Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis
Authors: Ware Lorraine B. , Files D. Clark , Fowler Alpha , Aboodi Michael S. , Aggarwal Neil R. , Brower Roy G. , Chang Steven Y. , Douglas Ivor S. , Fields Scott , Foulkes Andrea S. , Ginde Adit A. , Harris Estelle S. , Hendey Gregory W. , Hite R. Duncan , Huang Weixing , Lai Poying , Liu Kathleen D. , Thompson B. Taylor , Matthay Michael A. ,   National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Steingrub Jay S. , Smithline Howard , Tidswell Mark , Kozikowski Lori , Thorton-Thompson Sherell , DeSouza Lesley , Kardos Cynthia , Romain Sarah , Oullette Scott , Hou Peter , Baron Rebecca M. , Hansen Christopher , Pinto Plata Victor , Lei Yuxiu , Riker Richard , Lord Christine , Searight Meghan , Shapiro Nathan I. , Talmor Daniel , Goodspeed Valerie , Stenson Bryan , Ellis Joshua , Dagan Alon , Shilvkina Tatyana , Sekhon Rupinder , Ottanelli Carlo , Grafals Ana , Redman Kim , Das Madhavan , Kattouf Nadim , Barca Alessio , Weingart Alexander , Filbin Michael R. , Hibbert Kathryn , Parry Blair Alden , Margolin Justin , Jones Alan E. , Galbraith James , Nandi Utsav , Hendrickson Carolyn , Kangelaris Kirsten , Hariharan Taarini , Groper Rachel , Ashktorab Kimia , Agrawal Anika , Schmiege Emma , Zhuo Hanjing , Leroux Carolyn , Chang Steven Y. , Hendey Gregory W. , Lim George , Sihota Hena , Levitt Joseph E. , Wilson Jenny G. , Rogers Angela J. , Vojnik Rosemary , Battu Shreya , Perez Cynthia , Albertson Timothy E. , Morrissey Brian , Wick Katherine , Hardy Erin , Puri Ruchira , Hafenstein Tessa , Hughes Alyssa , Almasri Eyad , Hibbard Shelly , Patel Bela , Akkanti Bindu , Doshi Pratik , Patarroyo Aponte Gabriel , Huebinger Ryan , Vidales Elizabeth , Udoh-Bradford Idorenyin , Aggarwal Neil , Ginde Adit A. , McKeehan Jeffrey , Higgins Carrie , Licursi Ashley , Fickes-Siler Jennifer , Slaughter Suzanne , Johnson Emily , Douglas Ivor S. , Haukoos Jason , Trent Stacy , Hiller Terra , Lyle Carolynn , Garcia Ana , Gravitz Stephnie , Tran Darwin , Lundin Mia , Dunn Julie , Stevens Eric , Nudell Nikiah , Baxter Bridget , Bins Scott , Smoot Brittany , Huckins Nichol , Co Ivan N. , Park Pauline K. , Hyzy Robert , Nelson Kristine , Jiminez J. Victor , Olbrich Normal , McSparron Jakob I. , Munroe Elizabeth , Choi Phillip , Jia Shijing , Sherwin Robert , Mazzocco Thomas , Buck Lauren , Pandrangi Teja , Swiderek Jennifer , Rivers Emanuel P. , Gill Jasreen Kaur , Day Jacqueline , Jaehne Anja Kathrina , Gong Michelle Ng , Moskowitz Ari , Mohamed Amira , Torres Martha , Garcia Ofelia , Andrea Luke , Lopez Brenda , Boujid Sabah , Marliere Manuel Hache , Richardson Lynne D. , Acquah Samuel , Goel Neha , Maher Patrick , Hypes Cameron , Campbell Elizabeth Salvagio , Lopez Anitza , Labus Mary , Hudock Kristin M. , Hite R. Duncan , Tanzeem Hammad , More Harshada , Khallaf Ashraf , Williams Benjamin , Duggal Abhijit , Dugar Siddharth , Mucha Simon , Mehkri Omar , Ashok Kiran , Chang Caleb , Pannu Sonal , Exline Matthew , Wang Henry , Karow Sarah , Swoope Gabrielle , Khan Maryiam , Smith David , So Madison , Schwartz Elli , Johnson M. Kelly , Files D. Clark , Miller Chawick , Gibbs Kevin W. , Flores Lori , Parks Lisa , Landreth Leigha , Koehler Lauren , Fowler Alpha A. (Berry) , de Wit Marjolein , Mason Jessica , Syed Aamer , Qiao Xian , Mitchell Kate , Johnson Nicholas J. , Robinson Bryce R.H. , Gundel Stephanie , Fuentes Megan , Newton Maranda , Peterson Emily , Thompson Kathryn , Rodriguez Armando , Paulsen Thomas , Kaur Ashdeep , Hough Catherine L. , Ward Molly , McDougal Madeline , Martinez Efrain Chavez , Wolwowicz Edlyn , Borchard Otmar , Khan Akram , Chen Peter , Paschal Ethan , Chen Po-En , Choi-Kuaea Yunkee , O'Mahony Shane , Wallick Julie , Duven Alexandria , Fletcher Dakota , Weissman Alexandria , Yealy Donald , Scholl Denise , McVerry Bryan J. , Huang David T. , Turturro Michael A. , Angus Derek C. , Schooler Jordan , Kass Lawrence E. , Gentile Nina T. , Marchetti Nathaniel , Reimer Hannah , Goodwin Andrew J. , Grady Abby , Lematty Caitlan , Terry Charles , Blender Melissa , Sturek Jeffrey , Sochor Mark , Marshall Mary , Simpson Ashley , Patel Nikhil , Taylor Bryce , Patem Daxita , Kearney-Bryan Jessica , Knox Daniel , Leither Lindsay M. , Lanspa Michael , Brown Samuel M. , Peltan Ithan , Gray Andrew , Aston Valerie , Burke Tyler , Jeppsen Joshua , Marshall Hunter , Klippel Carolyn , Armbruster Brent , Applegate Darrin , Harris Estelle , Middleton Elizabeth A. , Callahan Sean J. , Waddoups Lindsey J. , Yamane Misty B. , Barrios Macy AG , Wickersham Nancy , Putz Nathan , Gonski Samantha , Lin Jason , Lee Nury , Rice Todd , Ware Lorraine , Self Wesley H. , Hays Margaret , Semler Matthew W. , Frawley Liza , Schoenfeld David A. , Thompson B. Taylor , Hayden Douglas L. , Ringwood Nancy , Oldmixon Cathryn , Morse Richard , Muzikansky Ariela , Fitzgerald Laura , Lagakos Adrian , Huang Weixing , Lai Pouing , Carey Grace , Brower Roy G. , Punturieri Antonello , Reineck Lora A. , Beinstock Karen , Demissie Ejigayehu , Freemer Michelle , Kiley James , Kunz Lauren , Stylianou Mario , Maclawiw Myron , Weinmann Gail , Morrison Laurie J. , Brodie Daniel , Cairns Charles B. , Gillespie Mark N. , Kryscio Richard J. , Scales Daman , Truog Robert D. , Parsons Polly , Christie Jason D. , Dickert Neal , Diercks Deborah , Hall Jesse R. , Horton Nicholas J. , Levy Mitchell , Seigel Mark , Steill Ian , Zoloth Laurie S. , Page David B. , Russell Derek W. , Harris Donna S. , Gandotra Sheetal 
Published: May 2024

Importance

Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.

Objective

To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.

Design, Setting, and Participants

Phase 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.

Intervention

Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days.

Main Outcome and Measures

The 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.

Results

Of 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 Relevance

Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients.

Trial Registration

ClinicalTrials.gov Identifier: NCT04291508