PHARMACOKINETICS OF MIDAZOLAM ADMINISTERED BY CONTINUOUS INTRAVENOUS-INFUSION TO INTENSIVE-CARE PATIENTS

Objective: To determine the pharmacokinetics of continuously infused midazolam in patients during intensive care. Design: Descriptive trial. Setting: General ICU in a Swiss hospital. Subjects: Eight critically ill patients requiring mechanical ventilation. Interventions: To achieve an appropriate level of long-term sedation, the rate of iv infusion of midazolam in ICU patients was adjusted individually to between 6 and 15 mg/hr. Blood samples were taken during and after the continuous infusion of midazolam. Measurements: Measurements included plasma concentration time profiles of midazolam and pharmacokinetic parameters, such as elimination half-life, clearance, and volume of distribution. Results: The elimination half-life was prolonged (mean 5.4 vs. 2.3 hrs) and the volume of distribution was larger (3.1 vs. 0.9 L/kg) in patients vs. healthy volunteers. The clearance did not differ between groups (6.3 vs. 4.9 mL/min/kg in patients vs. volunteers, respectively). Conclusions: The increased volume of distribution in our critically ill patients is the major determinant for the observed slower elimination of midazolam. It is unlikely that the hepatic metabolism of midazolam was impaired in these patients.