Acetaminophen and Clinical Outcomes in Sepsis

Background

The Ibuprofen in Sepsis Study (ISS) randomized trial found no difference in duration of shock, ARDS, or mortality with ibuprofen treatment for sepsis. However, higher use of acetaminophen, a known hemoprotein reductant with potentially beneficial effects in sepsis, as an antipyretic in the control arm may have masked the clinical benefits from either drug.

Research Question

Does an association exist between administration of acetaminophen and clinical outcomes in adults with sepsis?

Study Design and Methods

We performed a retrospective propensity-matched analysis of the previously reported ISS trial. We created a propensity score for receiving acetaminophen during the first 2 study days using sex, age, presence of shock at enrollment, trial study drug assignment (ibuprofen or placebo), febrile status at enrollment, need for mechanical ventilation, and Acute Physiology and Chronic Health Evaluation II score at enrollment, and then matched trial participants 1:1 into acetaminophen-exposed and acetaminophen-unexposed groups based on their propensity scores. We tested the association between receipt of acetaminophen with 30-day mortality as the primary outcome. Secondary outcomes included development of renal failure and ventilator-free days (VFDs).

Results

Of 455 patients in the original trial, 276 patients (61%) were matched into acetaminophen-exposed and acetaminophen-unexposed groups. In the propensity-matched analysis, we found a lower mortality among acetaminophen-exposed patients compared with acetaminophen-unexposed patients (hazard ratio, 0.58; 95% CI, 0.40-0.84; P = .004). Additionally, acetaminophen-exposed patients experienced more days alive and free of mechanical ventilation compared with the acetaminophen-unexposed patients (OR, 2.09 for having 19-28 VFDs vs 0 or 1-18 VFDs; 95% CI, 1.12-3.95; P = .02). We observed no significant association between renal failure and receipt of acetaminophen.

Interpretation

In this propensity-matched retrospective analysis, adults with sepsis who received acetaminophen showed decreased mortality and more days alive and free of mechanical ventilation. This study highlights the potential of acetaminophen as a modulator of outcomes in sepsis and warrants further investigation.