Quantification of the EEG Effect of Midazolam by Aperiodic Analysis in Volunteers

Summary

The effects of midazolam on the EEG were related to plasma midazolam concentrations in 8 healthy male volunteers in order to develop a pharmacokinetic-pharmacodynamic model. The EEG parameters were derived by aperiodic analysis.

The EEG was recorded between Fp₁-M₁ and F_P2-M₂. Following a 15-minute baseline EEG registration, midazolam 15mg was given intravenously over 5 minutes. Venous blood samples were taken until 8 hours after the start of the infusion. Within 2 to 4 minutes of starting the infusion all subjects became asleep, with loss of eyelid reflex. The most obvious EEG changes, in the β frequency range (12 to 30Hz), were observed within 2 minutes of the start of drug administration. Seven subjects awoke 60 to 70 minutes after the start of the infusion and 1 awoke after 45 minutes.

The EEG parameter that best characterised the effect of midazolam was the total number of waves per second in the frequency range 12 to 30Hz (TNW_12–30). This was used as the effect parameter in the pharmacokinetic-pharmacodynamic modelling. The plasma concentration-time data were characterised by a triexponential function for all subjects. To allow for a possible delay between plasma midazolam concentration and EEG effect, a hypothetical effect compartment was included in the pharmacokinetic-pharmacodynamic model. A sigmoid maximum effect (E_max) model was used to characterise the effect compartment midazolam concentration-TNW_2–30 data. The plasma drug concentration corresponding to half the maximum increase in TNW_12–30 (EC50) was 290 ± 98 μg/L. The half-life reflecting equilibration between plasma concentration and effect (t 00BDk_eo) was estimated by a nonparametnc method and was 1.7 ± 0.7 minutes (mean ± SD).

The concentration at which the volunteers awoke was 131 ± 14 Mg/L. The EEG had returned to the baseline value 3 hours after the start of the infusion; at this time the plasma midazolam concentration was 60 ± 9 μg/L.

The conclusion is reached that, in volunteers, the effect of midazolam on the EEG can be quantified and adequately described with a sigmoid E_max model. TNW_12–30, a parameter derived from aperiodic analysis of the EEG, is a suitable, and possibly superior, alternative to psychomotor tests for the assessment of the central nervous system effects of this drug.