Clinical Relevance of Calcium Measures: QT-Based Comparison of Ionized, Total, and Albumin-Corrected Calcium.

KEY POINTS: Ionized calcium showed the strongest associations with the QT interval, whereas total and corrected calcium showed weaker associations. Calcium measures that correlated better with ionized calcium did not necessarily perform better for QT-based outcomes. These findings reinforced ionized calcium as the most clinically valid reference and supported outcome-based calcium assessment.

BACKGROUND

Ionized calcium (iCa) is the physiologically active fraction of circulating calcium, whereas total calcium (tCa) and albumin-corrected calcium (cCa) remain widely used. Despite growing concerns over the accuracy of correction formulas, most evaluations rely on concordance with iCa rather than meaningful physiologic outcomes. We compared iCa, tCa, and cCa and assessed their clinical validity using ventricular repolarization-reflected by the QT interval-as a physiologic end point.

METHODS

This single-center cross-sectional observational study included adults who visited our outpatient department with simultaneous measurements of iCa, tCa, electrolytes, albumin, and electrocardiography. iCa, tCa, and seven albumin-correction formulas were examined. Associations with the QT interval were evaluated using linear regression and restricted cubic splines; logistic regression assessed corrected QT prolongation. Sensitivity analyses included alternative QT-correction methods and analyses in hypoalbuminemia.

RESULTS

Among 647 participants (median age 68 years; 54% male), common comorbidities included hypertension (33%), diabetes (18%), and cardiac disease (11%). Correlations between iCa and other calcium measures varied widely. In fully adjusted analyses, iCa demonstrated the strongest association with QT interval (standardized β =-0.22; 95% confidence interval, -0.29 to -0.14). tCa and all cCa exhibited substantially weaker associations. Although some tCa and cCa demonstrated relatively higher correlation with iCa, they exhibited weaker associations with QT. In hypoalbuminemia (albumin <3.0 g/dl, n =118), agreement with iCa declined for all cCa, and associations with QT were attenuated; only iCa (standardized β =-0.25; 95% confidence interval, -0.44 to -0.06) and limited formulas (notably Payne) retained modest associations.

CONCLUSIONS

iCa is the physiologically and clinically valid measure of calcium status consistently demonstrating the strongest associations with ventricular repolarization. By contrast, tCa and cCa demonstrate substantially reduced clinical relevance and numerical concordance with iCa does not reflect clinical validity. These findings support outcome-based validation of calcium measure and reinforce the importance of direct iCa measurement.