Abstract TP400: Intravenous Glibenclamide Reduces Water Uptake and Mass Effect in Large Hemispheric Infarction (GAMES-RP Study)

Introduction: Prior studies have shown a linear relationship between CT-derived density and brain water uptake. We sought to determine whether intravenous (IV) glibenclamide (glyburide; BIIB093) would reduce water uptake and mass effect on serial CT scans from patients enrolled in the phase 2 GAMES-RP trial. Methods: Non-contrast CT scans performed between admission and day 7 (n=263) were analyzed in patients in the GAMES-RP modified intention-to-treat sample. Midline shift (MLS) was measured at the level of maximal lateral displacement of the septum pellucidum. CT-derived radiodensity was measured in pre-defined regions of interest (ROI) within the infarct. The same ROIs were mirrored to the contralateral hemisphere. The change in CT radiodensity (change in water uptake) was averaged among gray and white matter regions separately, and across both regions together. Repeated measures mixed effects models were used to assess the effect of IV glibenclamide on MLS or CT-measured water uptake. Results: There was a median of 3 CT scans [IQR 2-5] per patient during the first 7 days after stroke. Greater change in water uptake was associated with more MLS (β=0.17, 95% CI 0.15 to 0.20, p <0.0001). Using repeated measures models, treatment with IV glibenclamide was associated with reduced water uptake (β= -2.25, 95% CI -4.37 to -0.13, p =0.037) and reduced MLS (β= -1.78, 95% CI -2.87 to -0.67, p =0.002), and adjusted for time. Treatment with IV glibenclamide reduced both gray and white matter water uptake independently. In mediation analysis, gray matter edema (β=0.10, 95% CI 0.05 to 0.16, p <0.001) mediated a greater proportion of MLS when compared to white matter (β=0.02, 95% CI -0.03 to 0.08, p =0.427). Conclusions: IV glibenclamide reduced water uptake and MLS after large hemispheric infarction. A phase 3 study is underway to determine whether IV glibenclamide treatment improves clinical outcome.