Benzodiazepines and Development of Delirium in Critically Ill Children: Estimating the Causal Effect

Abstract

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.

Conflict of interest statement

Disclosures: All authors have no relevant conflicts of interest to disclose.

The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Figure 1. Marginal structural model of association between time dependent variables and next-day delirium

Schematic of confounding pathways used in weight modeling for this study. The treatment/interventions included were: cognitive status (delirium, coma, or normal), benzodiazepine exposure, opiate exposure, and mechanical ventilation (based on statistical method in Pisani, et al.) (17).

Figure 2. Odds of developing new delirium after exposure to benzodiazepines

Subgroup analysis to include only days when patients had a normal cognitive status (n=1540 days with normal cognitive status and benzodiazepine exposure). The bars represent 95% confidence intervals for delirium development after exposure to benzodiazepines. On left, the unadjusted OR for delirium development after exposure to benzodiazepines is 8.7. On right, after controlling for mechanical ventilation and opiate exposure, benzodiazepines more than quadrupled risk of subsequent delirium.

Figure 3. Benzodiazepines and risk for delirium development

Probability of transitioning to delirium (%) increases with dose of benzodiazepine (mg/kg/day midazolam equivalents) given during the previous day.