Trial Outcomes & Findings for L-citrulline for Prevention of Sequelae of Acute Lung Injury in Pediatrics Undergoing Cardiopulmonary Bypass for Heart Defects (NCT NCT02891837)

NCT ID: NCT02891837

Last Updated: 2023-02-23

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

189 participants

Primary outcome timeframe

28 Days

Results posted on

2023-02-23

Participant Flow

Participant milestones

Participant milestones
Measure	L-citrulline * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Overall Study STARTED	99	90
Overall Study COMPLETED	96	90
Overall Study NOT COMPLETED	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	L-citrulline * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Overall Study Lost to Follow-up	2	0
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

See section "Baseline Analysis Population Description".

Baseline characteristics by cohort

PRIMARY outcome

Timeframe: 28 Days

Population: All patients (mFAS)

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
A Composite Variable Consisting of the Longer of Either (1) Length of Time on Mechanical Ventilation or (2) Length of Inotrope Use.	3351.1 Minutes Standard Deviation 5230.8	3549.6 Minutes Standard Deviation 6069.1	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

The same definitions and analyses as described for the primary endpoint will be applied.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Length of Time on Mechanical Ventilation	2398.4 Minutes Standard Deviation 2031.8	5236.9 Minutes Standard Deviation 4714.7	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: All patients (mFAS)

The same definitions and analyses as described for the primary endpoint will be applied.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Length of Time on Positive Pressure Ventilation	2018.7 Minutes Standard Deviation 4918.5	1285.6 Minutes Standard Deviation 2354.8	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 days

Population: All patients (mFAS)

The same definitions and analyses as described for the primary endpoint will be applied.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Length of Time of Inotrope Use	2726.4 Minutes Standard Deviation 3637.5	3167.3 Minutes Standard Deviation 6035.2	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to 48 hours after separation from CBP

Population: All patients (mFAS)

Inotrope 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 inotrope 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 inotrope score in the citrulline group when compared to the placebo group. In this study, the score was calculated each hour post-operatively from the time of separation from bypass until the completion of study drug. Additionally, the total inotrope score over time until Day 28 or hospital discharge was derived. Inotrope score was calculated using the following formula: Total inotrope score = Dopamine dose (µg/kg/min) + Dobutamine dose (µg/kg/min) + 10 \* Milrinone dose (µg/kg/min) + 100 \* Epinephrine dose (µg/kg/min) + 100 \* Phenylephrine dose (µg/kg/min) + 100 \* Norepinephrine dose (µg/kg/min).

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Inotrope Score 40 hours after separation from CBP	1012.5 µg/kg/min Standard Deviation 7071.8	2004.3 µg/kg/min Standard Deviation 13688.8	—	—	—	—	—	—
Inotrope Score 1 hour after separation from CBP	1691.6 µg/kg/min Standard Deviation 11420.8	583.6 µg/kg/min Standard Deviation 4879.0	—	—	—	—	—	—
Inotrope Score 2 hours after separation from CBP	5076.2 µg/kg/min Standard Deviation 38880.0	537.1 µg/kg/min Standard Deviation 4870.3	—	—	—	—	—	—
Inotrope Score 3 hours after separation from CBP	5983.4 µg/kg/min Standard Deviation 39369.2	1258.2 µg/kg/min Standard Deviation 11744.0	—	—	—	—	—	—
Inotrope Score 4 hours after separation from CBP	6044.1 µg/kg/min Standard Deviation 39566.9	1257.4 µg/kg/min Standard Deviation 11744.1	—	—	—	—	—	—
Inotrope Score 5 hours after separation from CBP	6044.0 µg/kg/min Standard Deviation 39567.0	1257.3 µg/kg/min Standard Deviation 11744.1	—	—	—	—	—	—
Inotrope Score 6 hours after separation from CBP	5983.5 µg/kg/min Standard Deviation 39369.2	1243.4 µg/kg/min Standard Deviation 11677.9	—	—	—	—	—	—
Inotrope Score 7 hours after separation from CBP	5983.3 µg/kg/min Standard Deviation 39369.2	1243.4 µg/kg/min Standard Deviation 11677.9	—	—	—	—	—	—
Inotrope Score 8 hours after separation from CBP	5983.2 µg/kg/min Standard Deviation 2007.7	39369.2 µg/kg/min Standard Deviation 13688.2	—	—	—	—	—	—
Inotrope Score 9 hours after separation from CBP	5983.4 µg/kg/min Standard Deviation 39369.2	2007.1 µg/kg/min Standard Deviation 13688.3	—	—	—	—	—	—
Inotrope Score 10 hours after separation from CBP	5983.0 µg/kg/min Standard Deviation 39369.3	2007.0 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 11 hours after separation from CBP	5983.1 µg/kg/min Standard Deviation 39369.2	2007.0 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 12 hours after separation from CBP	5983.5 µg/kg/min Standard Deviation 39369.2	2006.8 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 13 hours after separation from CBP	5983.1 µg/kg/min Standard Deviation 39369.2	2006.7 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 14 hours after separation from CBP	3255.8 µg/kg/min Standard Deviation 16449.2	2006.6 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 15 hours after separation from CBP	3255.8 µg/kg/min Standard Deviation 16449.2	2006.5 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 16 hours after separation from CBP	3255.4 µg/kg/min Standard Deviation 16449.2	2006.6 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 17 hours after separation from CBP	3255.7 µg/kg/min Standard Deviation 16449.2	2006.5 µg/kg/min Standard Deviation 13688.4	—	—	—	—	—	—
Inotrope Score 18 hours after separation from CBP	3255.4 µg/kg/min Standard Deviation 16449.2	2006.2 µg/kg/min Standard Deviation 13688.5	—	—	—	—	—	—
Inotrope Score 19 hours after separation from CBP	3254.9 µg/kg/min Standard Deviation 16449.3	2006.1 µg/kg/min Standard Deviation 13688.5	—	—	—	—	—	—
Inotrope Score 20 hours after separation from CBP	3254.9 µg/kg/min Standard Deviation 16449.3	2005.7 µg/kg/min Standard Deviation 13688.5	—	—	—	—	—	—
Inotrope Score 21 hours after separation from CBP	2143.6 µg/kg/min Standard Deviation 12376.3	2107.8 µg/kg/min Standard Deviation 13707.6	—	—	—	—	—	—
Inotrope Score 22 hours after separation from CBP	2143.2 µg/kg/min Standard Deviation 12376.3	2005.7 µg/kg/min Standard Deviation 13688.5	—	—	—	—	—	—
Inotrope Score 23 hours after separation from CBP	2143.2 µg/kg/min Standard Deviation 12376.3	2005.6 µg/kg/min Standard Deviation 13688.6	—	—	—	—	—	—
Inotrope Score 24 hours after separation from CBP	2143.0 µg/kg/min Standard Deviation 12376.4	2005.3 µg/kg/min Standard Deviation 13688.6	—	—	—	—	—	—
Inotrope Score 25 hours after separation from CBP	2142.8 µg/kg/min Standard Deviation 12376.4	2005.2 µg/kg/min Standard Deviation 13688.6	—	—	—	—	—	—
Inotrope Score 26 hours after separation from CBP	2142.8 µg/kg/min Standard Deviation 12376.4	2004.9 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 27 hours after separation from CBP	2041.4 µg/kg/min Standard Deviation 2004.9	12352.5 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 28 hours after separation from CBP	2041.1 µg/kg/min Standard Deviation 12352.5	2005.4 µg/kg/min Standard Deviation 13688.6	—	—	—	—	—	—
Inotrope Score 29 hours after separation from CBP	2041.1 µg/kg/min Standard Deviation 12352.5	2004.7 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 30 hours after separation from CBP	2041.1 µg/kg/min Standard Deviation 12352.5	2004.7 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 31 hours after separation from CBP	2040.9 µg/kg/min Standard Deviation 12352.6	2004.6 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 32 hours after separation from CBP	2041.0 µg/kg/min Standard Deviation 12352.5	2004.7 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 33 hours after separation from CBP	2041.1 µg/kg/min Standard Deviation 12352.5	2004.6 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 34 hours after separation from CBP	2041.0 µg/kg/min Standard Deviation 12352.5	2004.6 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 35 hours after separation from CBP	2040.9 µg/kg/min Standard Deviation 12352.5	2004.4 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 36 hours after separation from CBP	2041.1 µg/kg/min Standard Deviation 12352.5	2004.5 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 37 hours after separation from CBP	2040.9 µg/kg/min Standard Deviation 12352.5	2004.4 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 38 hours after separation from CBP	2040.9 µg/kg/min Standard Deviation 12352.6	2004.4 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 39 hours after separation from CBP	2040.9 µg/kg/min Standard Deviation 12352.6	2004.3 µg/kg/min Standard Deviation 13688.7	—	—	—	—	—	—
Inotrope Score 41 hours after separation from CBP	1012.5 µg/kg/min Standard Deviation 7071.8	1282.1 µg/kg/min Standard Deviation 8736.4	—	—	—	—	—	—
Inotrope Score 42 hours after separation from CBP	1012.5 µg/kg/min Standard Deviation 7071.8	780.0 µg/kg/min Standard Deviation 7378.4	—	—	—	—	—	—
Inotrope Score 43 hours after separation from CBP	1012.4 µg/kg/min Standard Deviation 7071.8	779.9 µg/kg/min Standard Deviation 7378.4	—	—	—	—	—	—
Inotrope Score 44 hours after separation from CBP	1012.4 µg/kg/min Standard Deviation 7071.8	780.1 µg/kg/min Standard Deviation 7378.4	—	—	—	—	—	—
Inotrope Score 45 hours after separation from CBP	1012.3 µg/kg/min Standard Deviation 7071.8	780.0 µg/kg/min Standard Deviation 7378.4	—	—	—	—	—	—
Inotrope Score 46 hours after separation from CBP	1012.1 µg/kg/min Standard Deviation 7071.9	780.0 µg/kg/min Standard Deviation 7378.4	—	—	—	—	—	—
Inotrope Score 47 hours after separation from CBP	1012.1 µg/kg/min Standard Deviation 7071.8	780.0 µg/kg/min Standard Deviation 7378.4	—	—	—	—	—	—
Inotrope Score 48 hours after separation from CBP	1012.1 µg/kg/min Standard Deviation 7071.9	779.8 µg/kg/min Standard Deviation 7378.4	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 2 Days

Population: Modified FAS

Heart rate at hours 1, 2, 4, 12, 24 and 48.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Hemodynamic Improvement: Heart Rate 1 hour	80.1 Beats per minute Standard Deviation 67.9	83.6 Beats per minute Standard Deviation 60.1	—	—	—	—	—	—
Hemodynamic Improvement: Heart Rate 2 hours	111.2 Beats per minute Standard Deviation 45.7	116.0 Beats per minute Standard Deviation 46.7	—	—	—	—	—	—
Hemodynamic Improvement: Heart Rate 4 hours	130.4 Beats per minute Standard Deviation 27.7	133.5 Beats per minute Standard Deviation 20.1	—	—	—	—	—	—
Hemodynamic Improvement: Heart Rate 12 hours	120.9 Beats per minute Standard Deviation 22.0	161.9 Beats per minute Standard Deviation 17.6	—	—	—	—	—	—
Hemodynamic Improvement: Heart Rate 24 hours	122.2 Beats per minute Standard Deviation 22.2	118.3 Beats per minute Standard Deviation 14.9	—	—	—	—	—	—
Hemodynamic Improvement: Heart Rate 48 hours	125.9 Beats per minute Standard Deviation 18.7	125.4 Beats per minute Standard Deviation 21.0	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 2 Days

Population: Modified FAS

Systemic arterial blood pressure at hours 1, 2, 4, 12, 24 and 48.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Hemodynamic Improvement: Systemic Arterial Blood Pressure 24 hours	41.0 Millimeters of mercury Standard Deviation 12.2	40.1 Millimeters of mercury Standard Deviation 10.8	—	—	—	—	—	—
Hemodynamic Improvement: Systemic Arterial Blood Pressure 4 hours	42.4 Millimeters of mercury Standard Deviation 12.1	42.1 Millimeters of mercury Standard Deviation 12.3	—	—	—	—	—	—
Hemodynamic Improvement: Systemic Arterial Blood Pressure 12 hours	39.7 Millimeters of mercury Standard Deviation 12.1	40.7 Millimeters of mercury Standard Deviation 10.6	—	—	—	—	—	—
Hemodynamic Improvement: Systemic Arterial Blood Pressure 1 hour	18.4 Millimeters of mercury Standard Deviation 16.2	15.3 Millimeters of mercury Standard Deviation 14.9	—	—	—	—	—	—
Hemodynamic Improvement: Systemic Arterial Blood Pressure 2 hours	31.7 Millimeters of mercury Standard Deviation 17.9	32.5 Millimeters of mercury Standard Deviation 18.2	—	—	—	—	—	—
Hemodynamic Improvement: Systemic Arterial Blood Pressure 48 hours	40.3 Millimeters of mercury Standard Deviation 15.8	42.1 Millimeters of mercury Standard Deviation 11.6	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 2 Days

Population: Modified FAS

Oxygen saturation at hours 1, 2, 4, 12, 24 and 48.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Hemodynamic Improvement: Oxygen Saturation 24 hours	97.1 Percentage of hemoglobin bound to oxygen Standard Deviation 4.0	97.6 Percentage of hemoglobin bound to oxygen Standard Deviation 2.7	—	—	—	—	—	—
Hemodynamic Improvement: Oxygen Saturation 48 hours	97.6 Percentage of hemoglobin bound to oxygen Standard Deviation 2.8	97.8 Percentage of hemoglobin bound to oxygen Standard Deviation 2.6	—	—	—	—	—	—
Hemodynamic Improvement: Oxygen Saturation 1 hour	97.2 Percentage of hemoglobin bound to oxygen Standard Deviation 7.9	95.7 Percentage of hemoglobin bound to oxygen Standard Deviation 15.8	—	—	—	—	—	—
Hemodynamic Improvement: Oxygen Saturation 2 hours	98.6 Percentage of hemoglobin bound to oxygen Standard Deviation 4.6	97.6 Percentage of hemoglobin bound to oxygen Standard Deviation 10.7	—	—	—	—	—	—
Hemodynamic Improvement: Oxygen Saturation 4 hours	98.5 Percentage of hemoglobin bound to oxygen Standard Deviation 2.1	98.1 Percentage of hemoglobin bound to oxygen Standard Deviation 2.7	—	—	—	—	—	—
Hemodynamic Improvement: Oxygen Saturation 12 hours	97.9 Percentage of hemoglobin bound to oxygen Standard Deviation 2.4	97.6 Percentage of hemoglobin bound to oxygen Standard Deviation 2.6	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 2 Days

Population: Modified FAS

Central venous pressure at hours 1, 2, 4, 12, 24 and 48.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Hemodynamic Improvement: Central Venous Pressure 4 hours	13.1 Millimeters of mercury Standard Deviation 23.7	13.2 Millimeters of mercury Standard Deviation 27.4	—	—	—	—	—	—
Hemodynamic Improvement: Central Venous Pressure 12 hours	9.7 Millimeters of mercury Standard Deviation 4.1	9.0 Millimeters of mercury Standard Deviation 3.6	—	—	—	—	—	—
Hemodynamic Improvement: Central Venous Pressure 1 hour	10.2 Millimeters of mercury Standard Deviation 20.1	12.9 Millimeters of mercury Standard Deviation 28.0	—	—	—	—	—	—
Hemodynamic Improvement: Central Venous Pressure 72 hours	10.3 Millimeters of mercury Standard Deviation 5.6	13.2 Millimeters of mercury Standard Deviation 23.9	—	—	—	—	—	—
Hemodynamic Improvement: Central Venous Pressure 24 hours	10.9 Millimeters of mercury Standard Deviation 5.4	9.8 Millimeters of mercury Standard Deviation 3.6	—	—	—	—	—	—
Hemodynamic Improvement: Central Venous Pressure 48 hours	11.8 Millimeters of mercury Standard Deviation 6.2	9.6 Millimeters of mercury Standard Deviation 8.3	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: Modified FAS

The thoracotomy output is defined as the total volume of chest tube drainage recorded in cc prior to discontinuation of chest intubation. The total postoperative duration (in hours) that the chest tube is used will be calculated as the time from the end of the surgery to the time the chest tube is removed. If an additional chest tube is required or reinserted (until discharge from the hospital or at Day 28) the duration that the additional chest tube was used (from time of insertion to time of removal) will be added to the time the original chest tube was used for the total postoperative duration. If a subject did not use any chest tube the duration is set to 0. As a sensitivity analysis, subjects with no use of chest tube will be excluded. For subjects who died before discharge from the hospital or before Day 28, respectively, the observed duration of chest tube drainage will be used.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Thoracotomy Output	206.41 Milliliters Standard Deviation 137.26	198.94 Milliliters Standard Deviation 143.85	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: All patients (mFAS)

The length will be derived as the time in hours from separation from CPB until discontinuation of intubation. Any duration of re-use of intubation will continue to accrue. If a subject did not use any intubation the length is set to 0. As a sensitivity analysis, subjects with no use of intubations will be excluded. For subjects who died before discharge from the hospital or before Day 28, respectively, the observed length of time on intubation will be used. As sensitivity analyses subjects who died will (1) be excluded from analysis and (2) be assigned a length of time on intubation of 28 days. For the length of time on intubation the same analyses as described for the primary endpoint will be applied.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Length of Time of Intubation	1600.4 Minutes Standard Deviation 4488.9	1303.9 Minutes Standard Deviation 4408.3	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: All patients (mFAS)

The length of PICU stay will be calculated as the total number of days postoperative until discharge from PICU. For subjects who died before discharge from PICU or before Day 28, respectively, the observed length of PICU stay will be used. As sensitivity analyses subjects who died will (1) be excluded from analysis and (2) be assigned a length of PICU stay of 28 days. For the length of PICU stay the same analyses as described for the primary endpoint will be applied.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Length of Pediatric Intensive Care Unit (PICU) Stay	6.3 Days Standard Deviation 8.5	6.5 Days Standard Deviation 9.2	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: All patients (mFAS)

Length of time on vasodilators will be measured from first use following separation from bypass, until the subject is discharged from the hospital or at Day 28. The length will be derived as the time in hours from separation from CPB until discontinuation of all vasodilators.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Length of Time on Vasodilators	1668.4 Minutes Standard Deviation 5751.6	611.3 Minutes Standard Deviation 1212.5	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: All patients (mFAS)

The length of hospitalization will be calculated as the total number of days postoperative until discharge from the hospital. For subjects who died before discharge from the hospital or before Day 28, respectively, the observed length of hospitalization will be used. As sensitivity analyses subjects who died will (1) be excluded from analysis and (2) be assigned a length of hospitalization of 28 days. The same analyses as described for the primary endpoint will be applied.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Length of Hospitalization	7.1 Days Standard Deviation 5.1	3.9 Days Standard Deviation 3.9	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: All patients (mFAS)

Plasma citrulline concentrations will be assessed in both treatment groups to determine the number of patients who reach the therapeutic sustained target plasma citrulline level of ≥100 μmol/L. Blood collection for assessment of plasma citrulline concentrations will be taken prior to surgery, during surgery, 30 minutes post-decannulation after CPB (prior to bolus and 5 minutes after bolus), at the specified post-operative time points (6h, 12h, 24h, 48h), and at hospital discharge or Day 28, whichever occurs first.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Patients With Plasma Concentrations of Citrulline Day 0 - Intra-Op	2179.6 umol/L Standard Deviation 1046.8	26.4 umol/L Standard Deviation 9.1	—	—	—	—	—	—
Patients With Plasma Concentrations of Citrulline Day 0 - 0 hours (prior to bolus)	1808.9 umol/L Standard Deviation 12549.4	27.6 umol/L Standard Deviation 11.3	—	—	—	—	—	—
Patients With Plasma Concentrations of Citrulline Day 0 - 0 hours (post bolus)	1387.8 umol/L Standard Deviation 4957.5	27.8 umol/L Standard Deviation 11.6	—	—	—	—	—	—
Patients With Plasma Concentrations of Citrulline Day 0 - 6 hours	146.6 umol/L Standard Deviation 67.3	20.3 umol/L Standard Deviation 10.2	—	—	—	—	—	—
Patients With Plasma Concentrations of Citrulline Day 0 - 12 hours	123.8 umol/L Standard Deviation 41.3	18.5 umol/L Standard Deviation 8.4	—	—	—	—	—	—
Patients With Plasma Concentrations of Citrulline Day 1 - 24 hours	102.1 umol/L Standard Deviation 42.6	14.9 umol/L Standard Deviation 6.8	—	—	—	—	—	—
Patients With Plasma Concentrations of Citrulline Day 2 - 48 hours	68.2 umol/L Standard Deviation 44.9	12.1 umol/L Standard Deviation 5.8	—	—	—	—	—	—
Patients With Plasma Concentrations of Citrulline Day 28/ Discharge	21.9 umol/L Standard Deviation 29.5	16.9 umol/L Standard Deviation 6.2	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 28 Days

Population: The analysis of AEs included all patients who were randomized, underwent surgery and received study medication

Pre-treatment adverse events and treatment adverse events will be analyzed separately. The number of affected subjects will be reported.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Occurrence of Adverse and Serious Adverse Events Any adverse event	68 Participants	62 Participants	—	—	—	—	—	—
Occurrence of Adverse and Serious Adverse Events Pre-treatment adverse events	19 Participants	12 Participants	—	—	—	—	—	—
Occurrence of Adverse and Serious Adverse Events Treatment emergent adverse events	68 Participants	61 Participants	—	—	—	—	—	—
Occurrence of Adverse and Serious Adverse Events Any serious adverse event	11 Participants	6 Participants	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 2 Days

Population: SAF

Refractory hypotension is defined as a 20% drop of mean arterial pressure (MAP) below specific age-related criteria for more than 30 minutes. The number of subjects with any refractory hypotension from end of surgery until 48 hours will be compared between groups.

Outcome measures

Outcome measures
Measure	L-citrulline n=99 Participants * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo n=90 Participants * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	L-citrulline - All Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	L-citrulline - US Patients Off Mechanical Ventilation in >48 Hours * Bolus of 150 mg/kg at the initiation of cardiopulmonary bypass, but after removal of any crystalloid base; * L-citrulline at a concentration of 200 μmol/L given as a bolus during bypass. Administered as a one-time bolus or multiple administrations to compensate for fluids containing L-citrulline that may be removed from the patient during the course of the operation and thus to maintain the concentration of 200 μmol/L; * Bolus of 20 mg/kg 30 minutes after decannulation from cardiopulmonary bypass; * 9 mg/kg/hr continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in ≤48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - All Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.	Placebo - US Patients Off Mechanical Ventilation in >48 Hours * Bolus at the initiation of cardiopulmonary bypass; * Bolus during bypass. Administered as a one-time bolus or multiple administrations during bypass; * Bolus 30 minutes after decannulation from cardiopulmonary bypass; * Continuous infusion for up to 48 hours.
Number of Patients With Refractory Hypotension	0 Participants	0 Participants	—	—	—	—	—	—

POST_HOC outcome

Timeframe: 28 Days

Population: Only data from US patients on mechanical ventilation for ≤48 hours are analysed.

Mechanical ventilation (MV) = invasive or noninvasive MV incl. bilevel (biphasic) positive airway pressure or continuous positive airway pressure. Inotrope use = medications considered within the derivation of total inotrope score (dopamine, dobutamine, milrinone, epinephrine, phenylephrine, norepinephrine). Both measures recorded until earliest of subject hospital discharge or Day 28. Note: data are reported for post-hoc analyses based on a modified full analysis set (mFAS) targeting the US population for a 48-hour treatment period. Analysis method used was quartiles based, but followed prescribed statistical analysis plan methods. This is because chosen endpoints did not appear to be valid in the ex-US population due to differences in physician decision making. In the US, extubation occurs as soon as a patient's physical condition permits (only more severely ill children remain on mechanical ventilation); conversely, in ex-US sites, children remain on mechanical ventilation.