Inhibition of Lipid Peroxidation During Cardiac Surgery

Study Overview
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Brief Summary
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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.

Official Title
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Inhibition of Lipid Peroxidation During Cardiopulmonary Bypass

Conditions
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Cardiopulmonary Bypass Induced Lipid Peroxidation

Intervention / Treatment
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* Drug: Acetaminophen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery requiring CPB 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: Allergic reaction to ApAP (acetaminophen) Evidence of severe hepatic impairment (history of liver cirrhosis or total bilirubin >2.0mg/dl) Impaired renal function (serum creatinine >2.0 mg/dl) Emergency surgery Pregnancy Breast-feeding 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 History of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding the study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study History or evidence of active asthma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Acetaminophen<br>* Acetaminophen 1g every 6 hours for 4 doses over 24 hours<br>* Other names: Tylenol;|
| Active Comparator: Acetaminophen<br>Acetaminophen will ge given as 1g every 6 hours for 4 doses over a 24 hours study period | Drug: Acetaminophen<br>* Acetaminophen 1g every 6 hours for 4 doses over 24 hours<br>* Other names: Tylenol;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxidative stress, cardiopulmonary bypass, acetaminophen, hemolysis