PHARMACODYNAMIC MODELING OF THE ELECTROENCEPHALOGRAPHIC EFFECTS OF FLUMAZENIL IN HEALTHY-VOLUNTEERS SEDATED WITH MIDAZOLAM

The purpose of this study was to model pharmacodynamically the reversa l of midazolam sedation with flumazenil. Ten human volunteers underwen t four different sessions. In session 1, individual midazolam pharmaco kinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of seda tion (20% or 80% of the maximal midazolam electroencephalographic effe ct) for a period of 210 minutes. After obtaining a stable electroencep halographic effect and constant midazolam plasma concentrations, a zer o-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate be cause of the constant midazolam drug effect. The electroencephalograph ic response was measured during a 180-minute period and analyzed by ap eriodic analysis and fast-Fourier transforms. In session 4, a midazola m plasma concentration corresponding to a deep level of sedation was t argeted for 210 minutes to examine for the possible development of acu te tolerance. No flumazenil was given in session 4. For a light sedati on Level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ ml, the mean half-life of the equilibration rate constant of flumazeni l reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentrat ion causing 50% of E(max) is 13.7 +/- 5.8 ng/ml. For a deep level of s edation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1 .5 minutes, and the mean effect site concentration causing 50% of E(ma x) is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magni tude of the blood/central nervous system equilibration delay for fluma zenil antagonism of midazolam sedation and further defines the usefuln ess of the electroencephalogram as a measure of midazolam pharmacodyna mic effect.