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Benzodiazepine Use and Neuropsychiatric Outcomes in the ICU

A Systematic Review*

Kok, Lotte, DVM, MD, PhD1; Slooter, Arjen J., MD, PhD1; Hillegers, Manon H., MD, PhD2,3; van Dijk, Diederik, MD, PhD1; Veldhuijzen, Dieuwke S., PhD4

doi: 10.1097/CCM.0000000000003300
Review Articles

Objectives: A systematic assessment of the role of benzodiazepine use during ICU stay as a risk factor for neuropsychiatric outcomes during and after ICU admission.

Data Sources: PubMed/Medline, EMBASE, The Cochrane Library, CINAHL, and PsychINFO.

Study Selection: Databases were searched independently by two reviewers for studies in adult (former) ICU patients, reporting benzodiazepine use, and neuropsychiatric outcomes of delirium, posttraumatic stress disorder, depression, anxiety, and cognitive dysfunction.

Data Extraction: Data were extracted using a piloted extraction form; methodological quality of eligible studies was assessed by applying the Quality Index checklist.

Data Synthesis: Forty-nine of 3,066 unique studies identified were included. Thirty-five studies reported on neuropsychiatric outcome during hospitalization, 12 after discharge, and two at both time points. Twenty-four studies identified benzodiazepine use as a risk factor for delirium, whereas seven studies on delirium or related outcomes did not; six studies reported mixed findings. Studies with high methodological quality generally found benzodiazepine use to be a risk factor for the development of delirium. Five studies reported an association between benzodiazepine use and symptoms of posttraumatic stress disorder, depression, anxiety, and cognitive dysfunction after ICU admission; five studies reported mixed findings, and in four studies, no association was found. No association was found with methodological quality and sample size for these findings. Meta-analysis was not feasible due to major differences in study methods.

Conclusions: The majority of included studies indicated that benzodiazepine use in the ICU is associated with delirium, symptoms of posttraumatic stress disorder, anxiety, depression, and cognitive dysfunction. Future well-designed studies and randomized controlled trials are necessary to rule out confounding by indication.

1Department of Intensive Care Medicine, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

2Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

3Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center-Sophia, Rotterdam, The Netherlands.

4Leiden Institute for Brain and Cognition, Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden University, Leiden, The Netherlands.

*See also p. 1709.

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Dr. Hillegers’s institution received funding from Fonds Psychische Gezondhei, and she received support for article research from Fonds Psychische Gezondhei. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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