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 (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.

Keywords: brain edema; glyburide; humans; infarction; white matter.

Figures

Figure 1.. Edema and mass effect accumulate rapidly after large hemispheric infarction.

The amount of midline shift accumulation over time is shown in A). The net water uptake (NWU) is shown in B), and separately, the gray matter and white matter water uptake are shown in C) and D), respectively.

Figure 2.. Net water uptake (NWU) and mass effect (MLS) are correlated.

The correlation coefficient between MLS and NWU was r=0.636, p

Figure 3.. IV glibenclamide reduces NWU and MLS over time.

A) Treatment with IV glibenclamide reduced the amount of MLS over time, reflected by the downward shift in the curve (p=0.016) B) IV glibenclamide also reduced average NWU (p=0.016), C) gray matter NWU (p=0.003), and D) white matter NWU, p=0.006.