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

Condition(s) targeted: Transposition of Great Vessels; Congenital Heart Disease

Intervention: N-acetylcysteine (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: University of Michigan

Official(s) and/or principal investigator(s):
Ranjit M Aiyagari, MD, Principal Investigator, Affiliation: University of Michigan

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.

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

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome: To determine the effects of prophylactic N-acetylcysteine (NAC) on the severity of postoperative myocardial dysfunction following surgical repair of complex congenital heart disease in neonates.

Secondary outcome:

To determine the relationship between postoperative myocardial dysfunction and morbidity

To determine the effects of prophylactic NAC on postoperative morbidity

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.

Minimum age: N/A. Maximum age: 3 Months. Gender(s): Both.

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).

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

Related publications:

Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW, et al. 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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Starting date: February 2005
Ending date: June 2008
Last updated: June 5, 2008