Research in context
Evidence before this study
We searched PubMed for randomised controlled trials published in only English between Jan 1, 2000, and March 4, 2016, with the search terms “ischemic stroke”, AND “brain edema”, AND “glyburide”, OR “glibenclamide”, OR “sulfonylurea”. We found 12 preclinical studies that showed that continuous glyburide administration led to a reduction in brain oedema and mortality in rodent models of stroke. A pilot trial of intravenous glyburide in patients with acute, large hemispheric stroke showed feasibility and initial safety of treatment of critically ill stroke patients at high risk for oedema. Interpretation of these retrospective and prospective pilot data is limited by the absence of double-blind, placebo controlled trials.
Added value of this study
To our knowledge, this is the first trial to assess the effect of early (within 10 h) and continuous administration of an intravenous glyburide for the prevention of brain oedema after a large hemispheric stroke in a randomised, double-blind, placebo-controlled trial. Treatment was well tolerated, hypoglycaemia was uncommon and successfully treated with a prespecified hypoglycaemia protocol. Although the percentage of people who had a modified Rankin Scale score of 0–4 at 90 days without decompressive craniectomy (primary endpoint) was not significantly different in the glyburide and placebo groups, and mortality was non-significantly reduced overall, functional outcome measured by the modified Rankin Scale was improved in patients treated with the active drug. There was an association with a reduction in midline shift of the brain and lower plasma matrix metalloproteinase-9 concentrations in patients treated with intravenous glyburide compared with placebo.
Implications of all the available evidence
Our findings suggest that the sulfonylurea receptor pathway is implicated in the formation of brain oedema after stroke in patients. Early and continuous intravenous administration of glyburide favourably affects markers of brain oedema and suggests that there might be a clinical effect on mortality and functional outcome at 90 days. These findings need to be replicated in a larger phase 3 trial in patients with large hemispheric infarction.