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.

Public Health Relevance

Using a machine that enables blood to bypass the heart and lungs, so called, cardiopulmonary bypass (CPB), is needed stop the heart and keep it still during operations to repair complicated anatomic abnormalities babies are often borne with termed congenital heart disease (CHD), This strategy enables life saving surgeries, but also contributes to organ injury or failure and at times the death experienced by children surviving this initial surgical repair. After CPB, release of both stress-related hormones and inflammatory molecules the body makes contribute to blood vessel inflammation and post-operative organ dysfunction. Furthermore, these molecules and hormones may mediate insulin resistance and contribute to the high rate of high blood sugars (called hyperglycemia) often seen in children after CPB. We believe that hyperglycemia negatively impacts organ function, increases the risk of getting an infection during the recovery period in the hospital, prolongs the time in the intensive care unit in very sick patients, but especially in patients following heart surgery. A collaborative, NIH-sponsored trial of infants undergoing CPB for CHD is being performed to determine whether tightly controlling the blood sugar in the post- operative time frame can alter these outcomes. Hyperglycemia and its main therapy, insulin, have been shown to impact the production of these problematic molecules in both humans and animals who are critically ill;however, the mechanism by which this approach affects the immune response remains unknown. Notably, a particular cell type that circulates in the blood stream called dendritic cell (DCs) play an important role in optimizing the function of the immune system and these cells are significantly decreased by inflammation as occurs after infections and probably CPB. This loss of DCs has been attributed to increased proinflammatory molecules and altered cellular energy states and most importantly has been shown to increase the risk of getting an infection. Furthermore, we've already observed a significant lowering of proinflammatory cytokine expression from circulating cells after CPB that we think may be due to unique changes on the parts of the DNA that determines how a molecule will be made or not. The current trial of tight glycemic control in pediatric cardiac surgical patients provides the opportunity to explore potential ways to reduce proinflammation, organ dysfunction and development of infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097361-04
Application #
8316242
Study Section
Special Emphasis Panel (ZHL1-CSR-G (F1))
Program Officer
Pemberton, Victoria
Project Start
2009-06-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$387,189
Indirect Cost
$121,470
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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