A Phase 2 interventional study of N-acetylcysteine and Placebo in Transposition of Great Vessels and Congenital Heart Disease, sponsored by University of Michigan. Completed at 1 site in United States. Open to participants aged Up to 3 Months. Per ClinicalTrials.gov, last updated 2012-01-19.
Sponsored by University of Michigan · Phase 2, Interventional, and Treatment
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.
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.
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Exclusion Criteria:
These patients receive a placebo infusion of D5W prior to and after surgery
Drug: Placebo
These patients receive a loading dose of N-Acetylcysteine 100 mg/kg in D5W IV 1 hour prior to surgery. They receive a maintenance infusion of N-Acetylcysteine 10 mg/kg/hr in D5W IV for 24 hours after surgery.
Drug: N-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.
D5W bolus prior to surgery and D5W infusion after surgery in an equal volume to the drug arm.
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
| Milestone | Placebo | N-acetylcysteine |
|---|---|---|
| Started | 10 | 11 |
| Completed | 9 | 10 |
| Not completed | 1 | 1 |
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.
| L/min/m2 | Placebo | N-acetylcysteine |
|---|---|---|
| Maximum Decline in Measured Cardiac Output | 0.68 ± 0.59 | 0.29 ± 0.56 |
Maximum serum creatinine over first 3 days postoperative.
| mg/dL | Placebo | N-acetylcysteine |
|---|---|---|
| Max Creatinine | 0.99 ± 0.44 | 0.74 ± 0.24 |
Total urine output over the first 24 hours postoperative
| mL | Placebo | N-acetylcysteine |
|---|---|---|
| Urine Output | 96 ± 54 | 176 ± 55 |
Collected over Duration of hospitalization. Non-serious events are listed at a 2.3% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | — | 1/10 (10%) | 4/10 (40%) |
| N-acetylcysteine | — | 2/11 (18.2%) | 7/11 (63.6%) |
| Event | Placebo | N-acetylcysteine |
|---|---|---|
| Grade II bleeds on head ultrasoundCardiac disorders | 1/10 | 0/11 |
| Bleeding requiring surgical re-explorationSurgical and medical procedures | 0/10 | 1/11 |
| Patient placed on ECMO in operating roomSurgical and medical procedures | 0/10 | 1/11 |
| Event | Placebo | N-acetylcysteine |
|---|---|---|
| Junctional Ectopic TachycardiaCardiac disorders | 1/10 | 2/11 |
| SVTCardiac disorders | 1/10 | 2/11 |
| HypoglycemiaEndocrine disorders | 1/10 | 0/11 |
| Poor urine outputRenal and urinary disorders | 1/10 | 0/11 |
| Venous congestion of left legVascular disorders | 1/10 | 0/11 |
| Persistent feversInfections and infestations | 0/10 | 1/11 |
| SeizuresNervous system disorders | 0/10 | 1/11 |
| HemothoraxRespiratory, thoracic and mediastinal disorders | 0/10 | 1/11 |
| Age Continuous(years) | Placebo | N-acetylcysteine | Total |
|---|---|---|---|
| Mean | 0.02 ± 0.007 | 0.02 ± 0.006 | 0.02 ± 0.007 |
| Sex: Female, Male(Participants) | Placebo | N-acetylcysteine | Total |
|---|---|---|---|
| Female | 5 | 3 | 8 |
| Male | 5 | 8 | 13 |
| Region of Enrollment(participants) | Placebo | N-acetylcysteine | Total |
|---|---|---|---|
| United States | 10 | 11 | 21 |
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