Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis
Lorraine B. Ware, D. Clark Files, Alpha A. Fowler, Michael S. Aboodi, Neil R. Aggarwal, Roy G. Brower, Steven Y. Chang, Ivor S. Douglas, Scott A. Fields, Andrea S. Foulkes, Adit A. Ginde, Estelle S. Harris, Gregory W. Hendey, R. Duncan Hite, Weixing Huang, Poying Lai, Kathleen D. Liu, Bruce Thompson, Michael A. Matthay, Jay S. Steingrub, Howard Smithline, Mark Tidswell, Lori Kozikowski, Sherell Thorton-Thompson, Lesley DeSouza, Cynthia Kardos, Sarah Romain, Scott Oullette, Peter C. Hou, Rebecca M. Baron, Christopher J. Hansen, Víctor Pinto Plata, Yuxiu Lei, Richard R. Riker, Christine Lord, Meghan Searight, Nathan I. Shapiro, Daniel Talmor, Valerie Banner‐Goodspeed, Bryan Stenson, Joshua Ellis, Alon Dagan, Tatyana Shilvkina, Rupinder Sekhon, Carlo Ottanelli, Ana Grafals, Kim Redman, M. Das, Nadim Kattouf, Alessio Barca, Alexander Weingart, Michael R. Filbin, Kathryn A. Hibbert, Blair A. Parry, Justin Margolin, Alan E. Jones, James Galbraith, Utsav Nandi, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Taarini Hariharan, Rachel Groper, Kimia Ashktorab, Anika Agrawal, Emma Schmiege, Hanjing Zhuo, Carolyn Leroux, Steven Y. Chang, Gregory W. Hendey, George Lim, Hena Sihota, Joseph E. Levitt, Jenny G Wilson, Angela J. Rogers, Rosemary Vojnik, Shreya Battu, Cynthia Pérez, Timothy E. Albertson, Brian Morrissey, Katherine Wick, Erin Hardy, Ruchira Puri, Tessa Hafenstein, Alyssa Hughes, Eyad Almasri, Shelly Hibbard, Bela Patel, Bindu Akkanti, Pratik Doshi, Gabriel Patarroyo‐Aponte, Ryan Huebinger, Elizabeth Vidales, Idorenyin Udoh-Bradford, Neil R. Aggarwal, Adit A. Ginde, Jeffrey McKeehan, Carrie Higgins, Ashley Licursi, Jennifer Fickes-Siler, Suzanne Slaughter
Abstract
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.