UMEM Educational Pearls

Background:

Acetaminophen can reduce hemoprotein induced oxidative damage.  There has been growing discussion about its benefits in critically ill patients with sepsis.  Multiple observational studies have found conflicting results on mortality in critically ill patients with sepsis.  The ASTER trial found no difference in number of days alive and free of organ support. Interestingly their secondary outcomes found significantly less development of ARDS in the acetaminophen group 2.2% vs 8.5%, p = .01.  There was also a non-statistically significant difference in mortality between the groups in favor of the acetaminophen group, 17% vs 22% p = 0.19. This study looked to further evaluate if acetaminophen used in critically ill patients with sepsis would have a decrease in mortality and increase in ventilator free days. 

Study:

- Retrospective analysis of the Ibuprofen in Sepsis Study (ISS)

              - The ISS was a randomized clinical trial comparing ibuprofen with placebo in critically ill patients with sepsis.  Careful documentation of Acetaminophen use was recorded for the trial

- Critically-ill adults across 7 ICU’s in the US and Canada with known or suspected infection and severe organ dysfunction

- Acetaminophen use within 48 hours of enrollment = Acetaminophen exposed

- Primary outcome: 30-day mortality

- Secondary outcome: Renal failure and ventilator free days up to day 28

- 455 patients. 172 Acetaminophen unexposed, 235 Acetaminophen exposed.

Results:

- Propensity-matched analysis showed a lower mortality risk at 30 days in patients exposed to acetaminophen compared to unexposed, 32% vs 49% (HR 0.58, p .004)

- Secondary outcomes found acetaminophen exposed group had more ventilator free days (p .02) but there was no difference in renal failure among the groups. 

Limitations:

- Major risk for confounding variables

- Retrospective and the data used was from decades ago (1989 -1995). Sepsis care has evolved and improved since this time

- Dose and frequency of acetaminophen administration was not standardized 

Take Home Points:

- Interesting research that provides further support on the possible benefit to using acetaminophen in the management of critically ill patients with sepsis.

- With the ASTER trial showing a signal for the decrease in development of ARDS and this study showing improvement in mortality one could make a case for starting acetaminophen early in the course for these patients.  However, the data is conflicting and more prospective, RCT’s are needed to confirm these findings before making this a staple for sepsis care in critically ill patients.

References

Obeidalla, S. N., Bernard, G. R., Ware, L. B., & Kerchberger, V. E. Acetaminophen and Clinical Outcomes in Sepsis: A Retrospective Propensity Score Analysis of the Ibuprofen in Sepsis Study. CHEST Critical Care. 2025;3(1):100-118. https://doi.org/10.1016/j.chstcc.2024.100118

Ware LB, Files DC, Fowler A, et al. Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial. JAMA. 2024;332(5):390–400. doi:10.1001/jama.2024.8772