Myocardial dysfunction and resulting low cardiac output syndrome (LCOS) contribute significantly to postoperative morbidity and mortality in pediatric heart surgery. Despite major advances in diagnostic accuracy and intra-operative myocardial protection strategies, LCOS remains an important clinical problem with an estimated incidence of ~25% in infants undergoing cardiopulmonary bypass. This application proposes a multi-center, randomized, double blind, placebo-controlled clinical trial, to investigate whether preoperative administration of glucocorticoids (methylprednisolone, steroids) and/or erythropoietin (EPO) will afford protection from ischemia-reperfusion injury and thereby reduce the incidence of LCOS for infants undergoing cardiopulmonary bypass. Furthermore, although there are important interactions between these two agents, the primary signaling pathways are distinct;hence, combined use may result in a synergistic reduction in the incidence of LCOS. There will be four preoperative treatment arms: 1) placebo;2) steroids;3) EPO;and 4) steroids and EPO combined. The study design assumes that intra-operative steroids will be administered. This assumption is based on a recent published survey documenting this as common practice in pediatric centers, and our own investigations that demonstrate an improved benefit from pre- and intraoperative steroid use. The Primary Aim of the proposed study is to compare the effect of preoperative steroids and/or EPO with placebo on LCOS incidence through the first 48 hours following cardiopulmonary bypass surgery. Hypotheses to be tested include: 1) Preoperative steroids protect against ischemia-reperfusion injury to enhance myocardial performance postoperatively, resulting in a lower incidence of LCOS. 2) Preoperative EPO protects cardiomyocytes during ischemia-reperfusion, resulting in improved myocardial performance postoperatively with a subsequent reduction in the incidence of LCOS. 3) Concurrent administration of preoperative steroids and EPO will have a synergistic effect to reduce the incidence of LCOS. The Primary Outcome is LCOS. The diagnosis of LCOS will be based on a composite of clinical signs and symptoms, biochemical markers, and the need for additional inotropic/mechanical support. Five Secondary Aims will assess treatment effects on mortality and clinical measures of morbidity, postoperative myocardial performance, inflammatory and non-inflammatory mediators of myocardial dysfunction pre- and post-heart surgery, cardiomyocyte protection and apoptosis pre- and post-cardiopulmonary bypass surgery and the incidence of renal injury within 48 hours after cardiopulmonary bypass surgery. Completion of the proposed studies should greatly improve our understanding of ischemia-reperfusion injury and therapies to prevent LCOS following surgery with cardiopulmonary bypass in infants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL085057-04
Application #
7687500
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M1))
Program Officer
Pearson, Gail D
Project Start
2006-09-04
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$291,300
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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