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

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.

Timeline

Start

2005-02

Primary completion

2008-06

Completion

2008-06

Publications

• Background 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

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Indications