Background: Surgical repair of congenital heart defects with cardiopulmonary bypass (CPB) places children at significant risk of global ischemia/reperfusion, systemic inflammation, and organ injury. Prognostic markers and therapeutic interventions for CPB related-injury are limited. Alkaline phosphatase (AP) is an endogenous enzyme that may protect against inflammation and ischemia/reperfusion through detoxification of endotoxin and dephosphorylation of extracellular ATP leading to protective adenosine signaling. Treatment with exogenous AP improves inflammation/outcomes in animal models and adult studies of inflammatory bowel disease and sepsis. AP may also play a significant role during cardiac surgery. We recently demonstrated a substantial decrease in AP activity 24 hours after cardiac surgery in infants. Low AP activity was independently associated with increased post-operative support and increased systemic inflammation. Additional research is needed to fully understand the role of AP in this patient population as a diagnostic marker and potential therapeutic agent.Hypothesis: Low AP activity after infant CPB increases the risk of systemic inflammation, organ injury, prolonged post-operative ICU support, and poor outcomes including cardiac arrest, mechanical circulatory support, or death.Specific Aims:1)Confirm association of AP activity with intensity of post-operative su pport/clinical outcomes and establish the threshold most predictive of adverse outcomes. 2) Determine if change in AP activity following CPB is due to protein loss or alteration of enzyme function. 3) Define relationship of AP activity to cytokine release, endotoxemia, activation of host defense pathways, and organ injury. Study Design: Prospective observational cohort study of 120 infants undergoing cardiac surgery with CPB. Total AP activity and isoform concentrations will be measured at 0, 6, 24, 48, and 72 hours after surgery. AP activity will be correlated to post-operative support and the combined outcome of cardiac arrest, mechanical circulatory support, or death. We will test for associations between AP activity and key markers of inflammation, host-defense pathways, and end-organ injury using MesoScale multiplex immunoassays. Potential Impact: The results of this study will fully establish AP as a novel predictive biomarker in this population and help direct our future studies of AP treatment aimed at improving outcomes after pediatric cardiac surgery.
|Program type||Mentored Clinical & Population Research Program|
|Effective start/end date||07/01/2013 → 08/01/2014|