Acetaminophen lowers acute respiratory distress syndrome development in sepsis

Key takeaways:

• Acetaminophen and placebo use in sepsis both yielded similar numbers of days alive and free of organ support.
• Mortality at 28-days also did not significantly differ between groups.

SAN DIEGO — Fewer patients with sepsis receiving acetaminophen vs. placebo developed acute respiratory distress syndrome, according to research presented at the American Thoracic Society International Conference.

Further, those receiving acetaminophen had significantly lower/improved Sequential Organ Failure Assessment (SOFA) scores on select days, according to researchers.

“Background research work ... emphasized that cell-free hemoglobin can be an injurious factor in sepsis,” Michael A. Matthay, MD, professor of medicine and anesthesia at the University of California, San Francisco, said during his presentation. “Furthermore, [Lorraine B. Ware’s, MD, research group] and others identified acetaminophen as an interesting factor treatment that could reduce the injury produced by cell-free hemoglobin.”

In a randomized, double-blind phase 2b trial, Matthay and colleagues evaluated 447 adults (mean age, 64 years; 51% women) with sepsis and respiratory or circulatory organ dysfunction in the ICU within 36 hours of ED/acute hospital presentation to find out the impact of 5-day intravenous acetaminophen (1 g every 6 hours) on days alive and free of organ support (vasopressors, mechanical ventilation, renal replacement therapy) vs. placebo by day 28.

Acetaminophen was assigned to 227 patients (mean age, 63.9 years; 50.7% men; 72.9% white), whereas the remaining 220 patients (mean age, 64.2 years; 48.2% men; 75.9% white) received placebo.

Researchers found several sites of infection in the total cohort but noted that pneumonia was the most frequent site in both groups (acetaminophen, 44.1%; placebo, 43.6%), followed by urinary tract infection (16.3%; 23.6%).

Additionally, more patients in this study population had baseline use of organ support in the form of vasopressors vs. assisted ventilation (76% vs. 42%).

In both groups, a small proportion of patients (7.5%-10%) had positive COVID-19 status 3 weeks before study enrollment.

When assessing dosing, researchers reported similarity between the acetaminophen group and the placebo group in the average number of doses (12.2 vs. 12.8) and average number of missed doses (1.2 vs. 0.9).

Liver enzymes, hypotension and fluid balance each did not differ between those who received acetaminophen and those who received placebo, Matthay said.

Further, the number of adverse events was comparable at 36 events in the acetaminophen group and 32 events in the placebo group.

By day 28, patients in the acetaminophen group had 20.2 days (95% CI, 18.8-21.6) alive and free of organ support, which was comparable to the 19.6 days (95% CI, 18.2-21) observed in the placebo group.

Other notable outcomes in which acetaminophen did not significantly differ from placebo included 28-day all-cause mortality (acetaminophen, 17.5%; placebo, 22.5%), 28-day hospital mortality (16.5% vs. 21.6%), 90-day all-cause mortality (26% vs. 31.7%) and 90-day hospital mortality (22.3% vs. 24.8%).

Although the main and above outcomes did not significantly differ between the two groups, researchers did find a significant difference in acute respiratory distress syndrome (ARDS) development. Fewer patients receiving acetaminophen developed ARDS in the first 7 days of hospital admission than patients receiving placebo (2.2% vs. 8.5%; P = .01).

One other significant difference between the acetaminophen group and the placebo group was found during assessment of changes in total, respiratory and coagulation SOFA scores on days 2 through 4, Matthay said.

As an additional analysis, researchers split up the cohort according to presence of a plasma cell-free hemoglobin level above 10 mg/dL at baseline to observe whether the impact of acetaminophen treatment changed based on a higher (n = 188) or lower (n = 239) level.

Patients with high vs. low plasma cell-free hemoglobin levels had similar, nonsignificant differences in days free of organ support, assisted ventilation, vasopressors and kidney replacement therapy to day 28.

In the cohort of patients with higher levels, those receiving acetaminophen significantly differed from those receiving placebo in terms of respiratory SOFA score on days 2 through 4 and rates of initiation of assisted ventilation to day 28 (8% vs. 23%).

“In contrast, the daily respiratory SOFA score in the lower cell-free hemoglobin was not different,” Matthay said.

Initiation of assisted ventilation also did not differ between the treatments in the lower level group.

Despite not reaching statistical significance, Matthay did point out that in the elevated plasma cell-free hemoglobin group, fewer patients receiving acetaminophen vs. placebo died by day 28 (12% vs. 21%). In the low plasma cell-free hemoglobin group, mortality rates of the two groups were closer (22% vs. 25%).

“These findings in this phase 2 trial add additional evidence to support a phase 3 trial to test the efficacy of acetaminophen in sepsis and the predictive enrichment potential of cell-free hemoglobin,” Matthay said.

“This is acetaminophen, this is safe, it’s inexpensive, and it might make a difference,” he added. “We’ve been looking for predictive enrichment for a long time in sepsis and ARDS. This cell-free hemoglobin has a strong mechanistic basis for compounding the injury in sepsis, so this could be a really good approach to measure it at the time a patient has enrolled.”

Lastly, when asked how clinicians should interpret these findings, Matthay said “there’s not enough evidence here for us to change therapy” for those suffering with sepsis.

References:

• Acetaminophen shows promise in warding off acute respiratory distress syndrome, organ injury in patients with sepsis. https://www.nhlbi.nih.gov/news/2024/acetaminophen-shows-promise-warding-acute-respiratory-distress-syndrome-organ-injury. Published May 20, 2024. Accessed May 20, 2024.
• Ware LB, et al. JAMA. 2024;doi:10.1001/jama.2024.8772.