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Randomized, Placebo-Controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis

The Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis Trial*

Janz, David R. MD, MSc1; Bastarache, Julie A. MD2; Rice, Todd W. MD, MSc2; Bernard, Gordon R. MD2; Warren, Melissa A. MD2; Wickersham, Nancy BS2; Sills, Gillian BS2; Oates, John A. MD3; Roberts, L. Jackson II MD3; Ware, Lorraine B. MD2,4 for the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis Study Group

doi: 10.1097/CCM.0000000000000718
Clinical Investigations
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Objectives: This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma 2-isoprostanes">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: 2-Isoprostanes">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, 2-isoprostanes">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.

1Section of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University School of Medicine, New Orleans, LA.

2Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.

3Division of Clinical Pharmacology, Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, TN.

4Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.

* See also p. 698.

Drs. Janz, Bastarache, Rice, Bernard, Oates, Roberts, and Ware were involved in the study design. Dr. Janz, Dr. Warren, G. Sills, and N. Wickersham collected the data. Drs. Janz and Ware performed the statistical analysis. Dr. Janz drafted the article and all authors participated in the revision of this article. All authors read and approved the final article.

Supported, in part, by the Vanderbilt Clinical and Translational Science Award grant UL1 TR000445 from National Center for Research Resources/National Institutes of Health (NIH), NIH T32 HL087738, UL1 RR024975-01, HL103836, HL090785, HL117676, GM15431, and Courtney’s Race for the Acute Respiratory Distress Syndrome Cure and the Courtney Charneco Family.

Presented, in part, at the American Thoracic Society International Conference, May 18, 2014 (publication A6568) in abstract form.

Dr. Janz received support for article research from the National Institutes of Health (NIH). Dr. Bastarache received support for article research from the NIH and the American Heart Association. Her institution received grant support. Dr. Rice consulted for Avisa, LLC and GlaxoSmithKline, LLC (Member of DSMB) and received support for article research from the NIH. His institution received grant support from the NIH NHLBI. Dr. Bernard received support for article research from the NIH. His institution received grant support from the NIH. Dr. Oates received support for article research from the NIH and served as a board member for Cumberland Pharmaceuticals. His institution received grant support from the NIH and has a patent (use patent for acetaminophen in the treatment of diseases induced by hemeprotein catalyzed lipid peroxidation). Dr. Ware received support for article research from the NIH. Her institution received grant support from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: David R. Janz, MD, MSc, 1901 Perdido St., Suite 3205, New Orleans, LA 70112. E-mail: djanz@lsushc.edu

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