Inhibition of Lipid Peroxidation During Cardiac Surgery

• ClinicalTrials.gov Identifier: NCT01366976
• Recruitment Status: Completed
• First Posted: June 6, 2011
• Results First Posted: January 14, 2015
• Last Update Posted: January 27, 2015
• Sponsor: Vanderbilt University
• Information provided by (Responsible Party): Mias Pretorius, Vanderbilt University

Study Description

Brief Summary:

Acute kidney injury is a major complication of cardiac surgery requiring cardiopulmonary bypass (CPB). Hemolysis and rhabdomyolysis frequently occur during CPB. Hemolysis leads to an increase in free hemoglobin, whereas rhabdomyolysis leads to an increase in myoglobin. Free plasma hemoglobin and myoglobin have been shown to be independent predictors of the acute kidney injury that results from CPB. When these hemeproteins are released into the plasma, they undergo redox cycling, generating radical species that initiate lipid peroxidation and a cascade of oxidative damage to cellular membranes, notably in the kidney. F2-isoprostanes and isofurans are sensitive and specific markers of oxidative stress in vivo, and are increased after CPB, particularly in those patients with acute kidney injury. Acetaminophen inhibits the lipid peroxidation catalyzed by myoglobin and hemoglobin. Moreover, in an animal model of rhabdomyolysis-induced kidney injury, acetaminophen significantly attenuated the decrease in creatinine clearance compared to control. The current proposal tests the central hypothesis that acetaminophen will attenuate the lipid peroxidation associated with the hemolysis and rhabdomyolysis that occur in patients undergoing CPB. Demonstration that acetaminophen inhibits the lipid peroxidation resulting from CPB would provide a rationale for a prospective randomized trial to test the hypothesis that acetaminophen will reduce the acute kidney injury that results from CPB.

Condition or disease	Intervention/treatment	Phase
Cardiopulmonary Bypass Induced Lipid Peroxidation	Drug: Acetaminophen	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Inhibition of Lipid Peroxidation During Cardiopulmonary Bypass
• Study Start Date: July 2011
• Actual Primary Completion Date: June 2013
• Actual Study Completion Date: June 2013

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo	Drug: Acetaminophen; Acetaminophen 1g every 6 hours for 4 doses over 24 hours; Other Name: Tylenol
Active Comparator: Acetaminophen; Acetaminophen will ge given as 1g every 6 hours for 4 doses over a 24 hours study period	Drug: Acetaminophen; Acetaminophen 1g every 6 hours for 4 doses over 24 hours; Other Name: Tylenol

Outcome Measures

Primary Outcome Measures :

1. Plasma Isofuran Concentrations [ Time Frame: 24 hours ]
   Plasma isofuran concentrations as a measure of lipid peroxidation
2. Plasma F2-isoprostane Concentrations [ Time Frame: 24 hours ]
   Plasma F2-isoprostane concentrations as a measure of lipid peroxidation

Secondary Outcome Measures :

1. Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) [ Time Frame: 24 hours ]
   Changes in urinary NGAL (neutrophil gelatinase-associated lipocalin) as marker of acute kidney injury
2. Serum Creatinine [ Time Frame: 72 hours ]
   Serum creatinine measured over a 72 hour period

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery requiring CPB
2. For female subjects, the following conditions must be met:

postmenopausal for at least 1 year, or status-post surgical sterilization, or if of childbearing potential, utilizing adequate birth control and a negative urine beta-hcg prior to drug treatment

Exclusion Criteria:

1. Allergic reaction to ApAP (acetaminophen)
2. Evidence of severe hepatic impairment (history of liver cirrhosis or total bilirubin >2.0mg/dl)
3. Impaired renal function (serum creatinine >2.0 mg/dl)
4. Emergency surgery
5. Pregnancy
6. Breast-feeding
7. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
8. History of alcohol or drug abuse
9. Treatment with any investigational drug in the 1 month preceding the study
10. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
11. Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study
12. History or evidence of active asthma

Contacts and Locations

Locations

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University

Investigators

• Principal Investigator: Mias Pretorius, MBChB, MSCI; Vanderbilt University

More Information

Publications:

Billings FT 4th, Ball SK, Roberts LJ 2nd, Pretorius M. Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response. Free Radic Biol Med. 2011 Jun 1;50(11):1480-7. doi: 10.1016/j.freeradbiomed.2011.02.011. Epub 2011 Feb 18.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Billings FT 4th, Petracek MR, Roberts LJ 2nd, Pretorius M. Perioperative intravenous acetaminophen attenuates lipid peroxidation in adults undergoing cardiopulmonary bypass: a randomized clinical trial. PLoS One. 2015 Feb 23;10(2):e0117625. doi: 10.1371/journal.pone.0117625. eCollection 2015.

• Responsible Party: Mias Pretorius, Associate Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT01366976
• Other Study ID Numbers: 110423
• First Posted: June 6, 2011
• Results First Posted: January 14, 2015
• Last Update Posted: January 27, 2015
• Last Verified: January 2015

Keywords provided by Mias Pretorius, Vanderbilt University:

oxidative stress; cardiopulmonary bypass; acetaminophen; hemolysis

Additional relevant MeSH terms:

Acetaminophen; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Antipyretics