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Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.

ABSTRACT: Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (?=0.23; 95% CI, 0.20-0.26; P<0.001). Treatment with intravenous glibenclamide was associated with reduced NWU (?=-2.80; 95% CI, -5.07 to -0.53; P=0.016) and reduced MLS (?=-1.50; 95% CI, -2.71 to -0.28; P=0.016). Treatment with intravenous glibenclamide reduced both gray and white matter water uptake. In mediation analysis, gray matter NWU (?=0.15; 95% CI, 0.11-0.20; P<0.001) contributed to a greater proportion of MLS mass effect, as compared with white matter NWU (?=0.08; 95% CI, 0.03-0.13; P=0.001). Conclusions- In this phase 2 post hoc analysis, intravenous glibenclamide reduced both water accumulation and mass effect after large hemispheric infarction. This study demonstrates NWU is a quantitative and modifiable biomarker of ischemic brain edema accumulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.

SUBMITTER: Vorasayan P

PROVIDER: S-EPMC6817419 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.

Vorasayan Pongpat P Bevers Matthew B MB Beslow Lauren A LA Sze Gordon G Molyneaux Bradley J BJ Hinson Holly E HE Simard J Marc JM von Kummer Rüdiger R Sheth Kevin N KN Kimberly W Taylor WT

Stroke 20190920 11

Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc ex ...[more]

PMID: 31537189

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Project description:Glyburide (also known as glibenclamide) is a second-generation sulfonylurea drug that inhibits sulfonylurea receptor 1 (Sur1) at nanomolar concentrations. Long used to target KATP (Sur1-Kir6.2) channels for the treatment of diabetes mellitus type 2, glyburide was recently repurposed to target Sur1-transient receptor potential melastatin 4 (Trpm4) channels in acute central nervous system injury. Discovered nearly two decades ago, SUR1-TRPM4 has emerged as a critical target in stroke, specifically in large hemispheric infarction, which is characterized by edema formation and life-threatening brain swelling. Following ischemia, SUR1-TRPM4 channels are transcriptionally upregulated in all cells of the neurovascular unit, including neurons, astrocytes, microglia, oligodendrocytes and microvascular endothelial cells. Work by several independent laboratories has linked SUR1-TRPM4 to edema formation, with blockade by glyburide reducing brain swelling and death in preclinical models. Recent work showed that, following ischemia, SUR1-TRPM4 co-assembles with aquaporin-4 to mediate cellular swelling of astrocytes, which contributes to brain swelling. Additionally, recent work linked SUR1-TRPM4 to secretion of matrix metalloproteinase-9 (MMP-9) induced by recombinant tissue plasminogen activator in activated brain endothelial cells, with blockade of SUR1-TRPM4 by glyburide reducing MMP-9 and hemorrhagic transformation in preclinical models with recombinant tissue plasminogen activator. The recently completed GAMES (Glyburide Advantage in Malignant Edema and Stroke) clinical trials on patients with large hemispheric infarctions treated with intravenous glyburide (RP-1127) revealed promising findings with regard to brain swelling (midline shift), MMP-9, functional outcomes and mortality. Here, we review key elements of the basic science, preclinical experiments and clinical studies, both retrospective and prospective, on glyburide in focal cerebral ischemia and stroke.

Project description:BACKGROUND AND PURPOSE:We aimed to determine whether subjects aged ?70 years who were treated with intravenous glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. METHODS:GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82-300 cm3) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ?70 years treated with intravenous glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood-brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift). RESULTS:Participants ?70 years of age treated with intravenous glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P=0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous glyburide-treated subjects at 90 days (odds ratio, 2.31; P=0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous glyburide on the Barthel Index (P=0.03) and EuroQol group 5-dimension (P=0.05). Participants treated with intravenous glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P<0.001) and decreased midline shift (4.7 versus 9 mm; P<0.001) compared with participants who received placebo. CONCLUSIONS:In this exploratory analysis, participants ?70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous glyburide. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.

Project description:Background: In general, disease severity has been found to be associated with abnormal chloride levels in critically ill patients, but hyperchloremia is associated with mixed results regarding patient-centered clinical outcomes. We aimed to investigate the impact of maximum serum chloride concentration on the clinical outcomes of critically ill patients with large hemispheric infarction (LHI). Methods: We conducted a retrospective observational cohort study using prospective institutional neurocritical care registry data from 2013 to 2018. Patients with LHIs involving over two-thirds of middle cerebral artery territory, with or without infarction of other vascular territories, and a baseline National Institutes of Health Stroke Scale score of ≥13 were assessed. Those with a baseline creatinine clearance of <15 mL/min and required neurocritical care for <72 h were excluded. Primary outcome was in-hospital mortality. Secondary outcomes included 3-month mortality and acute kidney injury (AKI) occurrence. Outcomes were compared to different maximum serum chloride levels (5 mmol/L increases) during the entire hospitalization period using multivariable logistic regression analyses. Results: Of 90 patients, 20 (22.2%) died in-hospital. Patients who died in-hospital had significantly higher maximum serum chloride levels than did those who survived up to hospital discharge (139.7 ± 8.1 vs. 119.1 ± 10.4 mmol/L; p < 0.001). After adjusting for age, sex, and Glasgow coma scale score, each 5-mmol/L increase in maximum serum chloride concentration was independently associated with an increased risk of in-hospital mortality (adjusted odds ratio (aOR), 4.34; 95% confidence interval [CI], 1.98-9.50; p < 0.001). Maximum serum chloride level was also an independent risk factor for 3-month mortality (aOR, 1.99 [per 5 mmol/L increase]; 95% CI, 1.42-2.79; p < 0.001) and AKI occurrence (aOR, 1.57 [per 5 mmol/L increase]; 95% CI, 1.18-2.08; p = 0.002). Conclusions: High maximum serum chloride concentrations were associated with poor clinical outcomes in critically ill patients with LHI. This study highlights the importance of monitoring serum chloride levels and avoiding hyperchloremia in this patient population.

Project description:Background: Hypothermia is used in the treatment of large hemispheric infarction (LHI); however, its role in outcomes for LHI patients remains ambiguous. This systematic review and meta-analysis was conducted to evaluate the effect of hypothermia on the outcomes of LHI patients. Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, China Biological Medicine Database, and clinical trials registers before September 21, 2018, and then scanned the reference lists. Randomized controlled trials that compared hypothermia with normothermia in LHI patients were included. Primary outcomes that we reviewed were mortality and neurological outcome. Adverse events during treatment were defined as secondary outcomes. We performed a meta-analysis to calculate pooled risk ratios (RRs), standardized mean differences (SMDs), and 95% confidence intervals (CIs) using fixed-effect models. Results: Three randomized controlled trials involving 131 participants were included. No statistically significant association was revealed between hypothermia and mortality (RR, 1.12; 95% CI, 0.76-1.65). There was significant association between hypothermia and good neurological outcome as assessed by modified Rankin Scale score (mRS of 0-3) of survivors (RR, 2.09; 95% CI, 1.14-3.82), and with neurological outcome by mRS (SMD, -0.54; 95% CI, -1.07 to -0.01). However, significant associations were found between hypothermia and gastrointestinal bleeding, gastric retention, electrolyte derangement, and shivering. No significant differences were detected in the incidence of developing herniation in the rewarming process, pneumonia, cardiac arrhythmia, hemorrhagic transformation, hyperglycemia, hypotension, acute kidney injury, and venous thrombotic events in LHI patients who underwent hypothermia compared with those who had normothermia. Conclusions: This meta-analysis suggested that hypothermia was not associated with mortality in LHI patients. However, it was associated with the improvement of neurological outcome, but with a higher risk of adverse events during treatment. Future studies are needed to demonstrate the efficacy and safety of hypothermia for LHI. The protocol for this systematic review was obtained from PROSPERO (registration number: CRD42018111761).

Dataset Information

Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.

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Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.

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