International Journal of Clinical Pharmacy

, Volume 35, Issue 2, pp 210–216 | Cite as

Pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia

  • Diane E. T. BastiaansEmail author
  • Eleonora L. Swart
  • Jesse P. van Akkeren
  • Luc J. J. Derijks
Research Article


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.


Hypothermia Midazolam Pharmacokinetics Resuscitation 



Substantial contribution was made by Caroline H.M. Meerts (Department of Intensive Care, Máxima Medical Centre, Eindhoven/Veldhoven, The Netherlands) as clinical investigator.


No funding was provided for conduct of the study or preparation of the paper.

Conflicts of interest

The authors declare no conflict of interest.


  1. 1.
    Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–63.PubMedCrossRefGoogle Scholar
  2. 2.
    Group HaCAS. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–56.CrossRefGoogle Scholar
  3. 3.
    Fukuoka N, Aibiki M, Tsukamoto T, Seki K, Morita S. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia. Resuscitation. 2004;60:225–30.PubMedCrossRefGoogle Scholar
  4. 4.
    Bauer TM, Ritz R, Haberthur C, Ha HR, Hunkeler W, Sleight AJ, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet. 1995;346:145–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Swart EL, Zuideveld KP, de Jongh J, Danhof M, Thijs LG, Strack van Schijndel RM. Comparative population pharmacokinetics of lorazepam and midazolam during long-term continuous infusion in critically ill patients. Br J Clin Pharmacol. 2004;57:135–45.PubMedCrossRefGoogle Scholar
  6. 6.
    Rossen RV, Trumpie H. Onverklaarbare midazolamcoma’s mogelijk verklaard. Extract. 1996;7:3.Google Scholar
  7. 7.
    Vletter AA, Burm AG, Breimer LT, Spierdijk J. High-performance liquid chromatographic assay to determine midazolam and flumazenil simultaneously in human plasma. J Chromatogr. 1990;530:177–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen M, Ma L, Drusano GL, Bertino JS Jr, Nafziger AN. Sex differences in CYP3A activity using intravenous and oral midazolam. Clin Pharmacol Ther. 2006;80:531–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Vree TB, Shimoda M, Driessen JJ, Guelen PJ, Janssen TJ, Termond EF, et al. Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of midazolam in intensive care patients. Clin Pharmacol Ther. 1989;46:537–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Mc Donnell CG, Shorten G, Van Pelt FN. Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro. Anaesthesia. 2005;60:747–53.PubMedCrossRefGoogle Scholar
  11. 11.
    Hostler D, Zhou J, Tortorici MA, Bies RR, Rittenberger JC, Empey PE, et al. Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers. Drug Metab Dispos. 2010;38:781–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Diane E. T. Bastiaans
    • 1
    Email author
  • Eleonora L. Swart
    • 2
  • Jesse P. van Akkeren
    • 1
  • Luc J. J. Derijks
    • 1
  1. 1.Máxima Medical CentreEindhoven/VeldhovenThe Netherlands
  2. 2.Vrije Universiteit Medical Centre AmsterdamThe Netherlands

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