Inhibition of Lipid Peroxidation During Cardiac Surgery

Inhibition of Lipid Peroxidation During Cardiopulmonary Bypass

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.

Study Overview

• Status: Completed
• Conditions: Cardiopulmonary Bypass Induced Lipid Peroxidation
• Intervention / Treatment: Drug: Acetaminophen

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Acetaminophen; Acetaminophen 1g every 6 hours for 4 doses over 24 hours; Other Names: 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 Names: Tylenol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Isofuran Concentrations	Plasma isofuran concentrations as a measure of lipid peroxidation	24 hours
Plasma F2-isoprostane Concentrations	Plasma F2-isoprostane concentrations as a measure of lipid peroxidation	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin)	Changes in urinary NGAL (neutrophil gelatinase-associated lipocalin) as marker of acute kidney injury	24 hours
Serum Creatinine	Serum creatinine measured over a 72 hour period	72 hours

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Investigators: Principal Investigator: Mias Pretorius, MBChB, MSCI, Vanderbilt University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: June 2, 2011
• First Submitted That Met QC Criteria: June 3, 2011
• First Posted (Estimate): June 6, 2011

Study Record Updates

• Last Update Posted (Estimate): January 27, 2015
• Last Update Submitted That Met QC Criteria: January 14, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: acetaminophen; cardiopulmonary bypass; oxidative stress; hemolysis
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: 110423