Ionised Calcium

Ionised calcium is the free, physiologically active fraction of plasma calcium (about 45 to 50% of the total). It controls neuromuscular excitability, cardiac contractility, vascular tone and coagulation, and it is the fraction regulated by parathyroid hormone and vitamin D. It is measured by ion selective electrode on an analyser, usually a blood gas machine, with a pH-corrected value reported at pH 7.40.

Total calcium can mislead when albumin or acid base status is abnormal, so ionised calcium is the test of choice in critical illness, major transfusion, cardiac surgery, liver transplantation, neonatal care and during regional citrate anticoagulation. It is the more accurate measure of symptomatic calcium disorders.

Indications. Abnormal albumin, critical illness, sepsis, pancreatitis, massive transfusion (citrate binds calcium), cardiac surgery and bypass, liver transplantation, regional citrate anticoagulation in renal replacement therapy, plasma exchange, neonatal hypocalcaemia, chronic kidney disease, suspected hypocalcaemia with tetany or seizures, hyperventilation with paraesthesia, and discordant total calcium and clinical picture.

Specimen. The pre-analytical phase decides accuracy.

• Whole blood in a syringe with balanced (calcium titrated) dry heparin, filled and capped to exclude air, or in a gel serum tube filled completely and kept anaerobic.
• Analysed within 15 to 30 minutes at room temperature. Samples kept on ice can be stored for up to a few hours.
• Avoid a prolonged tourniquet and fist clenching, since both lower pH and raise ionised calcium.

Reference range. 1.15 to 1.30 mmol/L (4.6 to 5.2 mg/dL) in adults, adjusted to pH 7.40. Local ranges and analyser specifics take precedence.

Thresholds.

• Hypocalcaemia: under 1.15 mmol/L. Symptoms usually occur under 1.0 mmol/L. Under 0.8 mmol/L there is a risk of tetany, seizures, laryngospasm, hypotension and arrhythmia.
• Hypercalcaemia: over 1.30 mmol/L. Mild up to about 1.50 mmol/L, moderate about 1.50 to 1.80, and over 1.80 mmol/L carries a high risk of crisis.

Effect of pH. A rise of 0.1 in pH lowers ionised calcium by about 0.04 to 0.05 mmol/L by increasing albumin binding. Respiratory alkalosis from hyperventilation can cause symptomatic hypocalcaemia with normal total calcium, and acidosis raises the ionised fraction. Results are interpreted with the pH.

Causes of a low ionised calcium. Hypoparathyroidism, vitamin D deficiency, chronic kidney disease, hypomagnesaemia, acute pancreatitis, rhabdomyolysis, tumour lysis, sepsis and critical illness, massive transfusion, citrate anticoagulation, large volume crystalloid or albumin infusion, alkalosis, hungry bone syndrome, bisphosphonates, denosumab, foscarnet, and cardiopulmonary bypass.

Causes of a raised ionised calcium. The causes of hypercalcaemia: primary hyperparathyroidism, malignancy, vitamin D excess, granulomatous disease, thiazides, lithium, immobilisation, thyrotoxicosis, familial hypocalciuric hypercalcaemia, and acidosis.

Total to ionised calcium ratio. During regional citrate anticoagulation, a ratio of total calcium to ionised calcium over about 2.5 indicates citrate accumulation, which occurs in liver failure and shock, and signals the need to reduce citrate or stop it. A normal ratio is about 2.0.

Discordance with total calcium.

• Normal total with low ionised: alkalosis, high free fatty acids (heparin activated lipase in some samples), and some critical illness.
• Low total with normal ionised: hypoalbuminaemia.
• High total with normal ionised: hyperalbuminaemia, paraprotein binding calcium.

Critical findings needing immediate action.

• Ionised calcium under 0.8 mmol/L, or any value with tetany, seizures, laryngospasm, hypotension or a prolonged QT interval.
• Ionised calcium over 1.6 mmol/L, or any value with confusion, vomiting, acute kidney injury or shortening of the QT interval.
• During massive transfusion, a falling ionised calcium with hypotension and poor clotting.
• During citrate anticoagulation, a rising total to ionised ratio with a falling ionised calcium.

Interferences and pitfalls.

• Liquid or excess heparin binds calcium and lowers the result, and calcium balanced heparin avoids this.
• Exposure to air loses carbon dioxide, raises pH and lowers ionised calcium. Delay allows glycolysis to lower pH and raise ionised calcium in unseparated samples.
• Fist clenching and venous stasis lower pH and raise ionised calcium.
• Underfilled gel tubes and non-anaerobic handling alter the result.
• Analysers differ, and results are not interchangeable between devices. Some report values normalised to pH 7.40 and others the measured value.
• Samples from lines contaminated with infused fluids or calcium are unreliable.
• Haemolysis has little effect on the electrode, but lipaemia and very high protein can affect indirect methods.

Special groups.

• Neonates: ionised calcium is higher at birth (about 1.3 to 1.5 mmol/L), falls over the first 24 to 48 hours, and a value under about 1.0 mmol/L in term infants (under about 0.8 in preterm infants) is treated as hypocalcaemia.
• Children: values are slightly higher than in adults and fall to adult ranges after puberty.
• Pregnancy: ionised calcium stays in the non-pregnant range despite a fall in total calcium.
• Critical illness: low values are common and correlate with severity, and the optimal treatment threshold is uncertain.
• Chronic kidney disease: the corrected total is unreliable and ionised calcium is preferred when treatment decisions depend on it.

Follow up tests. Total calcium with albumin, parathyroid hormone, 25-hydroxyvitamin D, magnesium, phosphate, venous or arterial blood gas, lactate, urea and electrolytes, ECG, creatine kinase, lipase, 24-hour urine calcium.