High serum levels of endothelin-1 predict severe cerebral edema in patients with acute ischemic stroke treated with t-PA

Background and Purpose - Severe cerebral edema is associated with poor outcome in patients with acute stroke. Experimental studies suggest that astrocytic endothelin-1 (ET-1) has deleterious effects on water homeostasis, cerebral edema, and blood brain barrier (BBB) integrity, which contribute to more severe ischemic brain injury. In this study we analyze the association between high serum levels of ET-1 and the development of severe cerebral edema in patients treated with t-PA. Methods - One hundred thirty-four patients treated with t-PA according SITS-MOST (Safe Implementation of Thrombolysis in Stroke Monitoring Study) criteria were prospectively studied. Serum levels of ET-1, matrix metalloproteinase-9 (MMP-9), and cellular fibronectin (c-Fn) were determined by ELISA in serum samples obtained on admission, before t-PA bolus. Severe brain edema was diagnosed if extensive swelling caused any shifting of the structures of the midline was detected on the cranial CT performed at 24 to 36 hours. Stroke severity was evaluated before t-PA administration and at 24 hours by NIHSS. Functional outcome at 3 months was evaluated by the modified Rankin Scale (mRS). Results - Nineteen patients (14.2%) developed severe brain edema. Median ET-1 (8.4 [ 6.7, 9.6] versus 1.9 [ 1.6, 3.2] fmol/ mL, P < 0.0001) and c-Fn (6.0 [ 4.1, 6.7] versus 3.2 [ 2.1, 4.6] mg/ L, P < 0.0001) serum levels were significantly higher in patients with severe cerebral edema. The best cut-off values for ET-1 and c-Fn serum levels for the prediction of severe brain edema were 5.5 fmol/ mL (sensitivity 95% and specificity 94%) and 4.5 mg/ L (sensitivity 73% and specificity 77%) respectively. ET-1 serum levels > 5.5 fmol/ mL before t-PA treatment were independently associated with development of severe brain edema (OR, 139.7; CI95%, 19.3 to 1012.2; P < 0.0001), after adjustment for baseline stroke severity, early CT signs of infarction, serum levels of cFn > 4.5 mg/ L, and cardioembolic stroke subtype. Conclusions - ET-1 serum levels > 5.5 fmol/ mL are associated with severe brain edema in acute stroke patients treated with t-PA. These results suggest that ET-1 may be a new diagnostic marker for development of severe brain edema in patients with acute ischemic stroke treated with t-PA.