Evaluating post-op AKI criteria in infants with CHD and the protective effects of acetaminophen
Reid Chamberlain, MD
BACKGROUND: Post-operative acute kidney injury (AKI) is a major contributor to adverse outcomes and mortality in infants undergoing congenital heart defect (CHD) surgery. The study and prevention of AKI in children after CHD surgery is complicated by a multi-factorial causal pathway and numerous clinical criteria defining AKI. Emerging data support that acetaminophen may reduce AKI risk through reduction of nephrotoxic free hemoglobin radicals. GAP: First, the acetaminophen exposure-response relationship is unknown and precludes optimal individualized dosing to protect against AKI. Second, the most recent AKI criteria, Kidney Disease Improving Global Outcomes (KDIGO), have not been rigorously validated as predictors of adverse outcomes in infants following CHD surgery. HYPOTHESIS: First, the clearance of acetaminophen will correlate directly with age and weight at surgery and indirectly with cardiopulmonary bypass time. It will be feasible to identify an optimized acetaminophen exposure associated with 20% lower risk of ≥ stage 2 KDIGO-defined AKI. Second, subjects with ≥ stage 2 KDIGO-defined AKI will have a 3.5-fold increased risk of post-operative mortality after controlling for other surgical risk factors METHODS: Leveraging the existing infrastructure of the STRESS trial (STeroids to REduce Systemic inflammation after infant heart Surgery), this 2-part sub-study will: 1) use a prospective single-arm, open label per standard of care drug study to define the pharmacokinetics of acetaminophen and determine the exposure-response relationship of acetaminophen and AKI in 40 STRESS trial infants, and 2) evaluate the relationship between KDIGO-defined AKI and post-operative morbidity and mortality in 240 STRESS trial enrollees. RESULTS: A total of 40 participants enrolled with a mean age of 88 days and mean weight of 4.8 kg. Participants were predominantly female (21/40, 53.0%) and Caucasian (27/40, 67.5%). Intravenous acetaminophen dosing ranged from 11.6-15.1mg/kg/dose every 6 to 8 hours. The population estimate for acetaminophen volume of distribution is 10.5 L (95% CI 8.8-12.3L). The population estimate for acetaminophen clearance is 0.27L/hr (95% CI 0.21-0.34 L/hr). Further analysis is ongoing. IMPACT: Data from these studies will support a future prospective trial of acetaminophen for prevention of post-operative AKI after CHD surgery.