Non-linear relationship between ionised calcium and 28-day mortality in patients with sepsis: a retrospective cohort study from MIMIC-IV database

BMJ Open. 2025 Nov 13;15(11):e099781. doi: 10.1136/bmjopen-2025-099781.

ABSTRACT

OBJECTIVES: Sepsis is a life-threatening disease caused by a deregulated response to infection. This study aimed to investigate the linear and non-linear relationships between ionised calcium levels and 28-day mortality in patients with sepsis in the intensive care unit (ICU) and to generate hypotheses regarding laboratory index testing and calcium supplementation strategies.

DESIGN: A retrospective cohort study.

SETTING: Adult patients admitted to the ICU, using data extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database.

PARTICIPANTS: A total of 17 955 adult patients with sepsis, defined according to the sepsis-3 criteria, were included. Patients lacking ionised calcium (iCa) data were excluded.

OUTCOME MEASURES: The exposure variable was iCa level measured within the first 24 hours of ICU admission, and the primary outcome was 28-day all-cause mortality. Covariates included demographics, vital signs, comorbidities, infection sites, organ support and medication use. Multivariable logistic regression models were applied with stepwise adjustment. Non-linear associations were assessed using generalised additive models (GAM) and two-piecewise linear regression. Sensitivity analyses using iCa quartiles and subgroup analyses stratified by Sequential Organ Failure Assessment (SOFA) score were also performed.

RESULTS: The overall 28-day mortality rate was 18.3%. After full adjustment, patients in quartiles Q2-Q4 had significantly lower mortality risks than those in Q1 (P for trend <0.001). A U-shaped association was observed, with an inflection point at 1.16 mmol/L (95% CI 1.12 to 1.19). Below this threshold, each 0.1 mmol/L decrease in iCa was associated with a 13% higher risk of mortality (OR=0.87; 95% CI 0.82 to 0.92; p<0.001); whereas, above this point, mortality increased by 6% per 0.1 mmol/L increment (OR=1.06; 95% CI 1.00 to 1.10; p=0.004). Subgroup analyses stratified by SOFA score (<10 vs ≥10) confirmed the robustness of the U-shaped relationship (p>0.05).

CONCLUSION: The relationship between ionised calcium and 28-day mortality in patients with sepsis showed a U-shaped curve with an inflection point of 1.16 mmol/L, which is in the range of mild hypocalcaemia.

PMID:41248367 | PMC:PMC12625876 | DOI:10.1136/bmjopen-2025-099781