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

NCT00374088 | Completed Phase 2 Results DMC

• 1 other identifier: IRBMED No.: 2004-851
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Transposition of Great Vessels; Congenital Heart Disease

Keywords

N-acetylcysteine; Myocardial dysfunction; Transposition of the Great Arteries

Outcome Measures

Primary Outcomes (1)

• 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.

  24 hours

Study Arms (2)

Placebo

PLACEBO COMPARATOR

These patients receive a placebo infusion of D5W prior to and after surgery

Drug: Placebo

N-Acetylcysteine

EXPERIMENTAL

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

Interventions

N-acetylcysteine DRUG

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.

N-Acetylcysteine

Placebo DRUG

D5W bolus prior to surgery and D5W infusion after surgery in an equal volume to the drug arm.

Placebo

Eligibility Criteria

• Age: Up to 3 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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).

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Michigan: lead

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109-0204, United States

Location

Related Publications (15)

• Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW, Wessel DL. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation. 1995 Oct 15;92(8):2226-35. doi: 10.1161/01.cir.92.8.2226.

  PMID: 7554206 BACKGROUND

• Tossios P, Bloch W, Huebner A, Raji MR, Dodos F, Klass O, Suedkamp M, Kasper SM, Hellmich M, Mehlhorn U. N-acetylcysteine prevents reactive oxygen species-mediated myocardial stress in patients undergoing cardiac surgery: results of a randomized, double-blind, placebo-controlled clinical trial. J Thorac Cardiovasc Surg. 2003 Nov;126(5):1513-20. doi: 10.1016/s0022-5223(03)00968-1.

  PMID: 14666027 BACKGROUND

• Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985 Nov;76(5):1713-9. doi: 10.1172/JCI112160. No abstract available.

  PMID: 4056048 BACKGROUND

• Kofsky E, Julia P, Buckberg GD, Young H, Tixier D. Studies of myocardial protection in the immature heart. V. Safety of prolonged aortic clamping with hypocalcemic glutamate/aspartate blood cardioplegia. J Thorac Cardiovasc Surg. 1991 Jan;101(1):33-43.

  PMID: 1986168 BACKGROUND

• Julia P, Kofsky ER, Buckberg GD, Young HH, Bugyi HI. Studies of myocardial protection in the immature heart. III. Models of ischemic and hypoxic/ischemic injury in the immature puppy heart. J Thorac Cardiovasc Surg. 1991 Jan;101(1):14-22.

  PMID: 1986156 BACKGROUND

• Itoi T, Lopaschuk GD. Calcium improves mechanical function and carbohydrate metabolism following ischemia in isolated Bi-ventricular working hearts from immature rabbits. J Mol Cell Cardiol. 1996 Jul;28(7):1501-14. doi: 10.1006/jmcc.1996.0140.

  PMID: 8841937 BACKGROUND

• Matherne GP, Berr SS, Headrick JP. Integration of vascular, contractile and metabolic responses to hypoxia: effects of maturation and adenosine. Am J Physiol. 1996 Apr;270(4 Pt 2):R895-905. doi: 10.1152/ajpregu.1996.270.4.R895.

  PMID: 8967420 BACKGROUND

• Carr LJ, VanderWerf QM, Anderson SE, Kost GJ. Age-related response of rabbit heart to normothermic ischemia: a 31P-MRS study. Am J Physiol. 1992 Feb;262(2 Pt 2):H391-8. doi: 10.1152/ajpheart.1992.262.2.H391.

  PMID: 1539698 BACKGROUND

• Young JN, Choy IO, Silva NK, Obayashi DY, Barkan HE. Antegrade cold blood cardioplegia is not demonstrably advantageous over cold crystalloid cardioplegia in surgery for congenital heart disease. J Thorac Cardiovasc Surg. 1997 Dec;114(6):1002-8; discussion 1008-9. doi: 10.1016/S0022-5223(97)70014-X.

  PMID: 9434695 BACKGROUND

• Najm HK, Wallen WJ, Belanger MP, Williams WG, Coles JG, Van Arsdell GS, Black MD, Boutin C, Wittnich C. Does the degree of cyanosis affect myocardial adenosine triphosphate levels and function in children undergoing surgical procedures for congenital heart disease? J Thorac Cardiovasc Surg. 2000 Mar;119(3):515-24. doi: 10.1016/s0022-5223(00)70131-0.

  PMID: 10694612 BACKGROUND

• Nagashima M, Nollert G, Stock U, Sperling J, Hatsuoka S, Shum-Tim D, Takeuchi K, Nedder A, Mayer JE Jr. Cardiac performance after deep hypothermic circulatory arrest in chronically cyanotic neonatal lambs. J Thorac Cardiovasc Surg. 2000 Aug;120(2):238-46. doi: 10.1067/mtc.2000.106984.

  PMID: 10917937 BACKGROUND

• Ahola T, Fellman V, Laaksonen R, Laitila J, Lapatto R, Neuvonen PJ, Raivio KO. Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants. Eur J Clin Pharmacol. 1999 Nov;55(9):645-50. doi: 10.1007/s002280050687.

  PMID: 10638393 BACKGROUND

• Perry HE, Shannon MW. Efficacy of oral versus intravenous N-acetylcysteine in acetaminophen overdose: results of an open-label, clinical trial. J Pediatr. 1998 Jan;132(1):149-52. doi: 10.1016/s0022-3476(98)70501-3.

  PMID: 9470017 BACKGROUND

• Andersen LW, Thiis J, Kharazmi A, Rygg I. The role of N-acetylcystein administration on the oxidative response of neutrophils during cardiopulmonary bypass. Perfusion. 1995;10(1):21-6. doi: 10.1177/026765919501000105.

  PMID: 7795309 BACKGROUND

• Arstall MA, Yang J, Stafford I, Betts WH, Horowitz JD. N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction. Safety and biochemical effects. Circulation. 1995 Nov 15;92(10):2855-62. doi: 10.1161/01.cir.92.10.2855.

  PMID: 7586252 BACKGROUND

MeSH Terms

Conditions

Transposition of Great Vessels; Heart Defects, Congenital

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Ranjit Aiyagari, MD
• Organization: University of Michigan - Pediatric Cardiology

ranjita@umich.edu

734-647-8761

Study Officials

• Ranjit M Aiyagari, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Assistant Professor of Pediatrics

Study Record Dates

• First Submitted: September 7, 2006
• First Posted: September 8, 2006
• Study Start: February 1, 2005
• Primary Completion: June 1, 2008
• Study Completion: June 1, 2008
• Last Updated: January 19, 2012
• Results First Posted: January 19, 2012

Record last verified: 2011-12

Locations

US (1)