Furosemide in severe bronchopulmonary dysplasia: comparative effectiveness of a duration and dosage informed treatment strategy

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PROJECT SUMMARY/ABSTRACT The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) is to provide Nicolas A. Bamat, MD, MSCE, Instructor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania (Penn) and The Children’s Hospital of Philadelphia (CHOP) with the mentorship, training and research experience needed to become an independent clinical investigator. His long-term career goal is to improve outcomes for infants with neonatal lung disease by leading trials that identify evidence- based pharmacotherapeutic practices. His immediate career development goal is to acquire the skills needed to ensure a successful transition to research independence. To meet this goal, Dr. Bamat and his mentor team have devised a career development plan that integrates: (1) intensive mentorship from successful pediatric investigators; (2) focused training in clinical trials, clinical pharmacology and longitudinal data analysis; and (3) innovative research on furosemide treatment strategies for severe bronchopulmonary dysplasia (BPD). Complications of preterm birth are the leading pediatric contributor to disability-adjusted life years lost. BPD, or chronic lung disease of prematurity, is the most common major morbidity. BPD is particularly devastating for infants with severe BPD (sBPD), the worst severity class. Prolonged initial hospitalizations, co- morbid pulmonary hypertension, tracheostomy for prolonged ventilation and childhood death are common. Currently, no pharmacotherapies have proven clinical efficacy for improving respiratory disease course in sBPD. Despite this, medication exposures are common. The loop diuretic furosemide is most frequently used. Dr. Bamat’s mentored research will address key knowledge gaps surrounding furosemide use in sBPD. He will: (1) determine if and when tolerance to furosemide diuresis occurs in sBPD, (2) develop furosemide population pharmacokinetic models with covariate analysis for individualized dosage regimens, and (3) apply the knowledge gained in (1) and (2) to determine the comparative effectiveness of an informed furosemide treatment strategy versus standard of care for improving the respiratory severity score and decreasing the rate of furosemide-associated adverse effects. This research will be conducted by leveraging the existence of CHOP’s Chronic Lung Disease Program, a multidisciplinary referral program dedicated to infants with sBPD. Dr. Bamat’s findings will guide furosemide treatment strategies in sBPD, for testing in placebo- controlled multicenter trials, funded through R-series awards in his transition to research independence. The described career development and research activities will occur at Penn and CHOP, an ideal environment in which to train the next generation of scientists conducting NIH-supported patient-oriented research.