Sedative Choice and Neurocognitive Outcomes After Critical Illness in Early Childhood

Importance Sedatives, commonly administered in the clinical treatment of young children with critical illness, may be harmful to early brain development. Objective To investigate whether sedative choice during critical illness in early childhood is associated with long-term neurocognitive function. Design, Setting, and Participants This prospective cohort study was conducted among a subset of cognitively appropriate children with acute respiratory failure who were aged 8 years or younger when enrolled in the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE ) cluster-randomized clinical trial conducted in 31 pediatric intensive care units (PICUs) comparing a nurse-implemented, goal-directed sedation protocol with usual care. Patients underwent neurocognitive testing 3 to 8 years after hospitalization at regional neuropsychology testing centers. Neurocognitive testing was conducted from February 16, 2015, to November 27, 2018. Assessors were blinded to the sedation provided. Data were analyzed from September 2022 to March 2026. Exposures Critical illness and sedation. Main Outcomes and Measures The primary outcome was IQ, estimated by the age-appropriate Vocabulary and Block Design subtests of the Wechsler Intelligence Scale. Drug- and dose-dependent associations between sedatives and neurocognitive function were assessed, adjusting for baseline factors and severity and course of critical illness. Results Neurocognitive testing was performed among 256 children (median [IQR] age, 6.6 [5.4 to 9.0] years). Among 243 children with data, 228 children (93.8%) had age-appropriate global assessment of cognitive function (Pediatric Cognitive Performance Category = 1) at testing. Children were exposed to a median (IQR) of 8 (5 to 14) days of continuous sedation at a median (IQR) age of 1.0 (0.2 to 3.2) years. The mean (SD) estimated IQ was 100.3 (13.2), similar to the published test mean of 100. Mean (SD) estimated IQ at long-term follow-up was lowest in patients receiving an opioid- and benzodiazepine-only strategy (98.3 [11.8]), higher in patients receiving multiple sedative classes not including dexmedetomidine (100.6 [14.5]), and highest in patients receiving multiple sedative classes, including dexmedetomidine (101.9 [13.5]). Controlling for Hollingshead Socioeconomic Status score, severity of illness on PICU admission, and duration of mechanical ventilation, the adjusted mean difference in estimated IQ between the opioid- and benzodiazepine-only vs dexmedetomidine groups was −4.1 (95% CI, −7.3 to −0.9; P = .01). Conclusions and Relevance In this study of young children who received more than a week of PICU sedation, the estimated IQ was similar to that of the general population. Children who received an opioid- and benzodiazepine-only strategy scored lower than those who received a strategy that included dexmedetomidine when controlling for socioeconomic status, illness severity, and duration of mechanical ventilation. Trial Registration ClinicalTrials.gov Identifier: NCT02225041