Association between Milrinone Use and Mortality Risk in Sepsis: Insights from the MIMIC-IV Database

BACKGROUND: Milrinone is established in the management of heart failure. However, its therapeutic role in patients with sepsis remains uncertain and warrants further investigation. Objective: To examine the association between milrinone administration and mortality in patients diagnosed with sepsis. METHODS: This retrospective cohort study utilized data from the MIMIC-IV database. The primary exposure of interest was milrinone use. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were employed to balance baseline characteristics. The association between milrinone use and 7-，14-，and 28-day mortality in sepsis patients was assessed using multivariate Cox proportional hazards models, restricted cubic spline (RCS) curves, and longitudinal targeted maximum likelihood estimation (TMLE). RESULTS: Among 27,070 sepsis patients, 523 received milrinone at a median interval of 5.24 hours after ICU admission. In the unadjusted Cox model, milrinone use was associated with significantly lower mortality at 7 days (HR = 0.53, 95% CI: 0.33-0.85), 14 days (HR = 0.54, 95% CI: 0.38-0.78), and 28 days (HR = 0.60, 95% CI: 0.45-0.82). This association remained consistent after adjusting for multiple confounders. In the IPTW-adjusted cohort, Cox regression showed no significant association between milrinone use and mortality at day 7 or day 14; however, a statistically significant association was observed at day 28. Longitudinal TMLE analyses further indicated a protective effect for both 14-day (RR = 0.65, 95% CI: 0.48-0.88; P = 0.01) and 28-day mortality (RR = 0.58, 95% CI: 0.45-0.74; P < 0.001). RCS analysis demonstrated a linear inverse relationship between cumulative milrinone dosage and 7-day mortality risk, while a non-linear association was observed with 14-day and 28-day mortality. Subgroup analysis revealed a significant interaction between milrinone use and heart failure status, with reduced mortality associated with milrinone use only in patients with heart failure. CONCLUSION: Milrinone use appeared to be associated with reduced mortality risk at 7, 14, and 28 days in sepsis patients. This association was linear for 7‑day mortality, but nonlinear and potentially indicative of a threshold effect for 14‑and 28‑day mortality.