Role of Acetaminophen in Intensive Care Unit Delirium Prevention: A Retrospective Cohort Study.

Rationale: Pain and systemic inflammation are two factors associated with delirium, and subsequent adverse outcomes in Intensive Care Unit (ICU) patients. Acetaminophen might be effective in mitigating delirium incidence but has been poorly studied outside the postoperative population.

Objective: This study investigated the association between acetaminophen administration and the incidence of ICU delirium.

Methods: A retrospective cohort study was conducted in a tertiary-level hospital, including adult patients admitted to any ICU for ≥48 hours between 2015 and 2024. The primary exposure was acetaminophen administration (≥2g/day). Primary outcome was the incidence of ICU delirium, determined from Confusion Assessment Method-ICU assessments recorded every 12 hours as part of clinical care. Multivariate logistic regression was applied, and fractional polynomial modeling was conducted to study the association between the proportion of time under the effect of acetaminophen and the proportion of time experiencing delirium.

Results: Out of 17,818 patients included, 5,332 (29.9%) received acetaminophen during their ICU stay. 5,438 (30.5%) patients developed delirium. Acetaminophen was associated with a reduced incidence of delirium (Odd Ratios [ORadj] 0.66, 95%CI 0.59-0.73, Absolute Risk Difference [ARDadj] -6.0%, 95%CI -7.5% to -4.5%, p<0.001). There was a dose-dependent association between the time under the effect of acetaminophen (p<0.001) and a reduced time experiencing delirium, plateauing at coverage levels ≥40%.

Conclusion: Acetaminophen is associated with a clinically significant reduction of ICU delirium in unselected critically ill patients. Furthermore, the proportion of time under the effect of acetaminophen is inversely associated with the proportion of time experiencing delirium. These hypothesis generating results should be validated in a randomized controlled trial.