Is There Any Dose of Benzodiazepines Safe for Delirium in the PICU? A Secondary Analysis of the PICU Up! Pilot Trial Dataset

IMPORTANCE: A better understanding of the relationship between sedative dose and PICU delirium is crucial for delirium prevention. OBJECTIVES: To identify risk factors for delirium in critically ill children and characterize the dose-response relationship between benzodiazepine administration and next-day delirium in the PICU. DESIGN, SETTING, AND PARTICIPANTS: A secondary analysis of 10,644 patient-days from prospectively collected data, including sedative and analgesic use and delirium screening from the multicenter, randomized PICU Up! pilot trial, including seven PICUs and 1,006 patients. MAIN OUTCOMES AND MEASURES: Delirium odds were evaluated using a multivariable logistic regression model adjusted for known delirium risk factors. RESULTS: Benzodiazepines, opioids, and dexmedetomidine were commonly used in the PICU. A higher previous-day benzodiazepine dose was associated with increased odds of delirium on a given day with an adjusted odds ratio (aOR) of 1.12 per midazolam milligram equivalent per kilogram (95% CI, 1.02-1.25; p = 0.020). The most pronounced increase in delirium risk occurred at the lowest doses, between 0 and 0.01 mg/kg (p = 0.010), with risk continuing to rise at higher doses. Previous-day opioid dose was not associated with changes in the odds of delirium (aOR, 1.00; 95% CI, 1.00-1.00; p = 0.892). Any previous-day dexmedetomidine administration was associated with increased odds of next-day delirium (aOR, 1.26; 95% CI, 1.04-1.52; p = 0.019). Additionally, same-day physical restraint use was associated with increased odds of delirium (aOR, 1.72; 95% CI, 1.27-2.31; p < 0.001). CONCLUSIONS AND RELEVANCE: No safe benzodiazepine threshold was identified in critically ill children, with delirium risk increased even at minimal doses. The greatest increase in odds occurred at the lowest doses. Hence, regardless of dose, benzodiazepine use should be minimized or eliminated whenever possible. Physical restraints and dexmedetomidine use were also associated with increased risk of delirium; thus, a tailored approach for each patient with an emphasis on judicious use is critical.