Ionized Calcium (iCa) Testing: Clinical Applications
The ionized calcium (iCa) test measures the biologically active, unbound form of calcium in blood and is primarily used to diagnose and monitor disorders of calcium metabolism, assess calcium status during massive transfusion, and detect primary hyperparathyroidism that may be missed by total calcium measurements alone.
Primary Clinical Indications
Disorders of Calcium Metabolism
- iCa is the definitive test for evaluating calcium homeostasis in patients with suspected parathyroid disorders, malignancy-related hypercalcemia, vitamin D disorders, and other metabolic bone diseases 1, 2
- Total calcium (tCa) frequently misclassifies calcium status, with discordance occurring in 12.6% of all cases, but reaching 49% in hypercalcemic states and 92% in hypocalcemic states 2
- Reliance on total calcium alone would miss 45% of patients with ionized hypercalcemia 2
Detection of Primary Hyperparathyroidism
- iCa identifies cases of primary hyperparathyroidism that present with normal total calcium levels, a critical diagnostic advantage 2, 3
- In patients with histologically proven parathyroid disease, 24% presented with isolated ionized hypercalcemia while total calcium remained normal 2
- Among symptomatic patients with primary hyperparathyroidism and normal or fluctuating total calcium, 88.7% had elevated iCa values compared to only 30.5% with elevated total calcium 3
- These patients with isolated ionized hypercalcemia tend to be younger with milder disease and better renal function than those with concurrent elevation of both iCa and tCa 2
Monitoring During Massive Transfusion
- Ionized calcium levels should be monitored and maintained within the normal range (>0.9 mmol/L) during massive transfusion to prevent coagulopathy and cardiovascular complications 4
- Low ionized calcium at admission is associated with increased mortality and increased need for massive transfusion 4
- Hypocalcemia during the first 24 hours predicts mortality and transfusion requirements better than fibrinogen levels, acidosis, or platelet counts 4
Physiological Basis
Calcium's Role in Coagulation
- Calcium ions are essential cofactors for activation of coagulation factors II, VII, IX, and X, as well as proteins C and S 5
- Calcium enables binding of coagulation factors to cell membranes and is necessary for fibrin polymerization and platelet adhesion 5
- During massive transfusion, citrate anticoagulant in blood products chelates ionized calcium, leading to hypocalcemia that precipitates coagulopathy 4, 5
Calcium Distribution
- Extracellular calcium exists as 45% free ionized (biologically active) and 55% protein-bound (biologically inactive) 4
- Normal ionized calcium concentration ranges from 1.1 to 1.3 mmol/L and is pH-dependent 4
- A 0.1 unit increase in pH decreases ionized calcium by approximately 0.05 mmol/L 4
Critical Care Applications
ICU Monitoring Considerations
- At least half of ICU patients will have abnormal iCa values during their stay, though most do not have underlying calcium homeostasis disorders 6
- Abnormal iCa values are likely markers of disease severity rather than primary calcium disorders 6
- Most abnormal values normalize spontaneously with resolution of the primary disease process 6
- Widespread protocolized measurement and correction simply to normalize values should be discouraged in the absence of specific indications 6
Important Caveats
pH Adjustment Controversy
- Adjustment of iCa for pH 7.4 using published normative equations may not be valid and can misclassify calcium status 7
- pH-adjusted iCa failed to identify 15% of subjects with elevated raw iCa and 60% with low raw iCa 7
- When proper blood collection protocols are followed, unadjusted iCa (at actual pH) may be more physiologically relevant than pH-adjusted values 1, 7
Measurement Requirements
- iCa must be measured in accredited laboratories with established quality control programs 4
- Proper blood collection technique is essential to avoid sampling artifacts that affect results 7