What is Ionized Calcium?
Ionized calcium is the free, unbound, biologically active form of calcium in the blood that is essential for coagulation, cardiovascular function, neuromuscular activity, and cellular signaling. 1
Physiological Forms of Calcium
Calcium exists in three distinct forms in extracellular plasma 1:
- Ionized (free) calcium: 45-50% - This is the only physiologically active fraction 1, 2, 3
- Protein-bound calcium: 40% - Primarily bound to albumin (90%) and globulins (10%) in a biologically inactive state 1, 3
- Complexed calcium: 8-10% - Bound to anions such as citrate, lactate, bicarbonate, and phosphate 1, 3
Normal Reference Range
The normal concentration of ionized calcium ranges from 1.1 to 1.3 mmol/L (or 1.15-1.36 mmol/L) 1, 4. This value is pH-dependent: a 0.1 unit increase in pH decreases ionized calcium concentration by approximately 0.05 mmol/L 1.
Critical Physiological Functions
Coagulation
Ionized calcium is essential for the timely formation and stabilization of fibrin polymerization sites, and a decrease in cytosolic calcium concentration precipitates a decrease in all platelet-related activities 1. Even mild hypocalcemia impairs the coagulation cascade (factors II, VII, IX, X activation) and platelet adhesion 4.
Cardiovascular Function
Contractility of the heart and systemic vascular resistance are low at reduced ionized calcium levels 1. The level for ionized calcium concentration should be maintained >0.9 mmol/L to support cardiovascular function and coagulation 1, 4.
Neuromuscular Activity
Ionized calcium regulates neuromuscular excitability, with severe hypocalcemia causing paresthesias, Chvostek's and Trousseau's signs, bronchospasm, laryngospasm, tetany, seizures, and cardiac arrhythmias 4.
Clinical Measurement Considerations
Why Measure Ionized Calcium Directly?
Ionized calcium is considered a more accurate indicator of true calcium status compared to total calcium 2, 5, 3, particularly in critical care settings where:
- Albumin levels fluctuate significantly 2, 6, 3
- pH changes occur rapidly 1
- Massive transfusion is ongoing 1, 4
- Citrate toxicity is present 1, 4
Limitations of Correction Formulas
Correction formulas that adjust total calcium for albumin show good statistical correlation in populations but are generally poor predictors of true ionized hypo- or hypercalcemia in individual patients 2. These formulas have lower diagnostic accuracy than uncorrected total calcium in some clinical situations 3, and none have been validated in dialysis patients 6.
When Direct Measurement is Essential
Direct measurement of ionized calcium is preferred and sometimes necessary in 5, 7:
- Massive transfusion protocols - Citrate in blood products chelates calcium 1, 4
- Cardiac surgery and transplantation - Aggressive monitoring prevents cardiac catastrophes 7
- Critical illness with acid-base disturbances - pH directly affects ionized calcium levels 1
- Hepatic dysfunction - Impaired citrate metabolism worsens hypocalcemia 1, 4
- Hypothermia and shock states - These conditions impair calcium homeostasis 4, 8
Clinical Significance in Critical Care
Low ionized calcium levels at admission are associated with increased mortality, increased need for massive transfusion, platelet dysfunction, decreased clot strength, and coagulopathy 1, 4, 8. Hypocalcemia during the first 24 hours can predict mortality and the need for multiple transfusions better than the lowest fibrinogen concentrations, acidosis, and the lowest platelet counts 1.
Critical Pitfall
Standard coagulation tests may appear normal despite significant hypocalcemia-induced coagulopathy because laboratory samples are citrated then recalcified before analysis 4. This masks the true impact of hypocalcemia on coagulation in vivo 4.