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Opioids and benzodiazepines are commonly used to provide analgesia and sedation for critically ill children with cardiac disease. These medications have been associated with adverse effects including delirium, dependence, withdrawal, bowel dysfunction, and potential neurodevelopmental abnormalities. Our objective was to implement a risk-stratified opioid and benzodiazepine weaning protocol to reduce the exposure to opioids and benzodiazepines in pediatric patients with cardiac disease.A prospective pre- and postinterventional study.Critically ill patients less than or equal to 21 years old with acquired or congenital cardiac disease exposed to greater than or equal to 7 days of scheduled opioids ± scheduled benzodiazepines between January 2013 and February 2015.A 24-bed pediatric cardiac ICU and 21-bed cardiovascular acute ward of an urban stand-alone children’s hospital.We implemented an evidence-based opioid and benzodiazepine weaning protocol using educational and quality improvement methodology.One-hundred nineteen critically ill children met the inclusion criteria (64 post intervention, 55 pre intervention). Demographics and risk factors did not differ between groups. Patients in the postintervention period had shorter duration of opioids (19.0 vs 30.0 d; p < 0.01) and duration of benzodiazepines (5.3 vs 22.7 d; p < 0.01). Despite the shorter duration of wean, there was a decrease in withdrawal occurrence (% Withdrawal Assessment Tool score ≥ 4, 4.9% vs 14.1%; p < 0.01). There was an 8-day reduction in hospital length of stay (34 vs 42 d; p < 0.01). There was a decrease in clonidine use (14% vs 32%; p = 0.02) and no change in dexmedetomidine exposure (59% vs 75%; p = 0.08) in the postintervention period.We implemented a risk-stratified opioid and benzodiazepine weaning protocol for critically ill cardiac children that resulted in reduction in opioid and benzodiazepine duration and dose exposure, a decrease in symptoms of withdrawal, and a reduction in hospital length of stay.