Pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia

Int J Clin Pharm. 2013 Apr;35(2):210-6. doi: 10.1007/s11096-012-9725-0. Epub 2012 Nov 29.


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 °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.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Aged
  • Coma / therapy
  • Female
  • Humans
  • Hypnotics and Sedatives / pharmacokinetics*
  • Hypothermia, Induced / methods*
  • Intensive Care Units
  • Male
  • Midazolam / pharmacokinetics*
  • Middle Aged
  • Models, Biological
  • Netherlands
  • Nonlinear Dynamics
  • Prospective Studies
  • Resuscitation*
  • Temperature
  • Tissue Distribution


  • Hypnotics and Sedatives
  • Midazolam