Kinetics and dynamics of lorazepam during and after continuous intravenousinfusion

Objective: To evaluate the kinetics and dynamics of lorazepam during admini stration as a bolus plus an infusion, using electroencephalography as a pha rmacodynamic end point. Methods: Nine volunteers received a 2-mg bolus loading dose of lorazepam, c oincident with the start of a 2 mu g/kg/hr zero-order infusion. The infusio n was stopped after 4 hrs. Plasma lorazepam concentrations and electroencep halographic activity in the 13- to 30-Hz range were monitored for 24 hrs. Results: The bolus-plus-infusion scheme rapidly produced plasma lorazepam c oncentrations that were close to those predicted to be achieved at true ste ady state. Mean kinetic values for lorazepam were as follows: volume of dis tribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/mi n. Electroencephalographic effects were maximal 0.5 hr after the loading do se, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencepha lographic effect vs, plasma lorazepam concentration demonstrated counterclo ckwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect -site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid E-max model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50 % effective concentration, 13.1 ng/mL; and effect-site equilibration half-l ife, 8.8 mins. Conclusion: Despite the delay in effect onset, continuous infusion of loraz epam, preceded by a bolus loading dose, produces a relatively constant seda tive effect on the central nervous system, which can be utilized in the con text of critical care medicine. (Crit Care Med 2000; 28:2750-2757).