Trial Outcomes & Findings for Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol (NCT NCT01120964)
NCT ID: NCT01120964
Last Updated: 2022-07-27
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
22 participants
Primary outcome timeframe
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.
Results posted on
2022-07-27
Participant Flow
Participant milestones
| Measure |
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Overall Study
STARTED
|
11
|
11
|
|
Overall Study
COMPLETED
|
10
|
11
|
|
Overall Study
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Overall Study
Did not receive full treatment
|
1
|
0
|
Baseline Characteristics
Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
Baseline characteristics by cohort
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
Total
n=22 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
<=18 years
|
11 Participants
n=5 Participants
|
11 Participants
n=7 Participants
|
22 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Age, Continuous
|
28.5 Months
STANDARD_DEVIATION 22.4 • n=5 Participants
|
15.3 Months
STANDARD_DEVIATION 17.1 • n=7 Participants
|
21.9 Months
STANDARD_DEVIATION 20.6 • n=5 Participants
|
|
Sex: Female, Male
Female
|
5 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
6 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
1 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
10 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
17 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
11 participants
n=5 Participants
|
11 participants
n=7 Participants
|
22 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 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.Population: All randomized patients that received surgery, were treated with L-citrulline, and had at least 1 citrulline concentration measurement
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.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
L-citrulline Plasma Levels
Baseline
|
200.9 µmol/L
Standard Deviation 569.89
|
34.1 µmol/L
Standard Deviation 7.5
|
|
L-citrulline Plasma Levels
Post Bolus 1
|
2405.9 µmol/L
Standard Deviation 1517.4
|
29.5 µmol/L
Standard Deviation 5.96
|
|
L-citrulline Plasma Levels
Pre Bolus 2
|
890.9 µmol/L
Standard Deviation 1077.5
|
30.6 µmol/L
Standard Deviation 10.46
|
|
L-citrulline Plasma Levels
Hour 6
|
167.8 µmol/L
Standard Deviation 117.67
|
24.1 µmol/L
Standard Deviation 7.76
|
|
L-citrulline Plasma Levels
Hour 12
|
127.1 µmol/L
Standard Deviation 16.18
|
19.9 µmol/L
Standard Deviation 7.01
|
|
L-citrulline Plasma Levels
Hour 24
|
125.3 µmol/L
Standard Deviation 38.74
|
12.9 µmol/L
Standard Deviation 2.89
|
|
L-citrulline Plasma Levels
Hour 48
|
—
|
12.3 µmol/L
Standard Deviation 3.4
|
SECONDARY outcome
Timeframe: Measured in hours from the end of surgery until extubation, or Day 30, whichever occurs firstDuration of postoperative invasive mechanical ventilation was derived as the time in hours from separation from cardiopulmonary bypass until endotracheal extubation. If a patient required reintubation within 24 hours after extubation, the reintubation time was added in the main analysis. In a second analysis, the reintubation time was not included.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Postoperative Invasive Mechanical Ventilation (Mean and SD)
Re-intubation time included
|
5.1 Hours
Standard Deviation 8.15
|
37.1 Hours
Standard Deviation 65.41
|
|
Postoperative Invasive Mechanical Ventilation (Mean and SD)
Re-intubation time excluded
|
5.1 Hours
Standard Deviation 8.15
|
24.7 Hours
Standard Deviation 26.83
|
SECONDARY outcome
Timeframe: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred firstDuration of postoperative invasive mechanical ventilation was derived as the time in hours from separation from cardiopulmonary bypass until endotracheal extubation. If a patient required reintubation within 24 hours after extubation, the reintubation time was added in the main analysis. In a second analysis, the reintubation time was not included.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Postoperative Invasive Mechanical Ventilation (Median and Range)
Re-intubation time included
|
0.0 Hours
Interval 0.0 to 22.5
|
21.7 Hours
Interval 0.0 to 229.3
|
|
Postoperative Invasive Mechanical Ventilation (Median and Range)
Re-intubation time excluded
|
0.0 Hours
Interval 0.0 to 22.5
|
21.7 Hours
Interval 0.0 to 92.3
|
SECONDARY outcome
Timeframe: Baseline to discharge or Day 30, whichever occurs firstPopulation: All randomized patients that received surgery
Analysis included any invasive and non-invasive respiratory support required during the study period
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Total Duration of Respiratory Support
|
31.2 Hours
Standard Deviation 28.27
|
81.9 Hours
Standard Deviation 66.23
|
SECONDARY outcome
Timeframe: Measured at 48 hoursThe length of time on IV inotropes was documented from the time of first use after surgery until completion of the study medication at Hour 48 (i.e., duration of inotrope use was maximally 48 hours). Patients still receiving inotropes at Hour 48 were censored.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Postoperative Intravenous Inotrope Duration
|
13.4 Hours
Standard Deviation 14.78
|
26.1 Hours
Standard Deviation 23.0
|
SECONDARY outcome
Timeframe: PICU admission until Hour 48The inotrope dose was calculated each hour postoperatively from the time of PICU admission until the completion of study drug using the following scoring system: Dopamine (μg/kg/min) x 1 plus Dobutamine (μg/kg/min) x 1 plus Milrinone (μg/kg/min) x10 plus Epinephrine (Adrenaline) (μg/kg/min) x 100 plus Phenylephrine (μg/kg/min) x 100 plus Norepinephrine (Noradrenaline) (μg/kg/min) x 100 = Total inotrope score An ANOVA was performed. Additionally a repeated measures analysis of variance was used to compare total inotrope score between placebo and citrulline.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Total Inotrope Score
|
602.7 µg/kg/min
Standard Deviation 727.86
|
1162.6 µg/kg/min
Standard Deviation 951.31
|
SECONDARY outcome
Timeframe: Hour 0 to Hour 48The total number of hours on vasoactive medications, including nitroglycerin, nitroprusside and vasopressin, was calculated from the end of surgery until the discontinuation of vasoactive medications or end of study medication (Hour 48), whichever occurred first
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Time on Vasoactive Medications
|
6.3 Hours
Standard Deviation 7.18
|
9.8 Hours
Standard Deviation 15.09
|
SECONDARY outcome
Timeframe: Hour 0 to Hour 48Vasoactive score is reflective of the pharmacological support required by the cardiovascular system and is a good predictor of mortality and morbidity in patients undergoing bypass surgery. A lower vasoactive score represents less pharmacological support and would indicate a lower risk for a poor clinical outcome. Therefore, any treatment effect would be indicated by a lower score in the citrulline group when compared to the placebo group. In this study, the score was calculated post-operatively from the time of separation from bypass until the completion of study drug. Vasoactive score was calculated using the following formula: Total Vasoactive Score = nitroglycerin dose + nitroprusside dose + vasopressin dose The minimum value is zero (i.e., no vasoactive drugs administered), but it is not possible to define a maximum as this is wholly dependent upon the dose of each vasoactive drug administered.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Total Vasoactive Score
|
5.5 Score on a scale
Standard Deviation 10.62
|
10.6 Score on a scale
Standard Deviation 17.42
|
SECONDARY outcome
Timeframe: Measured in hours from the end of surgery to discharge from ICU or Day 30, whichever occurred firstDuration of ICU stay was analyzed once as the total number of postoperative hours spent in the ICU and once as the total number of postoperative hours that a patient required postoperative mechanical ventilator or continuous intravenous inotrope or vasodilator support. The latter combination of parameters represents another surrogate endpoint for ICU stay
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Length of ICU Stay
Duration of PICU stay
|
35.94 Hours
Standard Deviation 16.150
|
105.08 Hours
Standard Deviation 187.762
|
|
Length of ICU Stay
Longest duration of mechanical ventilation, IV inotrope or vasodilator use (re-intubation included)
|
14.5 Hours
Standard Deviation 13.99
|
44.4 Hours
Standard Deviation 63.62
|
|
Length of ICU Stay
Longest duration of mechanical ventilation, IV inotrope or vasodilator use (re-intubation excluded)
|
14.5 Hours
Standard Deviation 13.99
|
32.0 Hours
Standard Deviation 26.26
|
SECONDARY outcome
Timeframe: Until cessation of positive pressure ventilation and of inotrope therapy or Day 30, whichever occurred firstThe composite endpoint comprised the longer of the duration of positive pressure ventilatory support or of inotrope therapy. Since inotrope use was only documented until Hour 48 after surgery (end of study medication treatment), patients with inotrope use continuing until Hour 48 and with mechanical ventilation duration of ≤48 h were censored at this time point. If mechanical ventilation was continued beyond the 48-hour time point, the duration of mechanical ventilation was used in the analysis.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Composite Endpoint: Cessation of Positive Pressure Ventilation and of Inotrope Therapy
Re-intubation time included
|
14.3 Hours
Standard Deviation 14.06
|
44.4 Hours
Standard Deviation 63.62
|
|
Composite Endpoint: Cessation of Positive Pressure Ventilation and of Inotrope Therapy
Re-intubation time excluded
|
14.3 Hours
Standard Deviation 14.06
|
32.0 Hours
Standard Deviation 26.26
|
SECONDARY outcome
Timeframe: Measured from the day of surgery until discharge from hospital or Day 30, whichever occurred firstOutcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Length of Hospitalization
|
4.6 Days
Standard Deviation 1.21
|
8.4 Days
Standard Deviation 9.38
|
SECONDARY outcome
Timeframe: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred firstPopulation: It was not possible to reliably determine the presence of PVT in most patients due to low quality ECHO images. Additionally, no patients were identified with sufficient ECHO measurements to detect the presence of sustained mean pulmonary artery pressure greater than 20 mm Hg for at least 2 hours.
There were insufficient data to analyze ECHO measurements in summary statistics. Additionally, most images were of very low quality and the data from ECHO evaluations were insufficient to determine whether the affected patients had pulmonary hypertension.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Measured in hours from the end of surgery until removal of chest tubes or Day 30, whichever occurred firstOutcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Duration of Chest Tube Drainage
|
82.7 Hours
Standard Deviation 30.4
|
90.2 Hours
Standard Deviation 43.7
|
SECONDARY outcome
Timeframe: Measured in milliliters from the end of surgery until removal of chest tubes or Day 30, whichever occurred firstOutcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Volume of Chest Tube Drainage
|
211 mL
Standard Deviation 102
|
240 mL
Standard Deviation 257
|
SECONDARY outcome
Timeframe: Measured at 28 days post surgical repair28-day postoperative survival and survival to discharge
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Survival
|
11 Participants
|
11 Participants
|
SECONDARY outcome
Timeframe: Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU (Hour 0 to Hour 24) during Citrulline or Placebo infusion.Age specific mean arterial blood pressure (MAP) limits compared between the citrulline and placebo groups will be used to determine significant hypotension. Defined as MAP below a specific age-based value (infants and age 1 year, 40; ; age 2 years, 44; age 3 years, 47; age 4 years, 50; age 5 years, 52; age 6 years, 53), that lasted greater than 30 minutes and was unresponsive to therapeutic interventions such as fluid administration (volume bolus) and increasing inotropic support.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Number of Patients With Clinically Significant Hypotension.
|
2 Participants
|
1 Participants
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline to Hour 48Population: All randomized patients that received surgery, were treated with L-citrulline, and had at least 1 arginine concentration measurement
Citrulline is the precursor of arginine and nitric oxide. Nominal sampling times were Baseline, Post-bolus 1, Pre-bolus 2, and Hours 2, 6, 12, 24 and 48.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Arginine Concentrations
Baseline
|
49.6 µmol/L
Standard Deviation 15.72
|
58.7 µmol/L
Standard Deviation 12.37
|
|
Arginine Concentrations
Post Bolus 1
|
72.6 µmol/L
Standard Deviation 30.02
|
47.7 µmol/L
Standard Deviation 7.43
|
|
Arginine Concentrations
Pre Bolus 2
|
145.1 µmol/L
Standard Deviation 47.94
|
67.1 µmol/L
Standard Deviation 11.66
|
|
Arginine Concentrations
Hour 6
|
67.0 µmol/L
Standard Deviation 22.66
|
47.3 µmol/L
Standard Deviation 12.29
|
|
Arginine Concentrations
Hour 12
|
61.5 µmol/L
Standard Deviation 17.37
|
39.0 µmol/L
Standard Deviation 12.04
|
|
Arginine Concentrations
Hour 24
|
65.8 µmol/L
Standard Deviation 18.8
|
28.1 µmol/L
Standard Deviation 12.56
|
|
Arginine Concentrations
Hour 48
|
—
|
34.5 µmol/L
Standard Deviation 15.33
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline to Hour 48Population: All randomized patients that received surgery, were treated with L-citrulline, and had at least 1 arginine concentration measurement
Citrulline is the precursor of arginine and nitric oxide. Nominal sampling times were Baseline, Post-bolus 1, Pre-bolus 2, and Hours 2, 6, 12, 24 and 48.
Outcome measures
| Measure |
Intravenous L-Citrulline
n=11 Participants
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 Participants
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Nitric Oxide Concentrations
Baseline
|
31.6 µmol/L
Standard Deviation 13.51
|
69.5 µmol/L
Standard Deviation 41.34
|
|
Nitric Oxide Concentrations
Post Bolus 1
|
25.3 µmol/L
Standard Deviation 12.76
|
51.3 µmol/L
Standard Deviation 38.83
|
|
Nitric Oxide Concentrations
Pre Bolus 2
|
30.7 µmol/L
Standard Deviation 12.64
|
48.8 µmol/L
Standard Deviation 29.16
|
|
Nitric Oxide Concentrations
Hour 6
|
32.0 µmol/L
Standard Deviation 16.97
|
59.9 µmol/L
Standard Deviation 45.59
|
|
Nitric Oxide Concentrations
Hour 12
|
26.6 µmol/L
Standard Deviation 13.43
|
62.0 µmol/L
Standard Deviation 42.89
|
|
Nitric Oxide Concentrations
Hour 24
|
29.1 µmol/L
Standard Deviation 12.14
|
51.1 µmol/L
Standard Deviation 42.58
|
|
Nitric Oxide Concentrations
Hour 48
|
—
|
42.5 µmol/L
Standard Deviation 17.48
|
Adverse Events
Intravenous L-Citrulline
Serious events: 0 serious events
Other events: 8 other events
Deaths: 0 deaths
Placebo of Intravenous L-Citrulline
Serious events: 0 serious events
Other events: 11 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Intravenous L-Citrulline
n=11 participants at risk
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.
Intravenous L-Citrulline
|
Placebo of Intravenous L-Citrulline
n=11 participants at risk
Placebo administered according to the same schedule as L-citrulline
Placebo of Intravenous L-Citrulline: Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug
|
|---|---|---|
|
Blood and lymphatic system disorders
Anemia
|
18.2%
2/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Blood and lymphatic system disorders
Leukocytosis
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Atrial tachycardia
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Atrioventricular block
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Atrioventricular block complete
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Bradycardia
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Nodal rhythm
|
27.3%
3/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Pericardial effusion
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Tachycardia
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Cardiac disorders
Ventricular fibrillation
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Gastrointestinal disorders
Constipation
|
18.2%
2/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Gastrointestinal disorders
Nausea
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Gastrointestinal disorders
Vomiting
|
27.3%
3/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
General disorders
Pyrexia
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Infections and infestations
Abscess limb
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Infections and infestations
Tracheitis
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Investigations
Blood potassium decreased
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
18.2%
2/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Investigations
Blood pressure systolic decreased
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Investigations
Platelet count decreased
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
18.2%
2/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Investigations
Prothrombin time prolonged
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Atelectasis
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Chylothorax
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Haemothorax
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Pleural effusion
|
45.5%
5/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
36.4%
4/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Respiratory, thoracic and mediastinal disorders
Tachypnea
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
27.3%
3/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Vascular disorders
Hemorrhage
|
18.2%
2/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Vascular disorders
Hypertension
|
36.4%
4/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
27.3%
3/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Vascular disorders
Hypotension
|
18.2%
2/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
27.3%
3/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
|
Vascular disorders
Thrombosis
|
0.00%
0/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
9.1%
1/11 • From baseline until discharge, Day 28 or early termination
Obtained from signs and symptoms detected during peri- and postoperative clinical monitoring and from observations of the study personnel
|
Additional Information
Gurdyal Kalsi, MD, MFPM (Hon)
Asklepion Pharmaceuticals, LLC
Phone: +1 410.736.3750
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60