A National Institutes of Health (NIH) supported clinical trial found that intravenous acetaminophen significantly reduces the risk of organ injury and acute respiratory distress syndrome (ARDS) in sepsis patients. While the treatment did not improve overall mortality rates, it was particularly beneficial for those at the highest risk for organ damage, reducing their need for assisted ventilation and showing a slight, though statistically insignificant, reduction in mortality.
The findings were published in the recent issue of JAMA titled “Phase 2b Randomized Trial of Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Sepsis Patients”. Sepsis causes red blood cells to die at an abnormally high rate, releasing cell-free hemoglobin into the bloodstream. This excess hemoglobin can overwhelm the body’s ability to remove it, leading to organ damage.
Ware et al. indicated that, beyond its pain-relieving and fever-reducing properties, acetaminophen can block the harmful effects of cell-free hemoglobin on the lungs. Studies suggest it may be particularly effective for severe sepsis patients with high levels of cell-free hemoglobin, which is linked to a higher risk of ARDS and death. Identifying cell-free hemoglobin as a biomarker at hospital admission could revolutionize sepsis treatment by quickly pinpointing patients who would benefit from acetaminophen therapy. The researchers emphasized the importance of such biomarkers in critical care, where rapid patient deterioration necessitates timely intervention.
The researchers enrolled 447 adults with sepsis and respiratory or circulatory organ dysfunction at 40 U.S. academic hospitals from October 2021 to April 2023. Participants were randomized to receive either intravenous acetaminophen or a placebo every six hours for five days, followed by 28 days of monitoring. The trial specifically focused on patients with high levels of cell-free hemoglobin.
Among the 447 patients (average age 64, 51% female, average Sequential Organ Failure Assessment [SOFA] score 5.4), 227 received acetaminophen and 220 received placebo. Acetaminophen was safe, with no significant differences in liver enzymes, blood pressure, or fluid balance between groups. The days alive and free of organ support by day 28 were similar (acetaminophen: 20.2 days; placebo: 19.6 days). However, acetaminophen significantly lowered total, respiratory, and coagulation SOFA scores on days 2 to 4 and reduced ARDS rates within 7 days (2.2% vs. 8.5%).
The study showed that acetaminophen was safe for all sepsis patients, with no significant differences in adverse events. Secondary outcomes revealed that acetaminophen significantly reduced organ injury and ARDS incidence within seven days of admission. For patients with high cell-free hemoglobin, benefits were more pronounced: only 8% in the acetaminophen group required assisted ventilation compared to 23% in the placebo group. After 28 days, 12% of acetaminophen patients had died versus 21% in the placebo group, though this was not statistically significant.
The researchers acknowledged that while acetaminophen did not meet all expectations, it shows potential benefits for critically ill sepsis patients. They emphasized the need for further research to elucidate the underlying mechanisms and validate these findings. Larger trials focusing on patients with elevated cell-free hemoglobin levels is necessary to confirm the results and fully explore acetaminophen’s therapeutic potential. Such studies could lead to targeted treatments that improve outcomes for the most severely affected sepsis patients, offering hope for enhanced management strategies.
Reference
Ware LB, Files DC, Fowler A, Aboodi MS, Aggarwal NR, Brower RG, et al. Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial. JAMA [Internet]. 2024 May 19 [cited 2024 May 20]; Available from: https://doi.org/10.1001/jama.2024.8772