pressure (CPP) between 50-70 mmHg. We did subgroup analyses of MISTIE III trial to explore whether minimally invasive surgery (MIS) improves ICP or CPP and whether thresholds are associated with long term outcomes. Methods: MISTIE III was a randomized clinical trial including 499 patients with spontaneous ICH randomized to MIS+Alteplase or standard medical care (SMC). Primary outcomes were any threshold event of ICP &gt;20 and CPP &lt;60/70 mmHg. Secondary outcomes were poor modified Rankin Scale at one year and mortality at 30/365 days. We used multivariable models to investigate factors associated with ICP/CPP events and outcomes. Results: Of 72 patients with ICP monitored for median 92 (72-96) hours, 31 (43.1%) had at least one ICP reading &gt;20 and 52/35 (72.2/34.7%) had at least one CPP reading &lt;70/60 mmHg. Lower intraventricular hemorrhage volume and SMC group were associated with having any ICP threshold event &gt;20 and CPP event &lt;70 mmHg whereas CPP&lt;60 mmHg was associated with end of treatment (EOT) ICH volume, hydrocephalus on diagnostic CT and no prior antiplatelet agent use. On adjusted analyses, percentage of ICP readings &gt;20 were significantly less likely in patients undergoing MIS vs SMC (Coefficient -0.79, 95% Confidence Interval [CI] [(-)1.46-(-)0.11]; p=0.02). Percentage of CPP readings &lt;70 were significantly less frequent in MIS group (Coefficient -1.59 [(-)2.58-(-)0.59]; p=0.002). Patients who underwent successful MIS with EOT ICH volume &lt;15mL also had significantly lower percentage of readings at ICP&lt;20 (p=0.02), and CPP&lt;70 (p=0.05). Lower percentage of CPP readings &lt;60 mmHg was independently associated with lower mortality at 30 and 365 days (p=0.02 and 0.04) and CPP &lt;70 was associated with lower one-year mortality (p=0.04). There were no significant associations with one-year functional outcome. Conclusion: Elevated ICP and inadequate CPP are not infrequent during ICP monitoring for large ICH. Burden of low CPP events predict higher short and long term mortality, but not functional outcomes. CPP may be more significant than ICP. MIS appears to mitigate ICP and CPP threshold events. </jats:p

Screening and Identification of Lactic Acid Bacteria with D-tagatose Production Capability

Aims: D-tagatose is a natural ketohexose which can be used as a functional sweetener in foods, diary and beverages products. Isolation of new bacterial strains having the ability to produce D-tagatose is a continuously trending topic of research.&#x0D; Study Design: Screening of strains with D-tagatose production by identification and determination of its ability to produce D-tagatose content.&#x0D; Place and Duration of Study: School of Food and Biological Engineering, Jiangsu University between May 2018 and April 2019.&#x0D; Methodology: We initially screened and identified the strains capable of producing D-tagatose through kimchi liquid, and determined the species and genetic characteristics of the strain by physiological, biochemical and molecular biological identification, and then determined the content of D-tagatose by high performance liquid chromatography. Finally calculate the ability of the strain to produce D-tagatose.&#x0D; Results: In this study, 4 strains of lactic acid bacteria (LAB) were isolated from kimchi sample. The isolates were identified as Lactobacillus spp. (Lactobacillus plantarum, Lactobacillus fermentum and Lactobacillus salivarius) on the basis of morphological, physicochemical characteristics and analysis of 16S rDNA gene sequence. Because of the novelty, strain designated as L. salivarius UJS 003 was considered for D-tagatose yield. Fermentation of D-tagatose was carried out using galactose as substrate for 48 hr at 37 °C, and HPLC method was used to determine the yield. The experimental results exhibited a D-tagatose yield of 3.134 g/L by L. salivarius UJS 003.&#x0D; Conclusion: The strain UJS 003 represented as a potent D-tagatose producer and could be             useful in a variety of biotechnological and industrial processes, particularly food and beverage industries.</jats:p

Abstract 12: An Evaluation of Functional Outcome at 1 Year of Poor Prognosis Patients in Mistie-III

Introduction: Clinical factors impacting prognosis following Intracerebral Hemorrhage (ICH) have been well described in the literature, with “poor” prognosis often leading to withdrawing life sustaining treatments (WoLST). The MISTIE-III trial data provides an opportunity to review 12 month outcome of “poor" prognosis subjects. Methods: In order to evaluate functional recovery of ICH survivors compared with patients who had WoLST we used a severity index (SI) score for predicting good functional recovery 1 year following ICH. The SI used 6 clinical univariate variables from the MISTIE-III analysis (age &gt; 67, Glasgow Coma Score [GCS] &lt; 8, deep ICH location, stability ICH volume &gt; 45mL, stability intraventricular hemorrhage (IVH) volume&gt;0.4mL) and &gt; 3 comorbidities (hypertension, hyperlipidemia, cardiovascular disease, and end-stage renal disease). Based on the SI scores for subjects who had WoLST, a matched cohort of survivors with “poor" prognosis (mRS 4-5) were tracked for functional recovery for 12 months. Results: Of the participants enrolled in MSITIE-III, 61 had WoLST. Of the non-WoLST ICH survivors, 16 progressed to death during the acute period. Another 48 had died prior to the 1 year (D365) follow up. At the 30 Day (D30) evaluation, there were 263 ICH survivors with “poor" prognosis SI scores having a mRS of 4 or 5 and 94% were still in a treatment facility. By D365, 47% of the “poor prognosis” patients had improved to mRS 0-3 (good outcome) with 98% living at home. Of the remaining, 36% had a mRS of 4 (moderately severe disability) with 64% living at home, and 17% had a mRS of 5 (severe disability) with 31% living at home. Conclusion: For family members of patients sustaining an ICH where clinical factors indicate a “poor" prognosis, the decision to continue or withdraw life sustaining treatment is difficult. Our data shows that ICH patients with clinical factors that are assumed to indicate “poor" prognosis for recovery can, when given time, achieve a favorable outcome. </jats:p

Abstract 76: Non-Contrast CT Markers and Pre- and Post-Surgical Hematoma Expansion in the MISTIE III Trial Surgical Cohort

Introduction: A range of findings on non-contrast CT (NCCT) have been found to predict hematoma expansion after spontaneous ICH, but it is unclear whether these findings predict peri-procedural bleeding. We explored whether any specific NCCT marker(s) predict pre- or post-surgical hematoma expansion events. Methods: NCCTs were reviewed for presence of black hole sign, blend sign, swirl sign, and island sign in the surgical cohort from the MISTIE-III trial which evaluated minimally invasive surgery plus alteplase in ICH &gt;30 mL. Hematoma expansion was defined as any expansion ≥6 mL or 33% ICH volume increase during pre-surgical period (Model 1) from diagnostic CT (DiagCT) to 24 hours post DiagCT and from stability CT (StabCT) to 24 hours post last dose of alteplase (Model 2). Blend sign was removed from analysis due to small sample size. Multivariable logistic regression analysis was performed to identify independent predictors of pre-op and post-op hematoma expansion. Results: Of 250 surgical subjects, 5 were excluded due to poor image quality. Expansion events occurred in 82 of 234 (35.0%) subjects in the pre-op interval and in 15 of 226 (7%) in the post-op interval. None of the markers were significant for pre-op expansion, but ICH volume and time from ictus to DiagCT were statistically significant predictors. Swirl sign, ICH volume, and posterior trajectory compared to lateral trajectory were independent predictors of post-op expansion events. Expansion volume pre-op and post-op were weakly associated with presence of swirl sign; Spearmans rho=0.3 p=0.065 and rho=0.60 p=0.047, respectively. Conclusion: This is the first analysis of impact of NCCT markers on re-bleeding post minimally invasive surgery from a large clinical trial. Despite an absence of association between NCCT markers and hematoma expansion in the pre-surgical period perhaps reflecting inclusion criteria for hemorrhage stability, swirl sign was associated with post-surgical rebleeding. </jats:p

Abstract TP131: Association Of Hemoglobin Over The First Week With Clinical Outcomes And Neuroimaging Characteristics In Patients With Spontaneous Intracerebral Hemorrhage

Introduction: Studies have shown independent associations of lower admission hemoglobin (HB) levels with larger spontaneous intracerebral hemorrhage (ICH) volumes and poor outcomes, possibly mediated by hematoma expansion (HE). Objective: We retrospectively investigated the association of HB levels over the first week post ICH with functional outcomes (FO) and neuroimaging findings in patients with spontaneous ICH (&gt;30 mL). We explored whether comorbidities modify the effects of HB. Methods: We analyzed HB levels from subjects enrolled in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial (MISTIE III). The exposure was admission HB and the HB nadir in the first week. The primary outcome was good FO at 180 days, defined as modified Rankin Scale of 0-3. Secondary outcomes were good FO at 365 days, 30-day mortality, admission ICH volume, and HE (&gt;6 mL). Linear and logistic regression models were used to test the association of HB with clinical outcomes and neuroimaging findings. All models were adjusted for age, sex, race, treatment (medical Vs. MISTIE), Glasgow Coma Scale, ICH volume, presence of intraventricular hemorrhage, and ICH location (deep Vs. lobar). We investigated effect modification of comorbidities on association of HB with FO. Results: A total of 493 of 499 enrolled patients (61% males, mean age 61(SD=12) years, median ICH volume 41.8 (IQR=30.8-51.5) mL) were included. Patients with good FO at 180 days had a higher admission HB (13.2 Vs. 12.6 g/dl, p=0.001) and a higher nadir HB (11.7 Vs. 10.9 g/dl, p&lt;0.001). In adjusted analyses, each additional g/dl in nadir HB (but not admission HB) was associated with higher odds of good FO at 180 (OR 1.29, p=0.005) and 365 (OR 1.18, P=0.048) days. Baseline (B= -1.16, p=0.02) and nadir HB (B= -1.71, p=0.001) were inversely associated with hematoma volumes, but not with HE. There was evidence of heterogeneity in the effects of diabetes on the association of nadir HB with day 180 FO (OR 0.67; p interaction = 0.045). Conclusions: In patients with ICH &gt; 30 mL, higher nadir HB in the first week was associated with better long-term FO and smaller ICH volumes, but not with HE. Early hemoglobin changes may serve as a prognostic biomarker and a potentially modifiable factor to improve FO. </jats:p

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

Abstract 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. </jats:sec

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 &amp;lt;70 and 60 mm Hg. Secondary outcomes included major disability (modified Rankin scale &amp;gt;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/ &amp;lt;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 &amp;lt;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 &amp;lt;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 &amp;lt;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.</jats:p

Abstract 17: An Evaluation of Patient Disposition and Long-term Health-related Quality of Life In MISTIE III: Opportunities to Improve Decision Making for Critically Ill Intracerebral Hemorrhage Patients

Introduction: Recovery in intracerebral hemorrhage (ICH) is prolonged and unpredictable, resulting in challenges in estimating health-related quality of life (HRQoL). We describe HRQoL and patient disposition for ICH survivors with similar clinical characteristics to ICH patients who had withdrawal of life-sustaining treatment (WoLST). Methods: Using MISTIE III trial data (N = 499), we performed a matched cohort analysis using a published modified severity index (mSI) to compare ICH survivors (N = 379) with WoLST patients (N = 61). We used multivariable logistic regression adjusting for age, Glasgow Coma Score, deep ICH location, stability ICH and intraventricular hemorrhage volume and ≥ 3 comorbidities to create the mSI. After matching survivors with equal mSI to WoLST patients, we compared EuroQoL (EQ) visual analog scale (VAS) scores (US norm 69-76; range 0-100) by mSI quartile and patient disposition. Results: We matched 224 survivors to WoLST patients by mSI (range 0-6.5), with data at all timepoints. Given the large mSI range, EQ VAS scores and patient disposition were evaluated by mSI quartile groups. The median (interquartile range [IQR]) EQ VAS score increase for all mSI groups from day 30 (D30) to 180 (D180) was 20 (0-35.5, p &lt; 0.0001), and 23.5 (5-40, p &lt; 0.0001) for D30 to 365 (D365). The highest percentage of survivors for all mSI groups were home by D365 (G1 55%, G2 88%, G3 84.5%, G4 90%). Median (IQR) EQ VAS scores by mSI quartile, patient disposition and timepoint are reported below. Conclusion: ICH survivors, matching WoLST individuals, in all mSI groups demonstrated improvement in HRQoL over time, and the majority were home by D365. This study challenges current practice of identifying poor outcomes in concert with decision making employing WoLST in ICH. If goals of care are to include return to home and HRQoL, these results strongly suggest that prognostication can be improved. Prospective studies of ICH prognostication and decision making are needed. </jats:p

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 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.</p