title: Benzodiazepine-associated delirium in critically ill adults.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Irene J
authors.initials: IJ
authors.lastname: Zaal
authors.affiliation: School of Pharmacy, Northeastern University, 360 Huntington Ave 140 TF RD218F, Boston, MA, 02118, USA. j.devlin@neu.edu.|Division of Pulmonary, Critical Care, and Sleep Medicine, Tufts Medical Center, Boston, USA. j.devlin@neu.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Devlin
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marijn
authors.initials: M
authors.lastname: Hazelbag
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Peter M C
authors.initials: PM
authors.lastname: Klein Klouwenberg
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Arendina W
authors.initials: AW
authors.lastname: van der Kooi
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: David S Y
authors.initials: DS
authors.lastname: Ong
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Olaf L
authors.initials: OL
authors.lastname: Cremer
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Groenwold
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Arjen J C
authors.initials: AJ
authors.lastname: Slooter
mesh_terms: D001569:Benzodiazepines / Q000009:adverse effects*; D003422:Critical Care; D016638:Critical Illness; D003693:Delirium / Q000139:chemically induced*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D001569:Benzodiazepines
keywords: Benzodiazepine; Delirium; Intensive care; Midazolam; Risk