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Administration of acetaminophen to patients with severe sepsis and detectable plasma levels of cell-free hemoglobin (CFH) improved kidney function but did not appear to reduce oxidative injury. David R. Janz, MD, Vanderbilt University, Nashville, Tennessee, USA, presented data from the Phase 2a randomized controlled trial of Acetaminophen for the Reduction of Oxidative Stress in Severe Sepsis trial [ACROSS; NCT01739361; Janz DR et al. Am J Respir Care Med 2014.]

Sepsis is associated with increased plasma levels of CFH, which causes oxidative injury to the kidney [Janz DR et al. Crit Care Med 2013]. Previous observational studies have suggested that acetaminophen can decrease detectable CFH plasma levels, reduce oxidative damage caused by CHF, and improve outcomes in patients with severe sepsis and detectable plasma CFH [Janz DR et al. Crit Care Med 2013]. The hypothesis of the ACROSS trial was that oxidative injury would decrease and renal function would improve by treatment with acetaminophen in patients with severe sepsis and detectable CFH.

In the Phase 2a trial, 45 patients with severe sepsis were randomly assigned to receive enteral acetaminophen (1 g every 6 hours for 3 days) or placebo within 24 hours of admittance to the intensive care unit. Patients were ineligible if they had taken acetaminophen within the past 48 hours, had no enteral access, had acute or chronic liver disease, were pregnant, or if death was imminent. Before randomization, blood was collected at baseline and Days 1, 2, and 3 and analyzed for CFH, F₂-isoprostanes, F₂-isofurans, and acetaminophen levels. Forty patients completed the trial (acetaminophen, n=18; placebo, n=22).

The primary outcome of the ACROSS trial was the concentration of F₂-isoprostanes on Day 3, a measure of oxidative injury. Secondary outcomes included F₂-isoprostanes levels on Day 2, F₂-isofuran levels on Day 3, and serum creatinine levels on Day 3.

The results were negative for the primary end point, with no significant decrease in F₂-isoprostanes levels on Day 3 (p=0.353) for patients who received acetaminophen compared to placebo (Figure 1). F₂-isofurans tended to decrease with acetaminophen treatment compared with placebo. Creatinine levels were significantly lower in the acetaminophen arm compared with the placebo arm beginning on Day 3 (p=0.039) and continuing to discharge or death (p=0.03; Figure 2).

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Figure 1.

Effect of Acetaminophen on F₂-isoprostanes Levels in Patients With Severe Sepsis

Square/circle=median; Upper and lower caps=interquartile range.Reproduced with permission from DR Janz, MD.

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Figure 2.

Effect of Acetaminophen on Kidney Function in Patients With Severe Sepsis

Square/circle=median; Upper and lower caps=interquartile range.Reproduced with permission from DR Janz, MD.

Adverse events included elevation of aspartate and alanine aminotransferase above 400 units/L in 6.8% of the study population, with 9.5% occurring in the acetaminophen arm and 4.3% occurring in the placebo arm. Aspartate aminotransferase levels were greatest on Day 1 of the study, whereas alanine aminotransferase levels were highest on Day 2 of the study.

In conclusion, Dr. Janz stated that the results from the ACROSS trial suggest that treatment of patients with severe sepsis and detectable CFH levels with acetaminophen did not result in a reduction in oxidative injury, the primary outcome; however, renal function was improved, as measured by serum creatinine. Overall, acetaminophen was well tolerated. Although further studies are needed to confirm the findings of the ACROSS trial, Dr. Janz stated that acetaminophen may improve renal outcomes of patients with severe sepsis and detectable CFH plasma levels.

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