• M F Bonfiglio, L E Fisher-Katz, L M Saltis, S M Traeger, B R Martin, N A Nackes, and T A Perkins.
• Department of Pharmacy, SUMMA Health System, Akron, Ohio, USA.
• Pharmacotherapy. 1996 Nov 1;16(6):1166-72.

Study ObjectivesTo develop a pharmacokinetic-pharmacodynamic model using quantitative electroencephalographic (EEG) analysis to compare two separate benzodiazepine antagonists and generate data concerning response variability.DesignA pilot study using a randomized, blinded, crossover design.SettingThe Neurology Laboratory at the Akron City Hospital campus of SUMMA Health System.PatientsFour healthy volunteers completed the protocol.InterventionsSubjects received midazolam 0.1-0.2 mg/kg by intravenous bolus on 3 study days, separated by a minimum washout period of 1 week. Subjects participated in an initial open-label response phase followed by a randomized, crossover trial of each benzodiazepine antagonist.Measurements And Main ResultsVenous blood samples were obtained to characterize the pharmacokinetics of all study compounds. The EEG parameter of total number of waves/second (recorded from FP1-F3 and FP2-F4 electrodes) in the frequency of 12-30 Hz was used to quantify effect. Flumazenil appeared to prolong the elimination half-life of midazolam significantly (p < 0.05). Theophylline (aminophylline) also appeared to prolong the half-life of flumazenil (p < 0.05). Despite considerable variability, flumazenil resulted in reversal of sedation at concentrations achieved by routine dosing. Resedation was apparent for all subjects following flumazenil reversal. Only partial reversal of sedation by theophylline was achieved by an aminophylline dose of 1-2 mg/kg.ConclusionsFlumazenil was consistently effective in reversing sedation by midazolam at routinely recommended dosing. Further investigation of aminophylline as a reversal agent should use an estimated dose of 6-8 mg/kg aminophylline. To achieve adequate reversal, some patients may require aminophylline dosages that exceed safe clinical administration.

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