title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Single-center, randomized, double-blind, placebo-controlled phase II trial.
  
  
  METHODS
  Medical ICU in a tertiary, academic medical center.
  
  
  METHODS
  Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: David R
authors.initials: DR
authors.lastname: Janz
authors.forename: Julie A
authors.initials: JA
authors.lastname: Bastarache
authors.forename: Todd W
authors.initials: TW
authors.lastname: Rice
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Bernard
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Warren
authors.forename: Nancy
authors.initials: N
authors.lastname: Wickersham
authors.forename: Gillian
authors.initials: G
authors.lastname: Sills
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000627:therapeutic use*; D002474:Cell-Free System; D003404:Creatinine / Q000097:blood; D016638:Critical Illness; D004311:Double-Blind Method; D028441:F2-Isoprostanes / Q000097:blood*; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction / Q000187:drug effects*; D015742:Propofol / Q000008:administration & dosage; D012121:Respiration, Artificial; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology
chemical_list: D018712:Analgesics, Non-Narcotic; D028441:F2-Isoprostanes; D006454:Hemoglobins; D000082:Acetaminophen; D003404:Creatinine; D015742:Propofol