Intensive Care Medicine

, Volume 41, Issue 12, pp 2130–2137 | Cite as

Benzodiazepine-associated delirium in critically ill adults

  • Irene J. Zaal
  • John W. Devlin
  • Marijn Hazelbag
  • Peter M. C. Klein Klouwenberg
  • Arendina W. van der Kooi
  • David S. Y. Ong
  • Olaf L. Cremer
  • Rolf H. Groenwold
  • Arjen J. C. Slooter



The association between benzodiazepine use and delirium risk in the ICU remains unclear. Prior investigations have failed to account for disease severity prior to delirium onset, competing events that may preclude delirium detection, other important delirium risk factors, and an adequate number of patients receiving continuous midazolam. The aim of this study was to address these limitations and evaluate the association between benzodiazepine exposure and ICU delirium occurrence.


In a cohort of consecutive critically ill adults, daily mental status was classified as either awake without delirium, delirium, or coma. In a first-order Markov model, multinomial logistic regression analysis was used, which considered five possible outcomes the next day (i.e., awake without delirium, delirium, coma, ICU discharge, and death) and 16 delirium-related covariables, to quantify the association between benzodiazepine use and delirium occurrence the following day.


Among 1112 patients, 9867 daily transitions occurred. Benzodiazepine administration in an awake patient without delirium was associated with increased risk of delirium the next day [OR 1.04 (per 5 mg of midazolam equivalent administered) 95 % CI 1.02–1.05). When the method of benzodiazepine administration was incorporated in the model, the odds of transitioning to delirium was higher with benzodiazepines given continuously (OR 1.04, 95 % CI 1.03–1.06) compared to benzodiazepines given intermittently (OR 0.97, 95 % CI 0.88–1.05).


After addressing potential methodological limitations of prior studies, we confirm that benzodiazepine administration increases the risk for delirium in critically ill adults but this association seems to be limited to continuous infusion use only.


Delirium Benzodiazepine Midazolam Risk Intensive care 



John W. Devlin’s efforts towards this project were supported, in part, by a Visitor’s Grant from the Netherlands Organization for Scientific Research (NWO 040.11.372).

Compliance with ethical standards

Conflicts of interest

None of the authors have potential conflicts of interest regarding this manuscript.

Supplementary material

134_2015_4063_MOESM1_ESM.docx (211 kb)
Supplementary material 1 (DOCX 210 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2015

Authors and Affiliations

  • Irene J. Zaal
    • 1
  • John W. Devlin
    • 2
    • 3
  • Marijn Hazelbag
    • 4
  • Peter M. C. Klein Klouwenberg
    • 1
    • 4
    • 5
  • Arendina W. van der Kooi
    • 1
  • David S. Y. Ong
    • 1
    • 4
    • 5
  • Olaf L. Cremer
    • 1
  • Rolf H. Groenwold
    • 4
  • Arjen J. C. Slooter
    • 1
  1. 1.Department of Intensive Care MedicineUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.School of PharmacyNortheastern UniversityBostonUSA
  3. 3.Division of Pulmonary, Critical Care, and Sleep MedicineTufts Medical CenterBostonUSA
  4. 4.Julius Center for Health Sciences and Primary CareUniversity Medical Center UtrechtUtrechtThe Netherlands
  5. 5.Department of Medical MicrobiologyUniversity Medical Center UtrechtUtrechtThe Netherlands

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