Journal
CRITICAL CARE MEDICINE
Volume 46, Issue 9, Pages 1486-1491Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000003194
Keywords
benzodiazepines; critical care; delirium; intensive care; pediatric; sedation
Categories
Funding
- Empire Clinical Research Investigator Program
- Clinical Translational Science Center [UL1-TR000457-06]
- Lubell Rosen
- Rissman, Barrett, Hurt, Donahue McLain
- Schenck, Price, Smith King
- Society of Critical Care Medicine
- National Institutes of Health
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Objectives: Benzodiazepine use may be associated with delirium in critically ill children. However, benzodiazepines remain the first-line sedative choice in PICUs. Objectives were to determine the temporal relationship between administration of benzodiazepines and delirium development, control for time-varying covariates such as mechanical ventilation and opiates, and evaluate the association between dosage of benzodiazepines and subsequent delirium. Design: Retrospective observational study. Setting: Academic tertiary care PICU. Patients: All consecutive admissions from January 2015 to June 2015. Interventions: Retrospective assessment of benzodiazepine exposure in a population that had been prospectively screened for delirium. Measurements and Main Results: All subjects were prospectively screened for delirium throughout their stay, using the Cornell Assessment for Pediatric Delirium, with daily cognitive status assigned as follows: delirium, coma, or normal. Multivariable mixed effects modeling determined predictors of delirium overall, followed by subgroup analysis to assess effect of benzodiazepines on subsequent development of delirium. Marginal structural modeling was used to create a pseudorandomized sample and control for time-dependent variables, obtaining an unbiased estimate of the relationship between benzodiazepines and next day delirium. The cumulative daily dosage of benzodiazepines was calculated to test for a dose-response relationship. Benzodiazepines were strongly associated with transition from normal cognitive status to delirium, more than quadrupling delirium rates (odds ratio, 4.4; CI, 1.7-11.1; p < 0.002). Marginal structural modeling demonstrated odds ratio 3.3 (CI, 1.4-7.8), after controlling for time-dependent confounding of cognitive status, mechanical ventilation, and opiates. With every one log increase in benzodiazepine dosage administered, there was a 43% increase in risk for delirium development. Conclusions: Benzodiazepines are an independent and modifiable risk factor for development of delirium in critically ill children, even after carefully controlling for time-dependent covariates, with a dose-response effect. This temporal relationship suggests causality between benzodiazepine exposure and pediatric delirium and supports limiting the use of benzodiazepines in critically ill children.
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