Cardiopulmonary Bypass Induced Lipid Peroxidation
Conditions
Keywords
oxidative stress, cardiopulmonary bypass, acetaminophen, hemolysis
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.
Interventions
DRUGAcetaminophen
Acetaminophen 1g every 6 hours for 4 doses over 24 hours
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Isofuran Concentrations | 24 hours | Plasma isofuran concentrations as a measure of lipid peroxidation |
| Plasma F2-isoprostane Concentrations | 24 hours | Plasma F2-isoprostane concentrations as a measure of lipid peroxidation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) | 24 hours | Changes in urinary NGAL (neutrophil gelatinase-associated lipocalin) as marker of acute kidney injury |
| Serum Creatinine | 72 hours | Serum creatinine measured over a 72 hour period |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled by the research nurse at the time of the preoperative evaluation for surgery. The study period was from January 2012 until April 2013.
Pre-assignment details
Patients were excluded for the following reasons: 1) allergy to acetaminophen, 2) evidence of severe hepatic impairment (history of liver cirrhosis or total bilirubin \>2.0mg/dL) 3) evidence of impaired renal function (serum creatinine \>2.0mg/dL) or 4) pregnancy.
Participants by arm
| Arm | Count |
|---|---|
| Acetaminophen IV acetaminophen 1g every 6 hours for 4 doses over a 24 hours study period | 30 |
| Placebo Saline in equivalent volume as study drug | 30 |
| Total | 60 |
Baseline characteristics
| Characteristic | Acetaminophen | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.5 years | 61.0 years | 63 years |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 10 Participants | 14 Participants | 24 Participants |
| Sex: Female, Male Male | 20 Participants | 16 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 30 | 4 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Plasma F2-isoprostane Concentrations
Plasma F2-isoprostane concentrations as a measure of lipid peroxidation
Time frame: 24 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetaminophen | Plasma F2-isoprostane Concentrations | baseline | 27.8 pg/mL | Standard Error 3.3 |
| Acetaminophen | Plasma F2-isoprostane Concentrations | 30min of bypass | 45.8 pg/mL | Standard Error 3.7 |
| Acetaminophen | Plasma F2-isoprostane Concentrations | 60min of bypass | 52.0 pg/mL | Standard Error 5.3 |
| Acetaminophen | Plasma F2-isoprostane Concentrations | post-bypass | 34 pg/mL | Standard Error 2.9 |
| Acetaminophen | Plasma F2-isoprostane Concentrations | ICU | 32.0 pg/mL | Standard Error 3.1 |
| Acetaminophen | Plasma F2-isoprostane Concentrations | postoperative day 1 | 26.5 pg/mL | Standard Error 2.9 |
| Placebo | Plasma F2-isoprostane Concentrations | ICU | 47.5 pg/mL | Standard Error 9.9 |
| Placebo | Plasma F2-isoprostane Concentrations | baseline | 30.6 pg/mL | Standard Error 3.5 |
| Placebo | Plasma F2-isoprostane Concentrations | post-bypass | 48.4 pg/mL | Standard Error 10.2 |
| Placebo | Plasma F2-isoprostane Concentrations | 30min of bypass | 49.1 pg/mL | Standard Error 4.9 |
| Placebo | Plasma F2-isoprostane Concentrations | postoperative day 1 | 26.0 pg/mL | Standard Error 2.6 |
| Placebo | Plasma F2-isoprostane Concentrations | 60min of bypass | 52.8 pg/mL | Standard Error 6 |
p-value: 0.12Mixed Models Analysis
Primary
Plasma Isofuran Concentrations
Plasma isofuran concentrations as a measure of lipid peroxidation
Time frame: 24 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetaminophen | Plasma Isofuran Concentrations | baseline | 61.5 pg/mL | Standard Error 6.8 |
| Acetaminophen | Plasma Isofuran Concentrations | 30min of bypass | 72.1 pg/mL | Standard Error 7.37 |
| Acetaminophen | Plasma Isofuran Concentrations | 60min of bypass | 83.4 pg/mL | Standard Error 7.55 |
| Acetaminophen | Plasma Isofuran Concentrations | post-bypass | 82.9 pg/mL | Standard Error 9.71 |
| Acetaminophen | Plasma Isofuran Concentrations | ICU | 85.3 pg/mL | Standard Error 8.53 |
| Acetaminophen | Plasma Isofuran Concentrations | postoperative day 1 | 70.4 pg/mL | Standard Error 8.45 |
| Placebo | Plasma Isofuran Concentrations | ICU | 88.0 pg/mL | Standard Error 8.81 |
| Placebo | Plasma Isofuran Concentrations | baseline | 67.7 pg/mL | Standard Error 5.97 |
| Placebo | Plasma Isofuran Concentrations | post-bypass | 96.1 pg/mL | Standard Error 8.22 |
| Placebo | Plasma Isofuran Concentrations | 30min of bypass | 82.7 pg/mL | Standard Error 6.02 |
| Placebo | Plasma Isofuran Concentrations | postoperative day 1 | 68.5 pg/mL | Standard Error 6.21 |
| Placebo | Plasma Isofuran Concentrations | 60min of bypass | 110.8 pg/mL | Standard Error 13.21 |
Comparison: We hypothesized that acetaminophen would reduce peak isofuran concentrations by 22 pg/mL (40% reduction from peak concentrations). If the true difference in the acetaminophen and placebo group means is 22 pg/mL (SD=30 pg/mL), we would need to study 30 experimental subjects and 30 control subjects to be able to reject the null hypothesis that the population means of the acetaminophen and placebo groups are equal with probability (power) 0.8.p-value: 0.05Mixed Models Analysis
Secondary
Serum Creatinine
Serum creatinine measured over a 72 hour period
Time frame: 72 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetaminophen | Serum Creatinine | postoperative day 1 | 0.89 mg/dL | Standard Error 0.04 |
| Acetaminophen | Serum Creatinine | postoperative day 2 | 0.96 mg/dL | Standard Error 0.04 |
| Acetaminophen | Serum Creatinine | postoperative day 3 | 0.93 mg/dL | Standard Error 0.04 |
| Acetaminophen | Serum Creatinine | baseline | 0.98 mg/dL | Standard Error 0.04 |
| Placebo | Serum Creatinine | baseline | 0.94 mg/dL | Standard Error 0.03 |
| Placebo | Serum Creatinine | postoperative day 1 | 0.90 mg/dL | Standard Error 0.04 |
| Placebo | Serum Creatinine | postoperative day 3 | 0.88 mg/dL | Standard Error 0.05 |
| Placebo | Serum Creatinine | postoperative day 2 | 0.96 mg/dL | Standard Error 0.04 |
Secondary
Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin)
Changes in urinary NGAL (neutrophil gelatinase-associated lipocalin) as marker of acute kidney injury
Time frame: 24 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetaminophen | Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) | baseline | 19.21 ng/mL | Standard Error 6.7 |
| Acetaminophen | Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) | pos-bypass | 145.8 ng/mL | Standard Error 49.6 |
| Acetaminophen | Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) | postoperative day 1 | 46.04 ng/mL | Standard Error 25.5 |
| Placebo | Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) | baseline | 23.2 ng/mL | Standard Error 8.4 |
| Placebo | Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) | pos-bypass | 138.4 ng/mL | Standard Error 43.5 |
| Placebo | Urinary NGAL (Neutrophil Gelatinase-associated Lipocalin) | postoperative day 1 | 16.8 ng/mL | Standard Error 2.4 |