Citrulline for Children Undergoing Cardiopulmonary Bypass Surgery

Cardiovascular Diseases Clinical Trial

Official title:

Phase I/II Clinical Trial to Determine the Pharmacokinetics and Safety Profile of Citrulline in Children Undergoing Cardiopulmonary Bypass

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00201214
• Other study ID #: 281
• Secondary ID: R01HL073317
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 16, 2005
• Last updated: September 10, 2013
• Start date: December 2003
• Est. completion date: December 2009

Study information

• Verified date: September 2013
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

This study will determine the pharmacokinetics and safety of intravenous citrulline given to children undergoing cardiopulmonary bypass for the correction of congenital heart defects.

Description:

BACKGROUND:

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.

DESIGN NARRATIVE:

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.

Other known NCT identifiers

• NCT00178815

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: December 2009
• Est. primary completion date: January 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

• Undergoing cardiopulmonary bypass via one of the following surgical procedures:

1. AVSD repair

2. VSD repair

3. Bidirectional Glenn

4. Modified Fontan

5. Arterial Switch

• Parents willing and able to sign consent

Exclusion Criteria:

• Pulmonary artery or vein abnormalities not being addressed surgically

• Preoperative requirement for mechanical ventilation or intravenous inotrope support

• Any condition that might interfere with study objectives

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Congenital Abnormalities
• Heart Defects, Congenital
• Heart Diseases

Intervention

Drug:
• Citrulline
Phase I - 150mg/kg IV bolus after initiation of cardiopulmonary bypass with dosage escalation study 50mg/kg, 100mg/kg, 150mg/kg IV at 6, 12, 24, 48 hours post operative. Phase II - 150mg/kg IV bolus after initiation of cardiopulmonary bypass with 9mg/kg/hr continuous IV starting 4 hours post bolus and infusing for 48 hours or discharge from PCCU.

Locations

Country	Name	City	State
United States	Vanderbilt University	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Vanderbilt University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Barr FE, Tirona RG, Taylor MB, Rice G, Arnold J, Cunningham G, Smith HA, Campbell A, Canter JA, Christian KG, Drinkwater DC, Scholl F, Kavanaugh-McHugh A, Summar ML. Pharmacokinetics and safety of intravenously administered citrulline in children undergoi — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Oxygen index (OI) data to assess increased PVT		Measured through the use of continuous mean arterial pressure monitoring	No
Primary	Qp:Qs ratios to assess increased PVT		Measured by blood gases collected 48 hours post-operative	No
Primary	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		Measured through the use of continuous mean arterial pressure monitoring 48 hours post-operative	Yes