Cerebral Metabolic, Vascular and Protective Effects of Midazolam Maleate

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Abstract
The effects of midazolam maleate and diazepam on cerebral metabolism and circulation were examined for each drug in 6 dogs maintained on N2O 70% and halothane < 0.1%. Midazolam maleate at 0.2 mg/kg and diazepam at 0.3 mg/kg (the ED 100% for induction of anesthesia for each drug in humans) did not decrease metabolite rate for O2 (CMRO2) but did decrease cerebral blood flow (CBF) to .apprx. 55% of control. Additional drug administrations (2.0, 5.0 and 10.0 mg/kg midazolam maleate, and 3.0 and 7.5 mg/kg diazepam) resulted in dose-related decreases in CMRO2 to a maximum of 55% of control after 10.0 mg/kg midazolam maleate. Concomitant with the initial decreases in CMRO2, there was a change in the EEG as reflected by a decrease in frequency and an increase in amplitude. This EEG change suggests that 2.0 mg/kg midazolam maleate and 3.0 mg/kg diazepam represent a comparable canine anesthetic dose. Each additional dose of midazolam maleate decreased CBF to a greater extent than did the added doses of diazepam. Brain biopsies taken at the end of the midazolam maleate studies revealed a normal cerebral energy state (phosphocreatine, ATP, ADP and AMP) and normal glucose, lactate and pyruvate concentrations. In a hypoxic mouse model (FIO2 [fractional concentration of inspired O2] = 0.05), midazolam maleate provided greater protection from hypoxia (2.8 .times. control survival time) than diazepam (1.6 .times. control survival time). By comparison barbiturates in this model provide a survival time which is 4.0 .times. control.