Trial Shows Promise from Using Acetaminophen to Treat Sepsis

The drug was safe and had the greatest benefit for those at risk of organ failure. Researchers also discovered a way to quickly test which patients are likely to benefit.

A clinical trial supported by the National Institutes of Health (NIH) has found that intravenous acetaminophen reduced sepsis patients’ risk of having organ injury or developing acute respiratory distress syndrome (ARDS), a serious condition that allows fluid to leak into the lungs.

Sepsis is the body’s uncontrolled and extreme response to an infection. While the trial did not improve mortality for all patients regardless of severity, the researchers found that acetaminophen gave the greatest benefit to the sepsis patients who were 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 May 19, 2024, in JAMA.

In sepsis, red blood cells become injured at abnormally high rates, releasing what is often 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, MD, professor of medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University Medical Center and the first author of the current study, showed that in addition to relieving pain and reducing fevers, acetaminophen could block the harmful effects of cell-free hemoglobin on the lungs, which are at major risk of injury during sepsis. Limited research had also suggested that acetaminophen might work better for patients with the most severe sepsis.

A higher level of cell-free hemoglobin has been linked to acute respiratory distress syndrome and death, and it could be used to identify which patients could benefit from acetaminophen therapy as soon as they are admitted to the hospital for sepsis.

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

Targeted research for the critically ill

The researchers enrolled 447 adults with sepsis and respiratory or circulatory organ dysfunction at 40 U.S. academic hospitals between October of 2021 and April of 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 that were above a certain threshold. The team's primary interest was the number of patients who were able to stay alive with no organ support, such as mechanical ventilation or treatment for kidney failure.

The researchers 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. They also found that organ injury was significantly lower in the acetaminophen group, as was the rate of ARDS 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, PhD, director of the Division of Lung Diseases at the National Heart, Lung and Blood Institute, which is part of NIH. “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.

“This trial opens the door to more personalized therapy in sepsis – in this case, targeting higher cell-free hemoglobin,” she said. “The results suggest that targeting specific therapies to specific patients may have a future in sepsis treatment. Sepsis is a very common syndrome for which we have no drug therapy other than treating the underlying infection. There is a tremendous unmet need in sepsis for new therapies.”

Funding: 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.

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit