In a recent phase 2b randomized clinical trial, researchers investigated whether intravenous acetaminophen could improve respiratory, circulatory, or kidney dysfunction in critically ill patients with sepsis. The trial included 447 adults and found that while acetaminophen was safe, it did not significantly increase the number of days patients were alive and free of organ support compared to a placebo.
Study Design and Participants
The trial, conducted from October 2021 to April 2023 across 40 U.S. academic hospitals, enrolled adults with sepsis and either respiratory or circulatory organ dysfunction. Participants were randomized to receive either 1 gram of acetaminophen intravenously every six hours or a placebo for 5 days. The primary endpoint was the number of days alive and free of organ support, including mechanical ventilation, vasopressors, and kidney replacement therapy, up to day 28.
Key Findings
The study, published in JAMA, found no meaningful difference in the primary outcome between the acetaminophen group (20.2 days) and the placebo group (19.6 days). The treatment effect did not vary significantly with the patients' cell-free hemoglobin levels. Additionally, secondary outcomes such as 28-day ventilator-free, vasopressor-free, and new kidney replacement-free days, as well as 28-day and 90-day mortality, showed no significant differences between the two groups.
However, acetaminophen was associated with a lower rate of acute respiratory distress syndrome within 7 days and showed improvements in total and respiratory Sequential Organ Failure Assessment (SOFA) scores on study days 1 through 4. The safety profile of acetaminophen was favorable, with no significant differences in liver enzyme levels, hypotension, or fluid balance compared to placebo.
Study Methods
Patients in the trial were required to have clinical evidence of a known or suspected infection and orders for antibiotics, with either hypotension requiring vasopressors or respiratory failure needing mechanical ventilation or high levels of supplemental oxygen. The trial was conducted under strict oversight with written informed consent obtained from all patients or their legal representatives.
Participants were randomized using a web-based system, ensuring balanced allocation to the acetaminophen or placebo groups. Both treatments were administered intravenously every 6 hours for up to 5 days, with strict monitoring for liver enzymes and hemodynamic stability.
Safety and Biological Markers
Safety analyses revealed no significant differences in adverse events between the groups. Liver function tests were similar, and no significant hemodynamic changes were associated with acetaminophen administration.
Biological markers such as IL-6, angiopoietin-2, TNFR1, cell-free DNA, and syndecan 1 did not show significant differences between the groups from baseline to day 3.
Conclusion
While intravenous acetaminophen was safe for critically ill sepsis patients, it did not significantly improve the number of days alive and free of organ support. These findings suggest that acetaminophen may not be an effective intervention for organ dysfunction in this patient population.
Clinical Implications
This study highlights the complexity of treating sepsis and the importance of continued research to find effective therapies. While acetaminophen showed some benefits in respiratory function, its overall impact on organ support-free days was not significant. Future research may explore other potential treatments or combinations of therapies to improve outcomes for critically ill sepsis patients.
A full list of disclosures can be found in the published research.