Calcium, Ionized

Ionized calcium binds to negatively charged sites on protein molecules, competing with hydrogen ions for the same binding sites on albumin and other calcium-binding proteins. This binding is pH dependent and alters the level of ionized calcium in the blood. An increase in pH, alkalosis, promotes increased protein binding, which decreases free calcium levels. Acidosis, on the other hand, decreases protein binding, resulting in increased free calcium levels.

The reference ranges for ionized calcium are as follows ^[1] :

• Newborn: 4.2-5.58 mg/dL or 1.05-1.37 mmol/L
• 2 months-18 years: 4.8-5.52 mg/dL or 1.2-1.38 mmol/L
• Adult: 4.5-5.6 mg/dL or 1.05-1.3 mmol/L

Critical values are as follows ^[2] :

• Less than 2 mg/dL (< 0.5 mmol/L) may produce tetany or life-threatening complications.
• In patients with multiple blood transfusions, 2-3 mg/dL (< 0.5-0.75 mmol/L) may require calcium administration.
• More than 7 mg/dL (>1.75 mmol/L) may cause coma.

Ionized calcium is interpreted in conjunction with the total serum calcium measurement. An ionized calcium value within the reference range implies adequate calcium homeostasis, as this is a direct measure of calcium in its active form.

Normal ionized calcium level/high total calcium level

This condition is referred to as pseudohypercalcemia. It may result from the following: ^[3]

• Hyperalbuminemia induced by extracellular volume depletion or by fluid movement out of the vascular space

• Multiple myeloma

• Increased exogenous vitamin D intake

Normal ionized calcium level/low total calcium level

This condition is referred to as pseudohypocalcemia. It may result from hypoalbuminemia due to hepatic or renal disease.

Low ionized calcium level/normal total calcium level

This may result from the following:

• Acute respiratory alkalosis

• Chronic respiratory alkalosis

• Hyperventilation in individuals with increased intracranial pressure, sepsis, or respiratory failure

• Bicarbonate administration to control metabolic acidosis

• Critical illness in persons with renal failure, cardiac failure, postsurgery, or burns

• Toxic shock syndrome

Low ionized calcium level/high total calcium level

This may result from iatrogenic causes.

Low ionized calcium level/low total calcium level

This may result from the following: ^[3]

• Hyperparathyroidism (secondary)

• Hypoparathyroidism (primary)

• Vitamin D deficiency

• Magnesium deficiency

• Rickets

• Hyperphosphatemia

• Hemodialysis

• Critical illness in persons with renal failure, cardiac failure, postsurgery, or burns

• Toxic shock syndrome

• Significant blood transfusions may chelate calcium, resulting in markedly decreased ionized calcium levels

• Fat embolism

• Acute pancreatitis (diabetic acidosis, sepsis)

High ionized calcium level/normal total calcium level

This may result from the following:

• Hypoalbuminemia ^[3]

• Hyperparathyroidism (25%)

• Acidosis ^[3]

• Sarcoidosis

High ionized calcium level/high total calcium level

This may result from the following: ^[3]

• Hyperparathyroidism (primary)

• Ectopic parathyroid hormone (PTH)–producing tumors

• Hypoparathyroidism (secondary)

• Malignant neoplasms

High ionized calcium level/low total calcium level

This may result from iatrogenic causes.

Specifics for collection and panels are as follows: ^{[4, 5]}

• Specimen type: Blood serum

• Container: Vacutainer, red-black top or red top

• Collection method: Venipuncture

• Specimen volume: 5 mL

• Panels: Serum electrolytes, basic metabolic panel, complete metabolic panel

• Other instructions: Patients must fast for 6 hours before the blood sample is drawn

• Measurement of ionized calcium is by ion-selective electrodes.

Related tests are as follows: ^[3]

• Serum chloride

• Serum potassium

• Serum bicarbonate

• Serum osmolality

• Blood urea nitrogen (BUN)

• Plasma glucose

• Urine electrolytes

• Urine osmolality

• Aldosterone

• Antidiuretic hormone (ADH)

• PTH

• Vitamin D

• Phosphorus

• Magnesium

Description

Calcium is the fifth most abundant element and is the most prevalent cation in the human body. Approximately 1-1.3 kg of calcium can be found in a healthy adult, 99% of which is in the form of hydroxyapatite in the skeleton; the remaining 1% is contained in the extracellular fluid (ECF).

Serum (plasma) calcium exists in 3 distinct forms. Approximately 15% is complexed calcium bound to organic and inorganic anions, 40% is bound to albumin, and the remaining 45% circulates as free ionized calcium.

Calcium is essential for bone mineralization, neuromuscular function, and secretion of hormones and enzymes. Because calcium is not made in the body, a diet that contains calcium is essential to maintain normal serum calcium levels. Calcium-rich foods include yogurt, cheese, eggs, milk, spinach, fish, okra, broccoli, almonds, sesame seeds, and peas. Calcitriol, the most active metabolite of vitamin D in calcium homeostasis, increases serum calcium levels by promoting calcium absorption in the intestines and kidney. It also promotes calcium mobilization from bone via resorption. ^[2]

The plasma concentration of calcium depends directly on the net balance of bone mineral deposition and resorption, intestinal absorption, and renal excretion. The hormones responsible for regulating these processes include PTH, calcitonin, and 1,25-dihydroxyvitamin D.

Ionized calcium binds to negatively charged sites on protein molecules, competing with hydrogen ions for the same binding sites on albumin and other calcium-binding proteins. This binding is pH dependent and alters the level of ionized calcium in the blood. An increase in pH, alkalosis, promotes increased protein binding, which decreases free calcium levels. Acidosis, on the other hand, decreases protein binding, resulting in increased free calcium levels.

Calcium is removed from the body in the form of skin, nails, hair, sweat, urine, and feces.

Indications/Applications

Assessing the total calcium level is part of a routine health screening, included in the comprehensive metabolic panel and basic metabolic panel, and is used to measure both ionized calcium and bound calcium. ^[2]

Measurement of the total calcium alone may sometimes be misleading, since this measurement can change without alteration in the ionized calcium concentration. In hypoalbuminemia, although ionized calcium levels remain normal, total calcium levels decrease. The equation used to measure corrected calcium in cases of hyperalbuminemia/hypoalbuminemia is as follows: ^[3]

Corrected (Ca) = Measured total (Ca) + (0.8 x [4.0 - (alb)])

Additionally, in patients who have chronic kidney disease and low serum bicarbonate levels, a low serum albumin level, or both, it is preferable to measure the ionized free calcium rather than the total calcium in order to diagnose hypocalcemia or hypercalcemia. ^[6]

Indications for testing of ionized calcium are as follows:

• Neonatal hypocalcemia due to immature parathyroid gland, resulting in a lack of hypocalcemia symptoms

• Critically illness

• Chronic liver disease

• Chronic kidney disease

• Abnormal total serum calcium levels

• Hyperparathyroidism/hypoparathyroidism

• Numbness around the mouth and in the hands and feet

• Muscle spasms around the mouth and in the hands and feet

Considerations

Drugs that increase ionized calcium levels include the following: ^[3]

• Calcium salts

• Hydralazine

• Lithium

• Thiazide diuretics

• Thyroxine

Drugs that decrease ionized calcium levels include the following: ^[2]

• Heparin

• Citrate

• Intravenous lipids

• Epinephrine

• Norepinephrine

• Isoproterenol

• Alcohol

• Ethylenediaminetetraacetic acid