Flumazenil reversal of midazolam in dogs: dose-related changes in cerebral blood flow, metabolism, EEG, and CSF pressure

Abstract

Large doses of flumazenil, given rapidly (over 5-10 s), are reported to elevate cerebral blood flow (CBF) and intracranial pressure to supranormal values when given to dogs receiving midazolam. This study examined the cerebral effects of giving smaller, graduated doses of flumazenil (0.0025, 0.01, 0.04, and 0.16 mg/kg), slowly (over 60 s), to dogs receiving midazolam and to dogs not receiving midazolam both when cerebrospinal fluid (CSF) pressure was normal and when CSF pressure was elevated (intracranial balloon) to about 30 mm Hg. In dogs with normal CSF pressure that were receiving midazolam, the effects of flumazenil were as follows: (a) low doses of flumazenil caused reversal of the reduction in cerebral metabolic rate for oxygen (CMRO2) and activity of the electroencephalogram produced by midazolam, (b) moderate doses of flumazenil produced a decrease of cerebral vascular resistance, and an increase of CBF and CSF pressure that did not significantly change cerebral perfusion pressure (CPP), and (c) the highest dose of flumazenil increased CBF to supranormal values. All of these flumazenil effects "peaked" at 3-6 min, with values returning to pre-flumazenil levels by 15-30 min. Flumazenil caused no such changes in dogs with elevated CSF pressure that were receiving midazolam or in dogs that were not receiving midazolam. The results are consistent with a specific, doserelated benzodiazepineantagonist action of flumazenil. Lack of flumazenil effect at elevated CSF pressure may reflect reversible changes in cerebral structure, metabolism, or benzodiazepine receptors produced by the intracranial balloon and elevation of CSF pressure. The doses of flumazenil used here to reverse the cerebral effects of midazolam appear unlikely to produce adverse effects because increase of CMRO2 was matched by increase of CBF, the mean increase of CSF pressure was modest (+9 +/- 3 mm Hg, mean +/- SEM), and CPP was unchanged.