Perioperative intravenous acetaminophen attenuates lipid peroxidation in adults undergoing cardiopulmonary bypass: a randomized clinical trial

Abstract

Background: Cardiopulmonary bypass (CPB) lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery.

Methods and results: In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9 ± 0.6 μg/mL (78.9 ± 3.9 μM) and 8.7 ± 0.3 μg/mL (57.6 ± 2.0 μM), respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05), and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03). Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation.

Conclusions: Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected.

Trial registration: ClinicalTrials.gov NCT01366976.

Fig 1. Free hemoglobin (A) and haptoglobin (B) concentrations.

CPB was associated with an increase in free hemoglobin concentrations and a decrease in haptoglobin concentrations with no significant difference between the acetaminophen and placebo group. base, baseline; 30min, 30min of CPB; 60min, 60min of CPB; post, post-bypass; ICU, intensive care unit; and POD1, postoperative day 1.

Fig 2. Effect of study drug on plasma and urine markers of lipid peroxidation.; isoF, isofurans; F₂isoP, F₂-isoprostanes; base, baseline; 30min, 30min of CPB; 60min, 60min of CPB; post, post-bypass; ICU, intensive care unit; and POD1, postoperative day 1.

Fig 3. Plasma free hemoglobin (A) and creatinine (B) concentrations in subjects that developed acute kidney injury (AKI) compared to subjects that did not.

base, baseline; 30min, 30min of CPB; 60min, 60min of CPB; post, post-bypass; ICU, intensive care unit; and POD, postoperative day.