Pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia

Background Patients who remain comatose after resuscitation are treated with moderate hypothermia. Little is known about the pharmacokinetics of drugs in patients who are treated with moderate hypothermia. Objective We investigated the pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia in comparison to normothermic and non-resuscitated patients. Setting This study was performed on the ICU of a Dutch non-academic hospital. The study population consisted of nine patients in the hypothermic group and eight patients in the control group. Method The resuscitated patients were cooled to a target temperature of 33 degrees C and rewarmed 24 h after start of cooling. Midazolam was given as continuous infusion. The control group consisted of non-resuscitated ICU-patients who were treated with midazolam as sedative. Plasma concentration-time data were collected for midazolam and its metabolites. Main outcome measure Non-linear mixed effect modelling was used to analyze midazolam population pharmacokinetics and identify possible covariates. Results A two-compartment pharmacokinetic model best describes the data. The pharmacokinetic models of the investigated groups are not significantly different. Pharmacokinetic parameter estimates for midazolam for the hypothermic group are a body clearance (CL) of 12.6 l/h, an apparent volume of the central compartment (V1) of 19.1 l, an apparent volume of the peripheral compartment (V2) of 108 l and an intercompartmental clearance (Q) of 18.4 l/h. Estimated parameters for the control group are CL of 14.2 l/h, a V1 of 15.7 l, a V2 of 171 l and Q of 25.6 l/h. In the covariate analysis, body temperature did not significantly improve the model. Conclusion We found no significant difference in the pharmacokinetics of midazolam between resuscitated patients treated with hypothermia during 24 h and the control group.