N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Ranjit Aiyagari, University of Michigan
ClinicalTrials.gov Identifier:
NCT00374088
First received: September 7, 2006
Last updated: December 14, 2011
Last verified: December 2011
  Purpose

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.


Condition Intervention Phase
Transposition of Great Vessels
Congenital Heart Disease
Drug: N-acetylcysteine
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Attenuation of Myocardial Dysfunction by N-Acetylcysteine in Infants Undergoing Arterial Switch Procedure

Resource links provided by NLM:


Further study details as provided by University of Michigan:

Primary Outcome Measures:
  • Maximum Decline in Measured Cardiac Output [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    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.


Enrollment: 21
Study Start Date: February 2005
Study Completion Date: June 2008
Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
These patients receive a placebo infusion of D5W prior to and after surgery
Drug: Placebo
D5W bolus prior to surgery and D5W infusion after surgery in an equal volume to the drug arm.
Experimental: N-Acetylcysteine
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.


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.

  Eligibility

Ages Eligible for Study:   up to 3 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00374088

Locations
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109-0204
Sponsors and Collaborators
University of Michigan
Investigators
Principal Investigator: Ranjit M Aiyagari, MD University of Michigan
  More Information

Publications:

Responsible Party: Ranjit Aiyagari, Clinical Assistant Professor of Pediatrics, University of Michigan
ClinicalTrials.gov Identifier: NCT00374088     History of Changes
Other Study ID Numbers: IRBMED No.: 2004-851
Study First Received: September 7, 2006
Results First Received: August 3, 2011
Last Updated: December 14, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Michigan:
N-acetylcysteine
Myocardial dysfunction
Transposition of the Great Arteries

Additional relevant MeSH terms:
Heart Diseases
Transposition of Great Vessels
Heart Defects, Congenital
Cardiovascular Diseases
Cardiovascular Abnormalities
Congenital Abnormalities
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on August 28, 2014