Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction

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 (β=0.23; 95% CI, 0.20-0.26; P<0.001). Treatment with intravenous glibenclamide was associated with reduced NWU (β=-2.80; 95% CI, -5.07 to -0.53; P=0.016) and reduced MLS (β=-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 (β=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 (β=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.