Innovative New Use of Acetaminophen Could Transform Sepsis Treatment

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Recent findings from an NIH-supported trial indicate that intravenous acetaminophen may help reduce organ injury and acute respiratory distress syndrome in sepsis patients, particularly those at severe risk. The study suggests potential benefits in using acetaminophen for critically ill patients, though further research is required.

Results from an NIH-supported clinical trial indicate that the drug is most effective in the most severely ill patients.

A clinical trial supported by the National Institutes of Health (NIH) has discovered that administering acetaminophen intravenously can lower the risk of organ damage and the development of acute respiratory distress syndrome (ARDS) in patients with sepsis. Sepsis is characterized by the body’s overwhelming and uncontrolled response to an infection.

While the trial did not improve mortality rates in all patients with sepsis regardless of severity, the researchers found that acetaminophen gave the greatest benefit to the patients most at risk for organ damage. With the therapy, those patients needed less assisted ventilation and experienced a slight, though statistically insignificant, decrease in mortality. The study was published in JAMA.

In sepsis, red blood cells become injured and die at abnormally high rates, releasing so called “cell-free hemoglobin” into the blood. The body becomes overwhelmed and can’t remove this excess hemoglobin which can lead to organ damage.

Previous work from Lorraine Ware, M.D., professor of medicine, pulmonary and critical care at Vanderbilt University, Nashville, Tennessee, and the first author of the current study showed that acetaminophen, in addition to relieving pain and reducing fevers, had been shown to block the harmful effects of cell-free hemoglobin on the lungs, which are at major risk of injury during sepsis. Limited research has also suggested that acetaminophen might work better for patients with the most severe sepsis – those with higher levels of cell-free hemoglobin, which have been linked to a greater risk of developing acute respiratory distress syndrome and a higher risk of death.

Potential for Biomarker Use in Treatment

Scientists note that identifying high levels of cell-free hemoglobin as a biomarker that could be tested when patients are first admitted to the hospital would be a breakthrough, because it could help quickly determine which patients with sepsis might benefit from acetaminophen therapy.

“One problem in critical care is the patients get sick so fast, that we do not normally have time to figure out which biomarkers help predict which therapy could give the best outcome,” said Michael Matthay, M.D., professor of medicine and anesthesia at the University of California, San Francisco, and the senior study author. “We hope that these findings will underscore the potential therapeutic value of using a biomarker to help successfully find a treatment that will work when patients need it the most.”

Details of the Clinical Trial

To test the therapeutic potential of acetaminophen more fully in a mid-stage clinical trial, researchers enrolled 447 adults with sepsis and respiratory or circulatory organ dysfunction at 40 U.S. academic hospitals from October 2021 to April 2023. Patients were randomized to receive either acetaminophen or a placebo intravenously every six hours for five days. The researchers then followed the patients for 28 days to see how they fared. They also completed a special analysis using data only from the patients with levels of cell-free hemoglobin above a certain threshold. The team’s primary interest overall was the number of patients who were able to stay alive with no organ support, such as mechanical ventilation or kidney failure treatment.

The researcher team found that intravenous acetaminophen was safe for all the sepsis patients, with no difference in liver injury, low blood pressure, or other adverse events compared to the placebo group. Among secondary outcomes, they also found that organ injury was significantly lower in the acetaminophen group, as was the rate of acute respiratory distress syndrome onset within seven days of hospital admission.

When looking more closely at the patients with higher cell-free hemoglobin, the researchers found that just 8% of patients in the acetaminophen group needed assisted ventilation compared to 23% of patients in the placebo group. And after 28 days, 12% of patients in the acetaminophen group had died, compared to 21% in the placebo group, though this finding was not statistically significant.

“While the anticipated effects of acetaminophen therapy were not realized for all sepsis patients, this study shows that it still holds promise for the most critically ill,” said James Kiley, Ph.D., director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute, part of NIH. “Though, more research is needed to uncover the mechanisms and validate these results.”

Ware said the results for the critically ill patients trended in a hopeful direction. She and Matthay plan to conduct a larger clinical trial, likely enrolling those patients primarily with higher cell-free hemoglobin levels.

Reference: “Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial” by Lorraine B. Ware, D. Clark Files, Alpha Fowler, Michael S. Aboodi, Neil R. Aggarwal, Roy G. Brower, Steven Y. Chang, Ivor S. Douglas, Scott Fields, Andrea S. Foulkes, Adit A. Ginde, Estelle S. Harris, Gregory W. Hendey, R. Duncan Hite, Weixing Huang, Poying Lai, Kathleen D. Liu, B. Taylor Thompson, Michael A. Matthay, National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Jay S. Steingrub, Howard Smithline, Mark Tidswell, Lori Kozikowski, Sherell Thorton-Thompson, Lesley DeSouza, Cynthia Kardos, Sarah Romain, Scott Oullette, Peter Hou, Rebecca M. Baron, Christopher Hansen, Victor Pinto Plata, Yuxiu Lei, Richard Riker, Christine Lord, Meghan Searight, Nathan I. Shapiro, Daniel Talmor, Valerie Goodspeed, Bryan Stenson, Joshua Ellis, Alon Dagan, Tatyana Shilvkina, Rupinder Sekhon, Carlo Ottanelli, Ana Grafals, Kim Redman, Madhavan Das, Nadim Kattouf, Alessio Barca, Alexander Weingart, Michael R. Filbin, Kathryn Hibbert, Blair Alden Parry, Justin Margolin, Alan E. Jones, James Galbraith, Utsav Nandi, Carolyn Hendrickson, Kirsten 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 Perez, 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 Aggarwal, Adit A. Ginde, Jeffrey McKeehan, Carrie Higgins, Ashley Licursi, Jennifer Fickes-Siler, Suzanne Slaughter, Emily Johnson, Ivor S. Douglas, Jason Haukoos, Stacy Trent, Terra Hiller, Carolynn Lyle, Ana Garcia, Stephnie Gravitz, Darwin Tran, Mia Lundin, Julie Dunn, Eric Stevens, Nikiah Nudell, Bridget Baxter, Scott Bins, Brittany Smoot, Nichol Huckins, Ivan N. Co, Pauline K. Park, Robert Hyzy, Kristine Nelson, J. Victor Jiminez, Normal Olbrich, Jakob I. McSparron, Elizabeth Munroe, Phillip Choi, Shijing Jia, Robert Sherwin, Thomas Mazzocco, Lauren Buck, Teja Pandrangi, Jennifer Swiderek, Emanuel P. Rivers, Jasreen Kaur Gill, Jacqueline Day, Anja Kathrina Jaehne, Michelle Ng Gong, Ari Moskowitz, Amira Mohamed, Martha Torres, Ofelia Garcia, Luke Andrea, Brenda Lopez, Sabah Boujid, Manuel Hache Marliere, Lynne D. Richardson, Samuel Acquah, Neha Goel, Patrick Maher, Cameron Hypes, Elizabeth Salvagio Campbell, Anitza Lopez, Mary Labus, Kristin M. Hudock, R. Duncan Hite, Hammad Tanzeem, Harshada More, Ashraf Khallaf, Benjamin Williams, Abhijit Duggal, Siddharth Dugar, Simon Mucha, Omar Mehkri, Kiran Ashok, Caleb Chang, Sonal Pannu, Matthew Exline, Henry Wang, Sarah Karow, Gabrielle Swoope, Maryiam Khan, David Smith, Madison So, Elli Schwartz, M. Kelly Johnson, D. Clark Files, Chawick Miller, Kevin W. Gibbs, Lori Flores, Lisa Parks, Leigha Landreth, Lauren Koehler, Alpha A. (Berry) Fowler, Marjolein de Wit, Jessica Mason, Aamer Syed, Xian Qiao, Kate Mitchell, Nicholas J. Johnson, Bryce R.H. Robinson, Stephanie Gundel, Megan Fuentes, Maranda Newton, Emily Peterson, Kathryn Thompson, Armando Rodriguez, Thomas Paulsen, Ashdeep Kaur, Catherine L. Hough, Molly Ward, Madeline McDougal, Efrain Chavez Martinez, Edlyn Wolwowicz, Otmar Borchard, Akram Khan, Peter Chen, Ethan Paschal, Po-En Chen, Yunkee Choi-Kuaea, Shane O’Mahony, Julie Wallick, Alexandria Duven, Dakota Fletcher, Alexandria Weissman, Donald Yealy, Denise Scholl, Bryan J. McVerry, David T. Huang, Michael A. Turturro, Derek C. Angus, Jordan Schooler, Lawrence E. Kass, Nina T. Gentile, Nathaniel Marchetti, Hannah Reimer, Andrew J. Goodwin, Abby Grady, Caitlan Lematty, Charles Terry, Melissa Blender, Jeffrey Sturek, Mark Sochor, Mary Marshall, Ashley Simpson, Nikhil Patel, Bryce Taylor, Daxita Patem, Jessica Kearney-Bryan, Daniel Knox, Lindsay M. Leither, Michael Lanspa, Samuel M. Brown, Ithan Peltan, Andrew Gray, Valerie Aston, Tyler Burke, Joshua Jeppsen, Hunter Marshall, Carolyn Klippel, Brent Armbruster, Darrin Applegate, Estelle Harris, Elizabeth A. Middleton, Sean J. Callahan, Lindsey J. Waddoups, Misty B. Yamane, Macy AG Barrios, Nancy Wickersham, Nathan Putz, Samantha Gonski, Jason Lin, Nury Lee, Todd Rice, Lorraine Ware, Wesley H. Self, Margaret Hays, Matthew W. Semler, Liza Frawley, David A. Schoenfeld, B. Taylor Thompson, Douglas L. Hayden, Nancy Ringwood, Cathryn Oldmixon, Richard Morse, Ariela Muzikansky, Laura Fitzgerald, Adrian Lagakos, Weixing Huang, Pouing Lai, Grace Carey, Roy G. Brower, Antonello Punturieri, Lora A. Reineck, Karen Beinstock, Ejigayehu Demissie, Michelle Freemer, James Kiley, Lauren Kunz, Mario Stylianou, Myron Maclawiw, Gail Weinmann, Laurie J. Morrison, Daniel Brodie, Charles B. Cairns, Mark N. Gillespie, Richard J. Kryscio, Daman Scales, Robert D. Truog, Polly Parsons, Jason D. Christie, Neal Dickert, Deborah Diercks, Jesse R. Hall, Nicholas J. Horton, Mitchell Levy, Mark Seigel, Ian Steill, Laurie S. Zoloth, David B. Page, Derek W. Russell, Donna S. Harris and Sheetal Gandotra, 19 May 2024, JAMA.
DOI: 10.1001/jama.2024.8772

This study was supported by NHLBI grants: U01 HL122989, U01 HL122998, U01 HL123004, U01 HL123008, U01 HL123009, U01 HL123010, U01 HL123018, U01 HL123020, U01 HL123022, U01 HL123023, U01 HL123027, U01 HL123031, and U01 HL123033.

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