OBJECTIVES: A recent in vitro study found that ibuprofen, naproxen, and ketorolac are competitive caspase inhibitors, a promising anti-inflammatory target for septic shock treatment. However, the impact of such NSAIDs on health outcomes among patients with sepsis is unknown.

METHODS: We conducted a retrospective cohort study of patients diagnosed with sepsis/septic shock admitted to Beth Israel Deaconess Medical Center in 2008-2019 from Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. We identified patients with the first sepsis admission using adapted Angus sepsis definition with ICD-9-CM/ICD-10-CM codes. Exclusion criteria included age <18 or no lab measurements during hospitalization. Patients were categorized into the user group if they filled at least one prescription of ibuprofen, naproxen, or ketorolac within 10 days after admissions. Outcomes were CRP levels (longitudinal outcome) and 30-day in-hospital mortality (survival outcome). Patients were followed until death, discharge, or day 30, whichever occurred first. We examined the association between NSAID use, CRP levels, and mortality over time using the semi-parametric joint modeling of survival and longitudinal data with JSM package in R. Covariates adjusted in the joint model were vital signs, demographics, laboratory measurements, comorbidities, antibiotic use, and corticosteroid use.

RESULTS: A total of 5,123 eligible individuals (749 NSAID users and 4,404 nonusers) were included. NSAID users were younger, less likely to receive antibiotics, had less comorbidities and lower levels of serum creatinine compared with nonusers. In the joint model, NSAID use was associated with decreased CRP levels over time (the coefficient of interaction term between CRP and time = -0.9151, p-value = 0.036) but not associated with higher mortality (HR=0.8732, 95% CI=0.5483-1.3921). Increased CRP levels were associated with higher mortality (HR=1.0046, 95% CI=1.0020-1.0072).

CONCLUSIONS: NSAIDs may not have a direct impact on survival but have an indirect effect on survival through CRP level reduction in patients with sepsis.