Optimizing caffeine exposure to reduce post-cardiopulmonary bypass acute kidney injury in neonates
Elizabeth Thompson, MD
BACKGROUND: For neonates requiring lifesaving heart surgery on cardiopulmonary bypass, acute kidney injury (AKI) is a common and deadly complication with no proven preventive or therapeutic options. Caffeine has been shown to decrease AKI in preterm neonates without heart disease, and may decrease AKI in neonates with heart disease through adenosine receptor antagonism. GAP: Disease- and cardiopulmonary bypass-specific factors affecting the caffeine dose-exposure-response relationship for protection against post-CPB AKI in neonates are unknown. This study will identify a potential drug to prevent post-bypass AKI and define the caffeine dose-exposure-AKI relationship in neonates with heart disease undergoing surgery on bypass. HYPOTHESIS: We hypothesize that bypass time, single ventricle disease, and gestational age will be significant covariates, accounting for up to 20% of the observed interindividual variability of caffeine clearance and that a 10% increase above the current labeled dose of caffeine will be needed pre-bypass to maintain a peak concentration >6 mg/L and reduce odds of AKI by 20%. Additionally, we hypothesize that our refined population pharmacokinetic (PopPK) model will adequately predict caffeine exposure in neonates with heart disease undergoing surgery on bypass, with mean prediction errors and mean absolute predictions errors <20%. METHODS: Leveraging the existing infrastructure of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial (NCT03119538) and the clinically integrated OPportunistic pharmacokinetic/pharmacokinetic (PK/PD) Trial in critically Ill Children (OPTIC; NCT05055830), this study will: 1) Refine an existing caffeine PopPK model with disease- and CPB-specific effects, 2) Conduct dosing simulations in RWD, and 3) Prospectively validate the PopPK model and dosing simulations in a cohort of neonates undergoing surgery with bypass. RESULTS: Pending. IMPACT: The results of this study will support a definitive prospective randomized efficacy trial of caffeine for the prevention of post-bypass AKI and establish a platform to evaluate factors affecting drug pharmacokinetics, scalable to other drugs in other vulnerable populations.