Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis
Author:
Ware Lorraine B.1, Files D. Clark2, Fowler Alpha3, Aboodi Michael S.4, Aggarwal Neil R.5, Brower Roy G.6, Chang Steven Y.7, Douglas Ivor S.8, Fields Scott9, Foulkes Andrea S.10, Ginde Adit A.5, Harris Estelle S.11, Hendey Gregory W.7, Hite R. Duncan12, Huang Weixing10, Lai Poying10, Liu Kathleen D.9, Thompson B. Taylor10, Matthay Michael A.9, , Steingrub Jay S.13, Smithline Howard13, Tidswell Mark13, Kozikowski Lori13, Thorton-Thompson Sherell13, DeSouza Lesley13, Kardos Cynthia13, Romain Sarah13, Oullette Scott13, Hou Peter13, Baron Rebecca M.13, Hansen Christopher13, Pinto Plata Victor13, Lei Yuxiu13, Riker Richard13, Lord Christine13, Searight Meghan13, Shapiro Nathan I.13, Talmor Daniel13, Goodspeed Valerie13, Stenson Bryan13, Ellis Joshua13, Dagan Alon13, Shilvkina Tatyana13, Sekhon Rupinder13, Ottanelli Carlo13, Grafals Ana13, Redman Kim13, Das Madhavan13, Kattouf Nadim13, Barca Alessio13, Weingart Alexander13, Filbin Michael R.13, Hibbert Kathryn13, Parry Blair Alden13, Margolin Justin13, Jones Alan E.13, Galbraith James13, Nandi Utsav13, Hendrickson Carolyn13, Kangelaris Kirsten13, Hariharan Taarini13, Groper Rachel13, Ashktorab Kimia13, Agrawal Anika13, Schmiege Emma13, Zhuo Hanjing13, Leroux Carolyn13, Chang Steven Y.13, Hendey Gregory W.13, Lim George13, Sihota Hena13, Levitt Joseph E.13, Wilson Jenny G.13, Rogers Angela J.13, Vojnik Rosemary13, Battu Shreya13, Perez Cynthia13, Albertson Timothy E.13, Morrissey Brian13, Wick Katherine13, Hardy Erin13, Puri Ruchira13, Hafenstein Tessa13, Hughes Alyssa13, Almasri Eyad13, Hibbard Shelly13, Patel Bela13, Akkanti Bindu13, Doshi Pratik13, Patarroyo Aponte Gabriel13, Huebinger Ryan13, Vidales Elizabeth13, Udoh-Bradford Idorenyin13, Aggarwal Neil13, Ginde Adit A.13, McKeehan Jeffrey13, Higgins Carrie13, Licursi Ashley13, Fickes-Siler Jennifer13, Slaughter Suzanne13, Johnson Emily13, Douglas Ivor S.13, Haukoos Jason13, Trent Stacy13, Hiller Terra13, Lyle Carolynn13, Garcia Ana13, Gravitz Stephnie13, Tran Darwin13, Lundin Mia13, Dunn Julie13, Stevens Eric13, Nudell Nikiah13, Baxter Bridget13, Bins Scott13, Smoot Brittany13, Huckins Nichol13, Co Ivan N.13, Park Pauline K.13, Hyzy Robert13, Nelson Kristine13, Jiminez J. Victor13, Olbrich Normal13, McSparron Jakob I.13, Munroe Elizabeth13, Choi Phillip13, Jia Shijing13, Sherwin Robert13, Mazzocco Thomas13, Buck Lauren13, Pandrangi Teja13, Swiderek Jennifer13, Rivers Emanuel P.13, Gill Jasreen Kaur13, Day Jacqueline13, Jaehne Anja Kathrina13, Gong Michelle Ng13, Moskowitz Ari13, Mohamed Amira13, Torres Martha13, Garcia Ofelia13, Andrea Luke13, Lopez Brenda13, Boujid Sabah13, Marliere Manuel Hache13, Richardson Lynne D.13, Acquah Samuel13, Goel Neha13, Maher Patrick13, Hypes Cameron13, Campbell Elizabeth Salvagio13, Lopez Anitza13, Labus Mary13, Hudock Kristin M.13, Hite R. Duncan13, Tanzeem Hammad13, More Harshada13, Khallaf Ashraf13, Williams Benjamin13, Duggal Abhijit13, Dugar Siddharth13, Mucha Simon13, Mehkri Omar13, Ashok Kiran13, Chang Caleb13, Pannu Sonal13, Exline Matthew13, Wang Henry13, Karow Sarah13, Swoope Gabrielle13, Khan Maryiam13, Smith David13, So Madison13, Schwartz Elli13, Johnson M. Kelly13, Files D. Clark13, Miller Chawick13, Gibbs Kevin W.13, Flores Lori13, Parks Lisa13, Landreth Leigha13, Koehler Lauren13, Fowler Alpha A. (Berry)13, de Wit Marjolein13, Mason Jessica13, Syed Aamer13, Qiao Xian13, Mitchell Kate13, Johnson Nicholas J.13, Robinson Bryce R.H.13, Gundel Stephanie13, Fuentes Megan13, Newton Maranda13, Peterson Emily13, Thompson Kathryn13, Rodriguez Armando13, Paulsen Thomas13, Kaur Ashdeep13, Hough Catherine L.13, Ward Molly13, McDougal Madeline13, Martinez Efrain Chavez13, Wolwowicz Edlyn13, Borchard Otmar13, Khan Akram13, Chen Peter13, Paschal Ethan13, Chen Po-En13, Choi-Kuaea Yunkee13, O'Mahony Shane13, Wallick Julie13, Duven Alexandria13, Fletcher Dakota13, Weissman Alexandria13, Yealy Donald13, Scholl Denise13, McVerry Bryan J.13, Huang David T.13, Turturro Michael A.13, Angus Derek C.13, Schooler Jordan13, Kass Lawrence E.13, Gentile Nina T.13, Marchetti Nathaniel13, Reimer Hannah13, Goodwin Andrew J.13, Grady Abby13, Lematty Caitlan13, Terry Charles13, Blender Melissa13, Sturek Jeffrey13, Sochor Mark13, Marshall Mary13, Simpson Ashley13, Patel Nikhil13, Taylor Bryce13, Patem Daxita13, Kearney-Bryan Jessica13, Knox Daniel13, Leither Lindsay M.13, Lanspa Michael13, Brown Samuel M.13, Peltan Ithan13, Gray Andrew13, Aston Valerie13, Burke Tyler13, Jeppsen Joshua13, Marshall Hunter13, Klippel Carolyn13, Armbruster Brent13, Applegate Darrin13, Harris Estelle13, Middleton Elizabeth A.13, Callahan Sean J.13, Waddoups Lindsey J.13, Yamane Misty B.13, Barrios Macy AG13, Wickersham Nancy13, Putz Nathan13, Gonski Samantha13, Lin Jason13, Lee Nury13, Rice Todd13, Ware Lorraine13, Self Wesley H.13, Hays Margaret13, Semler Matthew W.13, Frawley Liza13, Schoenfeld David A.13, Thompson B. Taylor13, Hayden Douglas L.13, Ringwood Nancy13, Oldmixon Cathryn13, Morse Richard13, Muzikansky Ariela13, Fitzgerald Laura13, Lagakos Adrian13, Huang Weixing13, Lai Pouing13, Carey Grace13, Brower Roy G.13, Punturieri Antonello13, Reineck Lora A.13, Beinstock Karen13, Demissie Ejigayehu13, Freemer Michelle13, Kiley James13, Kunz Lauren13, Stylianou Mario13, Maclawiw Myron13, Weinmann Gail13, Morrison Laurie J.13, Brodie Daniel13, Cairns Charles B.13, Gillespie Mark N.13, Kryscio Richard J.13, Scales Daman13, Truog Robert D.13, Parsons Polly13, Christie Jason D.13, Dickert Neal13, Diercks Deborah13, Hall Jesse R.13, Horton Nicholas J.13, Levy Mitchell13, Seigel Mark13, Steill Ian13, Zoloth Laurie S.13, Page David B.13, Russell Derek W.13, Harris Donna S.13, Gandotra Sheetal13
Affiliation:
1. Vanderbilt University Medical Center, Nashville, Tennessee 2. Wake Forest University, Winston Salem, North Carolina 3. Viginia Commonwealth University, Richmond 4. Montefiore Medical Center, New York, New York 5. University of Colorado School of Medicine, Aurora 6. Johns Hopkins University, Baltimore, MD 7. University of California, Los Angeles 8. Denver Health Medical Center, Denver, Colorado 9. University of California, San Francisco 10. Massachusetts General Hospital, Boston 11. University of Utah, Salt Lake City 12. University of Cincinnati, Cincinnati, Ohio 13. for the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network
Abstract
ImportanceAcetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.ObjectiveTo determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.Design, Setting, and ParticipantsPhase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation.InterventionPatients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days.Main Outcome and MeasuresThe primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL.ResultsOf 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, −1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, −6.3; 95% CI, −10.8 to −1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen.Conclusions and RelevanceIntravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients.Trial RegistrationClinicalTrials.gov Identifier: NCT04291508
Publisher
American Medical Association (AMA)
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