The goals of this proposal are two-fold: first to improve the clinical outcome of children undergoing cardiopulmonary bypass (CPB) by characterization and modulation of CPB-induced systemic inflammatory response syndrome (SIRS); and second, to develop the principal investigator as an independent researcher. CPB is an essential element in the surgical correction of congenital heart disease (CHD). However, CPB induces a SIRS that contributes to morbidity and mortality in children undergoing open heart surgery. The exact mechanism by which CPB induces SIRS has not been fully elucidated; however, there is evidence that endotoxin plays a significant role. Circulating endotoxin levels rise during and after CPB. A significant number of children with CHD are endotoxemic preoperatively, and preoperative endotoxemia correlates with worse clinical outcome. Endotoxin is partially responsible for the activation of complement and release of cytokines after CPB, and elevated cytokine and complement levels are associated with SIRS and multiorgan dysfunction in children undergoing CPB. Additionally, low preoperative anti-endotoxin antibody levels are associated with more complications after CPB. We hypothesize that inhibition of endotoxin perioperatively will improve outcome after CPB. Bactericidal/permeability-increasing protein (BPI) is an endotoxin-neutralizing protein released from activated neutrophils. A recombinant form of human BPI (rBPI-21) has been shown to be safe and effective in neutralizing endotoxin in human volunteers and to be safe and decrease morbidity in children with meningococcal sepsis.
The specific aim of this prospective randomized, double-blind, placebo controlled trial is to test whether perioperative administration of BPI improves clinical outcome in children undergoing CPB. Subsequent aims are to better characterize the inflammatory response to CPB in children and to identify and pursue novel anti-inflammatory strategies to improve clinical outcome in children undergoing CPB. The candidate's research career goals include acquiring expertise in the field of CPB-associated inflammatory response, completion of a randomized, double-blind placebo controlled trial of clinical significance, acquiring further education/training and expertise in clinical research to include courses in research design and statistical analysis, conduction of additional clinical trials and coordination of multi-center trials in the area of CPB and congenital heart surgery, and contribution to the training of ICU fellows in the conduction of clinical research.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
7K23HL073832-04
Application #
7227878
Study Section
Special Emphasis Panel (ZHL1-CSR-J (F1))
Program Officer
Scott, Jane
Project Start
2004-05-01
Project End
2009-05-31
Budget Start
2007-06-15
Budget End
2008-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$108,000
Indirect Cost
Name
Children's Mercy Hosp (Kansas City, MO)
Department
Type
DUNS #
073067480
City
Kansas City
State
MO
Country
United States
Zip Code
64108