Citrulline for Children Undergoing Cardiopulmonary Bypass Surgery
This study will determine the pharmacokinetics and safety of intravenous citrulline given to children undergoing cardiopulmonary bypass for the correction of congenital heart defects.
Heart Defects, Congenital
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Clinical Trial to Determine the Pharmacokinetics and Safety Profile of Citrulline in Children Undergoing Cardiopulmonary Bypass|
- Oxygen index (OI) data to assess increased PVT [ Time Frame: Measured through the use of continuous mean arterial pressure monitoring ] [ Designated as safety issue: No ]
- Qp:Qs ratios to assess increased PVT [ Time Frame: Measured by blood gases collected 48 hours post-operative ] [ Designated as safety issue: No ]
- Increased PVT as measured by a sustained mean pulmonary artery pressure greater than 20 mm Hg for at least 2 hours during the first 24 hours postoperatively [ Time Frame: Measured through the use of continuous mean arterial pressure monitoring 48 hours post-operative ] [ Designated as safety issue: Yes ]
|Study Start Date:||December 2003|
|Study Completion Date:||December 2009|
|Primary Completion Date:||January 2006 (Final data collection date for primary outcome measure)|
Increased pulmonary vascular tone (PVT) can complicate the postoperative course of the following six surgical procedures for congenital heart defects: 1) unrestrictive ventricular septal defect (VSD) repair; 2) atrioventricular septal (AVSD) repair; 3) arterial switch procedure for transposition of the great arteries (TGA); 4) Norwood I procedure; 5) bidirectional Glenn shunt procedure; and 6) Fontan procedure for single ventricle lesions. PVT is partially controlled by nitric oxide (NO). Arginine, the precursor to NO, is a product of the urea cycle. Preliminary data have been presented regarding 169 infants and children who have undergone one of the six previous surgical procedures. It was found that urea cycle function and plasma arginine levels were significantly decreased in all patients. Furthermore, patients with increased PVT had significantly lower arginine levels compared to patients with normal PVT. Finally, a genetic single nucleotide polymorphism (SNP) in the rate limiting urea cycle enzyme (carbamyl phosphate synthetase I [CPSl T1405N]) appeared to affect postoperative plasma arginine levels and PVT. The hypothesis is that genetic polymorphisms in the rate limiting urea cycle enzyme CPSl, and other important enzymes in the urea cycle, influence the availability of NO precursors. It is further hypothesized that perioperative enhancement of urea cycle function with the key urea cycle intermediate (citrulline) will increase plasma arginine and NO metabolites, and prevent elevations in PVT.
This phase I/II study will determine the pharmacokinetics and safety of three doses of intravenous citrulline that will be given to children undergoing cardiopulmonary bypass for the correction of congenital heart defects.
|United States, Tennessee|
|Nashville, Tennessee, United States, 37212|
|Study Chair:||Frederick E. Barr, MD, MSCI||Vanderbilt University|