Phase IB Double Blind, Randomized, Placebo Controlled Clinical Trial to Determine the Pharmacokinetics and Safety of a Revised Protocol of Intravenous L-Citrulline (Citrupress®) Versus Placebo in Children Undergoing Cardiopulmonary Bypass
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- L-citrulline Plasma Levels
研究概览
简要总结
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.
The objective of this study is to determine in a randomized placebo controlled phase IB multicenter clinical trial if a revised protocol of intravenous L-citrulline delivery given perioperatively achieves a plasma citrulline level of > 100 umol/L in children undergoing surgical repair of an atrial septal defect,ventricular septal defect or an atrioventricular septal defect.
详细描述
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. It is 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Investigator)
入排标准
- 年龄范围
- — 至 6 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed Consent signed by the subject's legal representative
- •Subjects < 6 years old
- •Subjects undergoing cardiopulmonary bypass for repair of an atrial septal defect, a ventricular septal defect or an atrioventricular septal defect
排除标准
- •Pulmonary artery or vein abnormalities being addressed surgically
- •Preoperative requirement for invasive mechanical ventilation or intravenous inotrope support
- •Any condition which, in the opinion of the investigator, might interfere with study objectives
研究组 & 干预措施
Intravenous L-Citrulline
IV bolus of 150 mg/kg L-citrulline at the initiation of bypass, followed by L-citrulline (200 μmol/L) addition to the filtration or hemoconcentration replacement fluid used during bypass. Plus L-citrulline (20 mg/kg) bolus 30 minutes after decannulation from bypass, immediately followed by 9 mg/kg/h continuous L-citrulline infusion for 48 hours.
干预措施: Intravenous L-Citrulline (Drug)
Placebo of Intravenous L-Citrulline
Placebo administered according to the same schedule as L-citrulline
干预措施: Placebo of Intravenous L-Citrulline (Drug)
结局指标
主要结局
L-citrulline Plasma Levels
时间窗: Measured in seven blood sample time points from the beginning of surgery until end of IV Citrulline Infusion; at either 48 hours postoperatively or at extubation, whichever comes first.
Citrulline Blood Levels: 1. Baseline sample in OR prior to Cardiopulmonary Bypass prior to administration of first bolus of Citrulline or Placebo 2. Immediately after Bolus 1 administered in Operating Room. 3. 30 minutes after separation from Cardiopulmonary Bypass; immediately prior to administration of Bolus 2 and start of continuous infusion of Citrulline or Placebo. 4. Six hours after after start of infusion. 5. 12 hours after start of infusion. 6. 24 hours after start of infusion. 7. 48 hours after start of infusion; or whenever infusion is discontinued if prior to 48 hours.
次要结局
- Postoperative Invasive Mechanical Ventilation (Mean and SD)(Measured in hours from the end of surgery until extubation, or Day 30, whichever occurs first)
- Postoperative Invasive Mechanical Ventilation (Median and Range)(Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first)
- Total Duration of Respiratory Support(Baseline to discharge or Day 30, whichever occurs first)
- Postoperative Intravenous Inotrope Duration(Measured at 48 hours)
- Length of Hospitalization(Measured from the day of surgery until discharge from hospital or Day 30, whichever occurred first)
- Total Inotrope Score(PICU admission until Hour 48)
- Time on Vasoactive Medications(Hour 0 to Hour 48)
- Total Vasoactive Score(Hour 0 to Hour 48)
- Length of ICU Stay(Measured in hours from the end of surgery to discharge from ICU or Day 30, whichever occurred first)
- Composite Endpoint: Cessation of Positive Pressure Ventilation and of Inotrope Therapy(Until cessation of positive pressure ventilation and of inotrope therapy or Day 30, whichever occurred first)
- 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 or Day 30, whichever occurred first)
- Duration of Chest Tube Drainage(Measured in hours from the end of surgery until removal of chest tubes or Day 30, whichever occurred first)
- Volume of Chest Tube Drainage(Measured in milliliters from the end of surgery until removal of chest tubes or Day 30, whichever occurred first)
- Survival(Measured at 28 days post surgical repair)
- Number of Patients With Clinically Significant Hypotension.(Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU (Hour 0 to Hour 24) during Citrulline or Placebo infusion.)