Effects of Midazolam on Brain Injury After Transient Focal Cerebral Ischemia in Rats^*

Abstract

The benzodiazepine, midazolam, is commonly used for sedation and anesthesia in the operating room and the intensive care unit where there is a risk of cerebral ischemia. We therefore examined its ability to reduce damage subsequent to cerebral ischemia. Male Wistar rats were randomly assigned to a high-dose midazolam group or a matched vehicle group and a lower dose of midazolam group or a matched vehicle group. The rats underwent 90 minutes of middle cerebral artery occlusion. In the midazolam groups, the first dose of midazolam (10 or 25 mg/kg) was given by a 10-minute intravenous infusion before ischemia; a second dose of ½ the initial dose (5 or 12.5 mg/kg) was given 1 hour after the onset of ischemia. In the vehicle groups, a similar volume of vehicle was given at the same time intervals. Infarct size, NeuN immunopositive cells in the ischemic penumbral and core regions, and neurologic outcome were determined 7 days after ischemia. Compared with vehicle-treated rats, the higher-dose midazolam (25 mg/kg)-treated rats had a smaller infarct size (93.9±63.5 mm³ vs. 152.0±53.7 mm³, P<0.05), more NeuN immunopositive cells in the ischemic core region (206.7±211.3/mm² vs. 40.0±66.3/mm², P<0.01), and better neurologic outcome (P<0.05). Midazolam at a lower dose (10 mg/kg) had no significant effects. Although midazolam generated dose-dependent hemolysis, this hemolysis was transient. Midazolam (25 mg/kg) caused a loss of the righting reflex in rats that lasted until 19.9±1.3 min after the injection, the anesthetic dose of midazolam in rats is approximately 100× greater than the anesthetic dose for humans. An anesthetic dose of midazolam in rats reduced neuronal damage and improved neurologic outcome 7 days after focal cerebral ischemia, however, it also caused transient hemolysis.