<p><strong>OBJECTIVES: </strong>Polypharmacy is common in hospitalized children in the United States and has been identified as a major risk factor for exposure to potential drug-drug interactions. Little is known about the characteristics and prevalence of exposure of pediatric patients to polypharmacy and potential drug-drug interactions in PICUs.</p>

<p><strong>DESIGN: </strong>Retrospective cohort study using the Pediatric Health Information System database.</p>

<p><strong>SETTING: </strong>Forty-two freestanding children's hospitals throughout the United States.</p>

<p><strong>PATIENTS: </strong>A total of 54,549 patients less than 18 years old cared for in PICUs in 2011. Patients in neonatal ICUs were not included.</p>

<p><strong>MEASUREMENTS AND MAIN RESULTS: </strong>PICU patients were on average exposed to 10 distinct drugs each hospital day and to 20 drugs cumulatively during their hospitalization. Seventy-five percent of patients were exposed to greater than or equal to one potential drug-drug interaction regardless of severity level, 6% to greater than or equal to one contraindicated potential drug-drug interaction, 69% to greater than or equal to one major potential drug-drug interaction, 57% to greater than or equal to one moderate potential drug-drug interaction, 19% to greater than or equal to one minor potential drug-drug interaction. Potential drug-drug interaction exposures were significantly associated with specific diagnoses (p &lt; 0.001), presence of complex chronic conditions (p &lt; 0.001), increasing number of total distinct drugs used (p &lt; 0.001), increasing length of stay in PICU (p &lt; 0.001), and white race (p &lt; 0.001).</p>

<p><strong>CONCLUSIONS: </strong>Many PICU patients are exposed to substantial polypharmacy and potential drug-drug interactions. Future research should identify the risk of adverse drug events following specific potential drug-drug interaction exposures, especially the risk of adverse drug events due to multiple potential drug-drug interaction exposures, and determine the probability and magnitude of the actual harm (if any) for each specific potential drug-drug interaction, especially for multiple potential drug-drug interaction exposures.</p>