Acetaminophen for Oxidative Stress After Cardiopulmonary Bypass

NCT01228305 | Completed DMC

• 1 other identifier: 090497
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The current proposal tests the central hypothesis that acetaminophen will attenuate the oxidative stress response associated with cardiopulmonary bypass (CPB)-induced hemolysis in children undergoing cardiac surgery.

Conditions

Congenital Heart Disease; Cardiopulmonary Bypass

Keywords

ventricular septal defect; atrioventricular septal defect; oxidative stress; cardiopulmonary bypass; acetaminophen; hemolysis; acute kidney injury; Congenital heart disease undergoing cardiopulmonary bypass

Outcome Measures

Primary Outcomes (1)

• oxidative stress response as measured by F2-isoprostane

  Test the hypothesis that acetaminophen attenuates the oxidative stress response, as measured by F2-isoprostanes, in children undergoing cardiopulmonary bypass. The primary outcome is the oxidative stress response as measured by F2-isoprostane

  24 hours after cardiopulmonary bypass

Secondary Outcomes (1)

• renal function

  for the first 24 hrs after cardiopulmonary bypass

Study Arms (2)

Acetaminophen

EXPERIMENTAL

Subjects will be randomly assigned to treatment using a permuted-block randomization algorithm. Acetaminophen will be given at a standard dose of 15 mg/kg IV every 6 hours for children \>=2 years of age, 12.5mg/kg IV every 6 hours for children 29 days to \<2 years of age, and 7.5mg/kg IV every 6 hours for neonates up to 28 days old for a total of 4 doses, starting shortly after intubation in the OR and before the start of CPB.

Other: Acetaminophen

Placebo

PLACEBO COMPARATOR

Subjects will be randomly assigned to treatment using a permuted-block randomization algorithm. Acetaminophen will be given at a standard dose of 15 mg/kg IV every 6 hours for children \>=2 years of age, 12.5mg/kg IV every 6 hours for children 29 days to \<2 years of age, and 7.5mg/kg IV every 6 hours for neonates up to 28 days old for a total of 4 doses, starting shortly after intubation in the OR and before the start of CPB.

Other: Acetaminophen

Interventions

Acetaminophen OTHER

Acetaminophen will be given at a standard dose of 15 mg/kg IV every 6 hours for children \>=2 years of age, 12.5mg/kg IV every 6 hours for children 29 days to \<2 years of age, and 7.5mg/kg IV every 6 hours for neonates up to 28 days old for a total of 4 doses, starting shortly after intubation in the OR and before the start of CPB.

Also known as: Tylenol

Acetaminophen; Placebo

Eligibility Criteria

• Age: 1 Day - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \) Infants or children (newborn to 17years of age) undergoing cardiopulmonary bypass for biventricular surgical correction of their congenital heart lesions.

You may not qualify if:

• Patients scheduled for single ventricle palliation will be excluded, in an effort to standardize the time of repair, time on CPB, and surgical procedure.
• Patients with severe neurological abnormalities at baseline.
• Patients with major non-cardiac congenital malformations, developmental disorders or serious chronic disorders. Benign congenital malformations (such as club foot, ear tags, etc.) will not exclude the subject from the study.
• Non-English speaking patients, or parent/legal guardians.
• Patients less than 3 kg, to limit risk of excessive blood loss from lab draws.
• Previous adverse reaction to acetaminophen
• History of acute or chronic kidney disease
• History of chronic liver disease
• Emergency surgery

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (21)

• Allen BS, Ilbawi MN. Hypoxia, reoxygenation and the role of systemic leukodepletion in pediatric heart surgery. Perfusion. 2001 Mar;16 Suppl:19-29. doi: 10.1177/026765910101600i104.

  PMID: 11334203 BACKGROUND

• Morita K, Ihnken K, Buckberg GD, Sherman MP, Young HH, Ignarro LJ. Role of controlled cardiac reoxygenation in reducing nitric oxide production and cardiac oxidant damage in cyanotic infantile hearts. J Clin Invest. 1994 Jun;93(6):2658-66. doi: 10.1172/JCI117279.

  PMID: 8201004 BACKGROUND

• Haase M, Haase-Fielitz A, Bagshaw SM, Ronco C, Bellomo R. Cardiopulmonary bypass-associated acute kidney injury: a pigment nephropathy? Contrib Nephrol. 2007;156:340-53. doi: 10.1159/000102125.

  PMID: 17464145 BACKGROUND

• Morrow JD. Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans. Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):279-86. doi: 10.1161/01.ATV.0000152605.64964.c0. Epub 2004 Dec 9.

  PMID: 15591226 BACKGROUND

• Vermeulen Windsant IC, Snoeijs MG, Hanssen SJ, Altintas S, Heijmans JH, Koeppel TA, Schurink GW, Buurman WA, Jacobs MJ. Hemolysis is associated with acute kidney injury during major aortic surgery. Kidney Int. 2010 May;77(10):913-20. doi: 10.1038/ki.2010.24. Epub 2010 Feb 24.

  PMID: 20182411 BACKGROUND

• Gbadegesin R, Zhao S, Charpie J, Brophy PD, Smoyer WE, Lin JJ. Significance of hemolysis on extracorporeal life support after cardiac surgery in children. Pediatr Nephrol. 2009 Mar;24(3):589-95. doi: 10.1007/s00467-008-1047-z. Epub 2008 Nov 12.

  PMID: 19002722 BACKGROUND

• Kadiiska MB, Gladen BC, Baird DD, Germolec D, Graham LB, Parker CE, Nyska A, Wachsman JT, Ames BN, Basu S, Brot N, Fitzgerald GA, Floyd RA, George M, Heinecke JW, Hatch GE, Hensley K, Lawson JA, Marnett LJ, Morrow JD, Murray DM, Plastaras J, Roberts LJ 2nd, Rokach J, Shigenaga MK, Sohal RS, Sun J, Tice RR, Van Thiel DH, Wellner D, Walter PB, Tomer KB, Mason RP, Barrett JC. Biomarkers of oxidative stress study II: are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning? Free Radic Biol Med. 2005 Mar 15;38(6):698-710. doi: 10.1016/j.freeradbiomed.2004.09.017.

  PMID: 15721980 BACKGROUND

• Christen S, Finckh B, Lykkesfeldt J, Gessler P, Frese-Schaper M, Nielsen P, Schmid ER, Schmitt B. Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation. Free Radic Biol Med. 2005 May 15;38(10):1323-32. doi: 10.1016/j.freeradbiomed.2005.01.016.

  PMID: 15855050 BACKGROUND

• Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002 Jul;97(1):215-52. doi: 10.1097/00000542-200207000-00030. No abstract available.

  PMID: 12131125 BACKGROUND

• Boutaud O, Moore KP, Reeder BJ, Harry D, Howie AJ, Wang S, Carney CK, Masterson TS, Amin T, Wright DW, Wilson MT, Oates JA, Roberts LJ 2nd. Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2699-704. doi: 10.1073/pnas.0910174107. Epub 2010 Feb 1.

  PMID: 20133658 BACKGROUND

• Ouellet M, Percival MD. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch Biochem Biophys. 2001 Mar 15;387(2):273-80. doi: 10.1006/abbi.2000.2232.

  PMID: 11370851 BACKGROUND

• Patel RP, Svistunenko DA, Darley-Usmar VM, Symons MC, Wilson MT. Redox cycling of human methaemoglobin by H2O2 yields persistent ferryl iron and protein based radicals. Free Radic Res. 1996 Aug;25(2):117-23. doi: 10.3109/10715769609149916.

  PMID: 8885329 BACKGROUND

• Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ 2nd. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9383-7. doi: 10.1073/pnas.87.23.9383.

  PMID: 2123555 BACKGROUND

• Montuschi P, Barnes PJ, Roberts LJ 2nd. Isoprostanes: markers and mediators of oxidative stress. FASEB J. 2004 Dec;18(15):1791-800. doi: 10.1096/fj.04-2330rev.

  PMID: 15576482 BACKGROUND

• Milne GL, Musiek ES, Morrow JD. F2-isoprostanes as markers of oxidative stress in vivo: an overview. Biomarkers. 2005 Nov;10 Suppl 1:S10-23. doi: 10.1080/13547500500216546.

  PMID: 16298907 BACKGROUND

• Roberts LJ 2nd, Fessel JP, Davies SS. The biochemistry of the isoprostane, neuroprostane, and isofuran Pathways of lipid peroxidation. Brain Pathol. 2005 Apr;15(2):143-8. doi: 10.1111/j.1750-3639.2005.tb00511.x.

  PMID: 15912887 BACKGROUND

• Fessel JP, Porter NA, Moore KP, Sheller JR, Roberts LJ 2nd. Discovery of lipid peroxidation products formed in vivo with a substituted tetrahydrofuran ring (isofurans) that are favored by increased oxygen tension. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16713-8. doi: 10.1073/pnas.252649099. Epub 2002 Dec 13.

  PMID: 12482927 BACKGROUND

• Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol. 2000 Mar-Apr;8(2):72-6. doi: 10.1159/000020651.

  PMID: 10729745 BACKGROUND

• Holt S, Reeder B, Wilson M, Harvey S, Morrow JD, Roberts LJ 2nd, Moore K. Increased lipid peroxidation in patients with rhabdomyolysis. Lancet. 1999 Apr 10;353(9160):1241. doi: 10.1016/S0140-6736(98)05768-7. No abstract available.

  PMID: 10217088 BACKGROUND

• Reeder BJ, Sharpe MA, Kay AD, Kerr M, Moore K, Wilson MT. Toxicity of myoglobin and haemoglobin: oxidative stress in patients with rhabdomyolysis and subarachnoid haemorrhage. Biochem Soc Trans. 2002 Aug;30(4):745-8. doi: 10.1042/bst0300745.

  PMID: 12196184 BACKGROUND

• Roberts LJ 2nd. Inhibition of heme protein redox cycling: reduction of ferryl heme by iron chelators and the role of a novel through-protein electron transfer pathway. Free Radic Biol Med. 2008 Feb 1;44(3):257-60. doi: 10.1016/j.freeradbiomed.2007.10.042. Epub 2007 Dec 5. No abstract available.

  PMID: 18067870 BACKGROUND

MeSH Terms

Conditions

Heart Defects, Congenital; Heart Septal Defects, Ventricular; Atrioventricular Septal Defect; Hemolysis; Acute Kidney Injury

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heart Septal Defects; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Scott A Simpson, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2010
• First Posted: October 26, 2010
• Study Start: July 1, 2011
• Primary Completion: January 1, 2014
• Study Completion: March 1, 2014
• Last Updated: April 21, 2017

Record last verified: 2017-04

Locations

US (1)