Effects of glycemic control on immunity

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Abstract: Cardiopulmonary bypass (CPB) is necessary to repair complex congenital heart disease (CHD), but also contributes to the morbidity and mortality in children surviving surgical repair. Following CPB, release of both stress-related hormones and pro-inflammatory cytokines contribute to post-operative organ dysfunction by mediating endothelial cell-leukocyte adhesion and vascular inflammation. Furthermore, proinflammatory cytokines and stress hormones may mediate insulin resistance and contribute to the high rate of hyperglycemia in children after CPB. Increasingly, there is evidence to suggest that hyperglycemia negatively impacts organ function, acquisition of nosocomial infections, intensive care unit (ICU) length of stay, and mortality in various critically ill patient populations-but particularly in post-operative cardiovascular patients. A collaborative, randomized controlled trial (RCT) of infants undergoing CPB for CHD is being conducted to determine whether tight glycemic control in the post-operative time frame can alter these detrimental outcomes. Hyperglycemia and insulin have been shown to impact the production of cytokines in human and animal models of critical illnesses; however, the mechanism(s) by which tight glycemic control affects this host immune response remains unknown. Notably, circulating dendritic cells (DCs) play a key role in linking the innate and adaptive immune responses and are significantly decreased by inflammatory insults. This loss of DCs has been attributed to increased proinflammatory cytokines and altered cellular energetics and has been shown to increase the host's risk of infection. Furthermore, we've observed significant attenuation of proinflammatory cytokine expression from circulating monocytes post- CPB that we propose is due to epigenetically-mediated changes on the promoter regions of canonical type 1 and type 2 cytokines. The current RCT of tight glycemic control in pediatric cardiac surgical patients provides the opportunity to explore potential immunobiologic mechanisms that reduce proinflammation, organ dysfunction and development of infection. In the context of this trial, we aim to test the hypothesis that tight glycemic control during the post-operative period will modify the infant's immune response resulting in decreased pro-inflammation, increased circulating DCs and modified epigenetic signature thereby decreasing organ dysfunction and post-operative infections.