Optimizing Caffeine Therapy for Hypoxia in Preterm Neonates: A Randomized Trial Assessing Efficacy, Acute Kidney and Brain Injury, Safety, and Pharmacokinetics

/ABSTRACT Acute kidney injury (AKI), a serious complication in up to half of preterm neonates, independently increases morbidity and mortality. Current detection methods, such as near-infrared spectroscopy (NIRS), can identify kidney hypoxia—a precursor to AKI—earlier than traditional methods. However, effective therapies to prevent or treat AKI in this vulnerable population remain elusive. Intriguingly, non-randomized studies suggest that caffeine, a common medication in neonatal care, may lower AKI risk. Yet, rigorous investigations, particularly randomized trials focused on AKI prevention, are lacking since the landmark Caffeine Therapy for Apnea of Prematurity trial. Our long-term goal is to conduct a multicenter clinical trial to test the hypothesis that treatment of kidney hypoxia with caffeine will reduce rates of AKI and improve two-year-old kidney outcomes. “Optimizing Caffeine Therapy for Hypoxia in Preterm Neonates: A Randomized Trial Assessing Efficacy, Acute Kidney and Brain Injury, Safety, and Pharmacokinetics” is a five-year R01 that responds specifically to PAR-23-130: Translational Research in Maternal and Pediatric Pharmacology and Therapeutics. Our research team has developed the necessary protocols and tools using NIRS to measure kidney and cerebral oxygenation in preterm neonates. We have found significant associations between improvements in kidney oxygenation after daily maintenance doses of caffeine in preterm neonates with kidney hypoxia. We propose to investigate if an additional bolus dose of caffeine (either 10 mg/kg or 20 mg/kg) is more effective than placebo in treating kidney hypoxia in preterm neonates <30 weeks’ gestation with at least 30 minutes of kidney hypoxia (oxygenation <50%) in a randomized clinical trial. We aim to investigate the immediate and short-term kidney (Aim 1) and brain outcomes (Aim 2) and to develop a pharmacokinetic model of kidney hypoxia and caffeine levels (Aim 3). Our research stands out for its innovative approach: using changes in kidney oxygenation, measured by NIRS, as the primary outcome to promptly assess the efficacy of our proposed intervention. The research holds significant potential; should the intervention prove effective, it paves the way for a large-scale, multi-center trial aimed at investigating caffeine's role in preventing and reducing the incidence of AKI, as well as improving kidney outcomes over a two-year period. Our team, with its robust pilot data and dedicated focus on neonatal kidney research, is ideally suited to fulfill the objectives of this award. Project Number: 1R01HD116793-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Matthew Harer | Institution: UNIVERSITY OF WISCONSIN-MADISON, MADISON, WI | Award Amount: $421,691 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 MCST-M (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11679301