Theophylline Prophylaxis during Hypothermia to Limit Neonatal Nephron Damage

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is commonly seen in infants diagnosed with hypoxic-ischemic encephalopathy (HIE) and is associated with increased rates of morbidity and mortality. Currently, there are no approved therapies that target the prevention of AKI. Several small trials in infants with HIE suggest that a single dose of theophylline given soon after birth attenuates the development of AKI. However, these studies were not performed in infants being treated with therapeutic hypothermia (the current standard of care for moderate to severe HIE), and only reported short-term outcomes. Therefore, few clinicians use theophylline in the management of these patients. Our long-term goal is to undertake an appropriately powered multicenter clinical trial to test the hypothesis that for infants > 35 weeks gestation treated with therapeutic hypothermia for HIE, intravenous theophylline (or aminophylline) within the first 12 hours after birth will result in a decreased incidence and/or severity of AKI or death (composite primary outcome) and improved long-term (2 year) renal outcomes. Before the conduct of a large trial, the feasibility of implementing the intervention and ability to measure relevant clinical outcomes need to be demonstrated. Therefore, we propose a small pilot and feasibility clinical trial to i) evaluate recruitment, protocol adherence, and data collection procedures in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to placebo in infants with HIE being treated with therapeutic hypothermia; ii) evaluate the utility and applicability of established measures (serum creatinine, urine output, fluid balance) and novel, exploratory approaches (urine biomarkers, large renal tubular extracellular vesicles and renal oxygen saturation) to identify AKI in infants; and iii) determine theophylline pharmacokinetic, pharmacodynamic, safety and preliminary effectiveness profiles of two different theophylline dosing regimens in a therapeutic trial of theophylline to decrease the incidence of AKI or death compared to placebo. Using a mixed methods data analysis strategy to assess the research and intervention process and examine outcomes of the intervention, we will generate the requisite data to inform development and implementation of an appropriately powered study to determine whether theophylline attenuates the risk and severity of AKI in infants with HIE treated with therapeutic hypothermia.