Investigating polypharmacy-related adverse events in critically ill children using electronic health records and simulated drug levels

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Polypharmacy is common in critically ill children and causes adverse events, including death. Identifying and understanding how specific drug combinations contribute to adverse events is challenging in critically ill children, requiring knowledge of drug levels and their relationships to adverse events. Although such information could be obtained from clinical trials, the execution of these trials for every drug combination is virtually impossible. Dr. Zimmerman aims to develop and evaluate an approach that combines electronic health records and simulated drug levels to identify and characterize polypharmacy-related adverse events in critically ill children. She hypothesizes that the combined approach will describe a relationship between drug levels and a specific adverse event similar to that identified through a clinical trial. This approach could then be used as a platform for evaluating safety in drug combinations frequently used in children. Dr. Zimmerman will conduct a pilot clinical trial to evaluate relationships between delirium scores and drug levels of fentanyl and dexmedetomidine in mechanically-ventilated children. She will then identify a single-center cohort from Duke electronic health records and apply PK models to predict drug levels in this population. Using advanced pharmacoepidemiologic methods, she will create statistical models to describe relationships between simulated drug levels and delirium scores. She will compare results to those obtained in the clinical trial. Finally, she will evaluate the broader applicability of the combined approach in a multicenter electronic health record cohort. Dr. Zimmerman is a pediatric intensivist with a proven commitment to patient-oriented research and a desire to acquire sophisticated skills in pharmacoepidemiologic methods. The skills achieved as a result of this proposal will facilitate the candidate's long-term career goal to advance public health by developing new methods to leverage information from large databases to increase the safety of drugs administered to critically ill children. The candidate's short-term career goals for the K23 program are to: 1) acquire knowledge and skills in optimal clinical trial design and pharmacoepidemiology; 2) develop the professional skills to successfully lead a clinical trial research team; and 3) produce preliminary data and publications to support an R01 grant application and establish a program of independent research in pediatric pharmacoepidemiology. This proposal will capitalize on unique opportunities provided by the Duke Clinical Research Institute (Smith, mentor) and the UNC epidemiology PhD program (Stürmer, PhD advisor). The mentorship team assembled is uniquely qualified, and strengths include extensive clinical research experience, internationally recognized thought leadership in trial design, clinical pharmacology, and pharmacoepidemiology; and a successful history of mentorship of junior faculty. At the conclusion of this program, Dr. Zimmerman will be well positioned to be an independent physician-scientist leading a research team.