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Kinetics and EEG Effects of Midazolam during and after 1-Minute, 1-Hour, and 3-Hour Intravenous Infusions

From the Department of Pharmacology and Experimental Therapeutics, the Department of Neurology, and the Division of Clinical Pharmacology, Tufts University School of Medicine and Tufts-New England Medical Center, Boston.

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three-way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant-rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13- to 30-Hz range were monitored for 24 hours. Based on separate analysis of each subject-trial, mean values for volume of distribution and distribution or elimination half-life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13- to 30-Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1-hour and 3-hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1-minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect-site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effectsite concentration was related to pharmacodynamic EEG effect via the sigmoid E_max model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1-minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.

Key Words: Midazolam • electroencephalography • pharmacokinetics • pharmacodynamics • intravenous infusions • kinetics

Address for reprints: David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.

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