Acetaminophen Attenuates Lipid Peroxidation in Children Undergoing Cardiopulmonary Bypass

Abstract

Objective Hemolysis, occurring during cardiopulmonary bypass (CPB), is associated with lipid peroxidation and postoperative acute kidney injury (AKI). Acetaminophen (ApAP) inhibits lipid peroxidation catalyzed by hemeproteins and in an animal model attenuated rhabdomyolysis-induced AKI. This pilot study tests the hypothesis that ApAP attenuates lipid peroxidation in children undergoing CPB. Design Single center prospective randomized double blinded study. Setting University-affiliated pediatric hospital. Patients Thirty children undergoing elective surgical correction of a congenital heart defect. Interventions Patients were randomized to ApAP (OFIRMEV® (acetaminophen) injection, Cadence Pharmaceuticals, San Diego, CA) or placebo every 6 hours for 4 doses starting before the onset of CPB. Measurement and Main Results Markers of hemolysis, lipid peroxidation (isofurans and F2-isoprostanes) and AKI were measured throughout the perioperative period. CPB was associated with a significant increase in free hemoglobin (from a pre-bypass level of 9.8±6.2 mg/dl to a peak of 201.5±42.6 mg/dl post-bypass). Plasma and urine isofuran and F2-isoprostane concentrations increased significantly during surgery. The magnitude of increase in plasma isofurans was greater than the magnitude in increase in plasma F2-isoprostanes. ApAP attenuated the increase in plasma isofurans compared to placebo (P=0.02 for effect of study drug). There was no significant effect of ApAP on plasma F2-isoprostanes or urinary makers of lipid peroxidation. ApAP did not affect postoperative creatinine, urinary neutrophil gelatinase-associated lipocalin or prevalence of AKI. Conclusion CPB in children is associated with hemolysis and lipid peroxidation. ApAP attenuated the increase in plasma isofuran concentrations. Future studies are needed to establish whether other therapies that attenuate or prevent the effects of free hemoglobin result in more effective inhibition of lipid peroxidation in patients undergoing CPB.

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

“…It has also been shown that AKI increases intracellular levels of free catalytic iron, which increases oxidative stress and renal injury after IR-AKI (35). Moreover, acetaminophen, which inhibits iron-catalyzed lipid peroxidation (7), attenuates serum and/or urinary isofuran/F2-isporsotane levels in patients with sepsis (27), and in patients undergoing cardiopulmonary bypass surgery (5,51). This indicates that therapeutic strategies designed to reduce the levels and/or activity of free catalytic iron can also be effective in patients with AKI.…”

The isoprostanes—25 years later

“…Interestingly, the aspirin treated group also showed lower baseline levels of F 2 -IsoPs at initiation of surgery. Others have studied the effect of acetaminophen treatment on the day of CPB surgery [135]. No effect of acetaminophen on levels of urinary F 2 -IsoPs was noted but the drug significantly lowered the magnitude of increase in urinary IsoFs during surgery.…”

Perioperative Intravenous Acetaminophen Attenuates Lipid Peroxidation in Adults Undergoing Cardiopulmonary Bypass: A Randomized Clinical Trial

“…[ 1 , 4 , 21 ] In our prior pediatric study we did not observe a significant decrease in intraoperative haptoglobin levels whereas in another study haptoglobin levels were only decreased 6 hours post-bypass. [ 1 , 4 ] One potential explanation for the difference between children and adults may be the more frequent use of plasma for CPB pump priming in pediatric patients, exogenously increasing circulating haptoglobin.…”

“…Cardiopulmonary bypass (CPB) lyses erythrocytes, increasing plasma concentrations of free hemoglobin. [ 1 – 4 ] Free hemoglobin undergoes hemeprotein redox cycling that, in the absence of antioxidants, initiates oxidation of free and phospholipid-esterified fatty acids. [ 5 ] Markers of lipid peroxidation are increased in patients with hemoglobinemia during cardiac surgery and in those that develop postoperative acute kidney injury (AKI).…”

“…Furthermore, in pediatric patients undergoing CPB, acetaminophen attenuated the increase in plasma isofuran concentrations but did not affect urinary makers of lipid peroxidation, serum concentrations of creatinine, or urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL). [ 4 ] The effect of acetaminophen on oxidative damage in adults undergoing CPB is unknown and deserves further study since intraoperative oxidative damage independently predicts postoperative AKI[ 7 ] and 500,000 patients undergo cardiac surgery each year. This study tested the hypothesis that acetaminophen reduces oxidant injury in adults undergoing elective cardiac surgery requiring CPB.…”