Congenital Heart Disease, Transposition of Great Vessels
Conditions
Keywords
N-acetylcysteine, Myocardial dysfunction, Transposition of the Great Arteries
Brief summary
The purpose of this study is to determine whether intravenous N-acetylcysteine (also known as Acetadote), an antioxidant medication that has been used for years to treat Tylenol overdose, helps prevent heart dysfunction in the early postoperative period following congenital heart surgery. Children undergoing major heart surgery, such as the arterial switch operation, routinely develop temporary heart dysfunction in the first 12-24 hours after surgery. This heart dysfunction may be severe and contributes to an increased risk for death or prolonged hospitalization. Current standard treatments include intravenous medications such as dopamine, epinephrine, and vasopressin that support your child's blood pressure and heart function. Unfortunately, high doses of these medications have the potential to cause severe side effects including loss of fingers and toes, liver and kidney dysfunction, and heart rhythm abnormalities. Our goal is to find a way to reduce heart dysfunction after major heart surgery in order to promote a smoother postoperative period, and reduce the risks associated with heart operations in children.
Detailed description
This is a randomized, placebo-controlled, blinded study of intravenous N-acetylcysteine (NAC) for the prevention of postoperative myocardial dysfunction and apoptosis in infants undergoing arterial switch for D-transposition of the great arteries. Subjects will be age 0-3 months, and no distinctions will be made based on gender or race. Infants operated before 36 weeks post-conceptional age or with birth weight less than 1.8 kilograms will be excluded. Informed consent will be obtained from the patient's parent by one of the investigators in the hospital before the infants undergo surgery. Subjects will be randomized based on a block randomization scheme to receive placebo or NAC infusion, starting with a loading dose 1 hour prior to surgery. If there is any concern by the ICU physician that the patient is developing toxicity to the medicine, the study drug will be discontinued and the patient removed from the study. Patients will have a thermodilution catheter placed during surgery for postoperative direct measurement of cardiac output. Endomyocardial biopsy will be performed by the surgeon pre- and post-bypass for measurement of markers of apoptosis. Postoperatively, patients will continue to receive an infusion of IV NAC for 24 hours. Blood draws will be through existing arterial and central venous catheters. Serum labs collected will include serial lactate values (already collected routinely), liver and renal function tests, CK-MB and troponin-I levels as a marker of myocardial injury, and S100b level as a marker of brain injury. Total additional blood removed for research purposes will be less than 15 mL. Cardiac output will be measured serially by thermodilution. Serial transthoracic echocardiography will be used to determine left ventricular function. Inotropic score, duration of mechanical ventilation, length of ICU stay, and length of hospitalization will be recorded.
Interventions
DRUGN-acetylcysteine
Loading dose: Subjects randomized to IV NAC will receive a total loading dose of 100 mg/kg of 10% (100 mg/mL) solution. Acetadote is supplied as a 20% solution (200 mg/mL) and will be diluted 1:1 with an equal volume of D5W. The volume of the loading dose will be 1 mL/kg, anticipated to be 2.5-5 mL in our patient population. The loading dose will be administered over 1 hr beginning 1 hr prior to the patient's OR time. Subjects in the placebo group will receive 1 mL/kg of D5W over 1 hr. Maintenance infusion: Subjects randomized to IV NAC will receive an infusion of 10 mg/kg/hr of 10% (100 mg/mL) solution for 24 hrs, starting in the OR after weaning from CPB. Acetadote is supplied as a 20% solution (200 mg/mL) and will be diluted 1:1 with an equal volume of D5W. The volume of the maintenance infusion will be 0.1 mL/kg/hr, anticipated to be 0.25-0.5 mL/hr in our patient population. Subjects in the placebo group will receive 0.1 mL/kg/hr of D5W for 24 hrs.
DRUGPlacebo
D5W bolus prior to surgery and D5W infusion after surgery in an equal volume to the drug arm.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 3 Months
Healthy volunteers
No
Inclusion criteria
* All patients transferred to or born at C.S. Mott Children's Hospital between 0 and 3-months-old undergoing ASO for d-TGA or anatomic variants (including double-outlet right ventricle with transposition physiology).
Exclusion criteria
* Less than 36-weeks post-conceptional age at the time of enrollment * Birth weight less than 1800 grams; * Evidence of significant renal, hepatic, or neurological dysfunction * Additional significant cardiac lesions other than patent ductus arteriosus, isolated ventricular septal defect, simple coarctation, and/or atrial septal defect * Preoperative extracorporeal membrane oxygenation (ECMO).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Decline in Measured Cardiac Output | 24 hours | Serial cardiac output was measured by thermodilution. The outcome of maximum decline in indexed cardiac output from 1 hour postoperative to lowest output within 24 hours postoperative was then calculated and compared between NAC and placebo groups. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients not treated with N-acetylcysteine | 10 |
| N-acetylcysteine Patients treated with N-acetylcysteine | 11 |
| Total | 21 |
Baseline characteristics
| Characteristic | Placebo | N-acetylcysteine | Total |
|---|---|---|---|
| Age Continuous | 0.02 years STANDARD_DEVIATION 0.007 | 0.02 years STANDARD_DEVIATION 0.006 | 0.02 years STANDARD_DEVIATION 0.007 |
| Region of Enrollment United States | 10 participants | 11 participants | 21 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 7 / 11 |
| serious Total, serious adverse events | 1 / 10 | 2 / 11 |
Outcome results
Primary
Maximum Decline in Measured Cardiac Output
Serial cardiac output was measured by thermodilution. The outcome of maximum decline in indexed cardiac output from 1 hour postoperative to lowest output within 24 hours postoperative was then calculated and compared between NAC and placebo groups.
Time frame: 24 hours
Population: Patients in which the surgeon was technically able to place a 4 French thermodilution catheter into the pulmonary artery at the time of surgery had cardiac output measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Decline in Measured Cardiac Output | 0.68 L/min/m2 | Standard Deviation 0.59 |
| N-acetylcysteine | Maximum Decline in Measured Cardiac Output | 0.29 L/min/m2 | Standard Deviation 0.56 |
Post Hoc
Max Creatinine
Maximum serum creatinine over first 3 days postoperative.
Time frame: 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Max Creatinine | 0.99 mg/dL | Standard Deviation 0.44 |
| N-acetylcysteine | Max Creatinine | 0.74 mg/dL | Standard Deviation 0.24 |
Post Hoc
Urine Output
Total urine output over the first 24 hours postoperative
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Urine Output | 96 mL | Standard Deviation 54 |
| N-acetylcysteine | Urine Output | 176 mL | Standard Deviation 55 |