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

December 14, 2011 updated by: Ranjit Aiyagari, University of Michigan

Attenuation of Myocardial Dysfunction by N-Acetylcysteine in Infants Undergoing Arterial Switch Procedure

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

21

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48109-0204
        • University of Michigan

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 3 months (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Decline in Measured Cardiac Output
Time Frame: 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.
24 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Michigan

Investigators

  • Principal Investigator: Ranjit M Aiyagari, MD, University of Michigan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2005

Primary Completion (ACTUAL)

June 1, 2008

Study Completion (ACTUAL)

June 1, 2008

Study Registration Dates

First Submitted

September 7, 2006

First Submitted That Met QC Criteria

September 7, 2006

First Posted (ESTIMATE)

September 8, 2006

Study Record Updates

Last Update Posted (ESTIMATE)

January 19, 2012

Last Update Submitted That Met QC Criteria

December 14, 2011

Last Verified

December 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRBMED No.: 2004-851

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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