Health & Medical intensive care

Acetaminophen for Oxidative Injury in Severe Sepsis

Acetaminophen for Oxidative Injury in Severe Sepsis

Abstract and Introduction

Abstract


Objectives This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin.

Design Single-center, randomized, double-blind, placebo-controlled phase II trial.

Setting Medical ICU in a tertiary, academic medical center.

Patients Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin.

Interventions Patients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration.

Measurements and Main Results F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24–41) and placebo (36 pg/mL; interquartile range, 25–80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19–36) when compared with placebo (36 pg/mL; interquartile range, 23–55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6–1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83–2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599).

Conclusions In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.

Introduction


Plasma levels of cell-free hemoglobin (CFH) are elevated in patients with a variety of illnesses, including critically ill patients with sepsis. Increased levels of CFH are associated with experimental and postoperative kidney injury and are independently associated with increased in-hospital mortality in patients with sepsis. CFH may mediate poor clinical outcomes via nitric oxide scavenging and vasoconstriction, vascular endothelial damage, and the ability of the iron moiety of CFH to undergo redox cycling, leading to oxidation of lipid membranes and release of F2-isoprostanes (F2-IsoPs).

Acetaminophen inhibits hemoprotein-mediated lipid peroxidation owing to its ability to reduce the iron protoporphyrin radical present within CFH. In animal studies, acetaminophen prevents oxidative injury and renal failure caused by rhabdomyolysis-induced release of the hemoprotein myoglobin. In an observational study of adults with severe sepsis, we reported that acetaminophen administration was associated with reduced plasma levels of F2-IsoPs and was independently associated with decreased in-hospital mortality; this protective association was only observed in patients with detectable CFH.

On the basis of these data suggesting that acetaminophen could reduce oxidative injury in patients with sepsis, we conducted a randomized, double-blind, placebo-controlled trial to test the primary hypothesis that the treatment of critically ill adults with severe sepsis and detectable plasma CFH with acetaminophen would decrease oxidative injury as measured by plasma F2-IsoPs. We further hypothesized that acetaminophen would improve renal function as measured by serum creatinine.

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