by Mody, Kalgi; Kaur,
Savneet; Mauer, Elizabeth A.; Gerber, Linda M.; Greenwald, Bruce M.; Silver,
Gabrielle; Traube, Chani
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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