High serum levels of endothelin-1 predict severe cerebral edema in patients with acute ischemic stroke treated with t-PA.
OBJECTIVE
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.
Moldes
Octavio
O
Department of Neurology, Clinical Neuroscience Research Laboratory, Hospital Clínico Universitario, University of Santiago de Compostela, Santiago de Compostela, Spain.
Sobrino
Tomás
T
Millán
Mónica
M
Castellanos
Mar
M
Pérez de la Ossa
Natalia
N
Leira
Rogelio
R
Serena
Joaquín
J
Vivancos
José
J
Dávalos
Antonio
A
Castillo
José
J
D000368:Aged; D001929:Brain Edema / Q000097:blood* / Q000175:diagnosis*; D002545:Brain Ischemia / Q000097:blood* / Q000175:diagnosis*; D019332:Endothelin-1 / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005353:Fibronectins / Q000097:blood; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D016017:Odds Ratio; D020521:Stroke / Q000097:blood* / Q000175:diagnosis*; D015912:Thrombolytic Therapy / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000097:blood*
D019332:Endothelin-1; D005353:Fibronectins; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9