Clinical trial NCT01366976: Inhibition of Lipid Peroxidation During Cardiac Surgery
Official title: Inhibition of Lipid Peroxidation During Cardiopulmonary Bypass
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cardiopulmonary Bypass Induced Lipid Peroxidation
Keywords: oxidative stress
cardiopulmonary bypass
acetaminophen
hemolysis
Lead sponsor: Vanderbilt University
Sponsor class: OTHER
First posted: 2011-06-06
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Plasma Isofuran Concentrations
timeFrame: 24 hours
measure: Plasma F2-isoprostane Concentrations
timeFrame: 24 hours
Secondary outcomes:
measure: Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin)
timeFrame: 24 hours
measure: Serum Creatinine
timeFrame: 72 hours
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University
name: Mias Pretorius, MBChB, MSCI
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.