Clinical trial NCT00335244: Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery
Official title: A Phase III Single-Blind, Randomized, Placebo Controlled, Clinical Trial to Determine the Safety and Efficacy of Intravenous L-Citrulline Versus Placebo in Children Undergoing Cardiopulmonary Bypass
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Defects, Congenital
Hypertension, Pulmonary
Lead sponsor: Asklepion Pharmaceuticals, LLC
Sponsor class: INDUSTRY
Collaborators: name: Vanderbilt University
First posted: 2006-06-09
Enrollment: 77
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Duration of postoperative mechanical ventilation in hours compared between treatment groups.
timeFrame: Measured in hours from the end of surgery until extubation
Secondary outcomes:
measure: 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
timeFrame: Measured in hours from the end of surgery until extubation
measure: Postoperative intravenous inotrope score
timeFrame: Measured at 48 hours
measure: Length and volume of chest tube drainage
timeFrame: Measured in hours from the end of surgery until removal of chest tubes
measure: Length of ICU stay
timeFrame: Measured in hours from the end of surgery to discharge from ICU
measure: Length of hospitalization
timeFrame: Measured from the day of surgery until discharge from hospital
measure: Survival
timeFrame: Measured at 30 days post surgical repair
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Fredrick E. Barr, MD, MSCI
role: PRINCIPAL_INVESTIGATOR
References: