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Introduction: Hemorrhagic transformation (HT) is an uncommon but adverse complication after a stroke that can cause secondary injury. We sought to determine whether glyburide can reduce HT in an ischemia/reperfusion model of stroke.Materials and Methods: We used a transient filament occlusion of the middle cerebral artery (tMCAo), with three hours of cerebral ischemia. Glyburide (n=10) was administered as an intravenous bolus followed by a subcutaneous continuous infusion using an osmotic pump to deliver a dose of 39.5 ug/day. Control animals (n=10) were administered dimethyl sulfoxide vehicle. At 48 hours, infarct size, brain edema and HT were analyzed. HT was quantified using three methods, 1) a categorical designation based on European Cooperative Acute Stroke Study (ECASS) criteria, 2) densitometry of color images and 3) direct measurement of the hemoglobin concentration using spectrophotometry.Results: Compared to vehicle control, continuous glyburide treatment improved neurological outcome (7.6±1.0 vs. 6.0±0.9, P<0.01), reduced infarct volume (323±42 vs. 484±60mm3, P<0.01), swelling volume (10±4 vs. 28±7%, P<0.01) and water content (84±1 vs. 85±1%, P<0.05). Glyburide administration also reduced HT based on ECASS categories, densitometry on color images (0.9±0.1 vs. 1.1±0.1, P<0.01) and quantitative evaluation of hemoglobin (2.7±1.5 vs. 5.1±2.6uL, P<0.05).Conclusion: In a prolonged ischemia/reperfusion model, glyburide reduced the amount of hemorrhagic transformation. Clinical evaluation of glyburide in combination with mechanical thrombectomy may be warranted in patients.