Role of the ionized-to-total calcium ratio in predicting sepsis mortality: a retrospective analysis from the MIMIC-IV database

BACKGROUND: Sepsis, an important cause of death in intensive care units (ICUs), frequently disrupts calcium homeostasis. Since ionized calcium does not consistently correlate with total calcium, we hypothesized that the ionized-to-total calcium ratio could serve as a prognostic marker. This study aimed to evaluate its association with sepsis mortality. METHODS: Using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, we conducted a retrospective cohort study of ICU patients with sepsis who had both ionized and total calcium measured after ICU admission. Patients were stratified into quartiles by the ionized-to-total calcium ratio. Primary outcomes were 28-day and 180-day mortality. Cox proportional hazards models, restricted cubic spline (RCS) analyses, and subgroup analyses were performed. RESULTS: Among 10,323 sepsis patients, a higher ionized-to-total calcium ratio was associated with lower mortality. Compared with the bottom quartile, the top quartile was associated with reduced 28-day mortality (adjusted hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.55-0.71, p < 0.001) and 180-day mortality (adjusted HR 0.69, 95% CI 0.62-0.77, p < 0.001). RCS analyses suggested an apparent U-shaped pattern in unadjusted models that was attenuated after full adjustment, showing an overall inverse association. Subgroup analyses suggested a stronger association in patients with higher body mass index and, for 180-day mortality, in male patients. CONCLUSION: The ionized-to-total calcium ratio may complement early risk stratification in sepsis. Prospective studies are needed to validate these findings and clarify mechanisms, including citrate-related pathways.