Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery

Phase 3

Completed

• Conditions: Heart Defects, Congenital; Hypertension, Pulmonary
• Interventions: Drug: Placebo of intravenous L-citrulline; Drug: L-citrulline

• Registration Number: NCT00335244
• Lead Sponsor: Asklepion Pharmaceuticals, LLC

Brief Summary

This clinical trial will determine the safety and effectiveness of intravenous L-citrulline in children undergoing cardiopulmonary bypass during heart surgery. Participants will be randomly assigned to either L-citrulline or a placebo (a substance that has no medicine in it).

Citrulline is a protein building block in the body that can convert into another substance, nitric oxide (NO), which controls blood pressure in the lungs. Increased blood pressure in the lungs can be an important surgical problem; it may also lead to problems following surgery, such as severe high blood pressure in the lungs (pulmonary hypertension), increased time spent on a breathing machine, and a longer stay in the intensive care unit (ICU). The hypothesis of this study is that perioperative supplementation with intravenous citrulline will increase plasma citrulline, arginine and NO metabolites and prevent elevations in the postoperative PVT leading to a decrease in the duration of postoperative invasive mechanical ventilation.

Detailed Description

Increased pulmonary vascular tone (PVT) can complicate the postoperative course of the following five 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) bidirectional Glenn shunt procedure; and 5) Fontan procedure for single ventricle lesions. PVT is partially controlled by 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 six previous surgical procedures. It was found that urea cycle function and plasma arginine levels were significantly decreased in all participants. Furthermore, participants with increased PVT had significantly lower arginine levels compared to participants 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.

Study Timeline

• Study Start: 2006-05
• Study First Submitted: 2006-06-07
• Study First Submitted QC: 2006-06-07
• Study First Posted: 2006-06-09
• Primary Completion: 2009-12
• Study Completion: 2009-12
• Disposition First Submitted: 2013-05-21
• Disposition First Submitted QC: 2013-05-21
• Disposition First Posted: 2013-05-29
• Status Verified: 2015-01
• Last Update Submitted: 2015-01-26
• Last Update Posted: 2015-02-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 77

Inclusion Criteria

• Undergoing cardiopulmonary bypass surgery with 1 of the following 5 procedures:

  1. AVSD repair
  2. VSD repair
  3. Bidirectional Glenn
  4. Modified Fontan
  5. Arterial switch

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, as determined by the investigator
• Pregnant

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Placebo of intravenous L-citrulline	Placebo of intravenous L-citrulline
1	L-citrulline	Intravenous L-citrulline

Primary Outcome Measures

Name	Time	Method
Duration of postoperative mechanical ventilation in hours compared between treatment groups.	Measured in hours from the end of surgery until extubation

Secondary Outcome Measures

Name	Time	Method
Length of hospitalization	Measured from the day of surgery until discharge from hospital
Length and volume of chest tube drainage	Measured in hours from the end of surgery until removal of chest tubes
Length of ICU stay	Measured in hours from the end of surgery to discharge from ICU
Postoperative intravenous inotrope score	Measured at 48 hours
Incidence of increased PVT (defined as a sustained mean pulmonary artery pressure greater than 20 mm Hg for at least 2 hours, measured during the first 48 hours	Measured in hours from the end of surgery until extubation
Survival	Measured at 30 days post surgical repair

Trial Locations

Locations (1)

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States