David R Janz1, Julie A Bastarache, Todd W Rice, Gordon R Bernard, Melissa A Warren, Nancy Wickersham, Gillian Sills, John A Oates, L Jackson Roberts, Lorraine B Ware. 1. 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.
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 withacetaminophen 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.
RCT Entities:
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 illpatients 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.
Authors: Chenell Donadee; Nicolaas J H Raat; Tamir Kanias; Jesús Tejero; Janet S Lee; Eric E Kelley; Xuejun Zhao; Chen Liu; Hannah Reynolds; Ivan Azarov; Sheila Frizzell; E Michael Meyer; Albert D Donnenberg; Lirong Qu; Darrel Triulzi; Daniel B Kim-Shapiro; Mark T Gladwin Journal: Circulation Date: 2011-07-11 Impact factor: 29.690
Authors: Christian Meyer; Christian Heiss; Christine Drexhage; Eva S Kehmeier; Jan Balzer; Anja Mühlfeld; Marc W Merx; Thomas Lauer; Harald Kühl; Jürgen Floege; Malte Kelm; Tienush Rassaf Journal: J Am Coll Cardiol Date: 2010-02-02 Impact factor: 24.094
Authors: Rasmus Larsen; Raffaella Gozzelino; Viktória Jeney; László Tokaji; Fernando A Bozza; André M Japiassú; Dolores Bonaparte; Moisés Marinho Cavalcante; Angelo Chora; Ana Ferreira; Ivo Marguti; Sílvia Cardoso; Nuno Sepúlveda; Ann Smith; Miguel P Soares Journal: Sci Transl Med Date: 2010-09-29 Impact factor: 17.956
Authors: David R Janz; Julie A Bastarache; Josh F Peterson; Gillian Sills; Nancy Wickersham; Addison K May; L Jackson Roberts; Lorraine B Ware Journal: Crit Care Med Date: 2013-03 Impact factor: 7.598
Authors: Ciara M Shaver; Melinda G Paul; Nathan D Putz; Stuart R Landstreet; Jamie L Kuck; Lauren Scarfe; Nataliya Skrypnyk; Haichun Yang; Fiona E Harrison; Mark P de Caestecker; Julie A Bastarache; Lorraine B Ware Journal: Am J Physiol Renal Physiol Date: 2019-07-31
Authors: Hallie C Prescott; Carolyn S Calfee; B Taylor Thompson; Derek C Angus; Vincent X Liu Journal: Am J Respir Crit Care Med Date: 2016-07-15 Impact factor: 21.405
Authors: Ciara M Shaver; Nancy Wickersham; J Brennan McNeil; Hiromasa Nagata; Adam Miller; Stuart R Landstreet; Jamie L Kuck; Joshua M Diamond; David J Lederer; Steven M Kawut; Scott M Palmer; Keith M Wille; Ann Weinacker; Vibha N Lama; Maria M Crespo; Jonathan B Orens; Pali D Shah; Chadi A Hage; Edward Cantu; Mary K Porteous; Gundeep Dhillon; John McDyer; Julie A Bastarache; Jason D Christie; Lorraine B Ware Journal: JCI Insight Date: 2018-01-25
Authors: Jamie L Kuck; Julie A Bastarache; Ciara M Shaver; Joshua P Fessel; Sergey I Dikalov; James M May; Lorraine B Ware Journal: Biochem Biophys Res Commun Date: 2017-11-09 Impact factor: 3.575
Authors: Nataliya I Skrypnyk; Paul Voziyan; Haichun Yang; Christian R de Caestecker; Marie-Claude Theberge; Mathieu Drouin; Billy Hudson; Raymond C Harris; Mark P de Caestecker Journal: Am J Physiol Renal Physiol Date: 2016-05-18
Authors: Ciara M Shaver; Cameron P Upchurch; David R Janz; Brandon S Grove; Nathan D Putz; Nancy E Wickersham; Sergey I Dikalov; Lorraine B Ware; Julie A Bastarache Journal: Am J Physiol Lung Cell Mol Physiol Date: 2016-01-15 Impact factor: 5.464