Calcium Ionized
Ionized calcium
Total calcium consists of free or ionized calcium (50%), calcium bound to protein (40-45%),
principally albumin and calcium complexed to anions (5-10%), e.g. citrate, lactate, bicarbonate.
Total calcium level does not give an indication of what is available at the cellular levelIonized
calcium, which accounts for 50% to 55% of total calcium, is the form of calcium that is readily
available to cells, is the physiologically active form of calcium.
Ionized calcium values are higher in children and young adults.
Ionized calcium values vary inversely with pH, approximately 0.2 mg/dL per 0.1 pH unit change.
Multiple biological functions of calcium
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Cell signalling
Neural transmission
Muscle function
Blood coagulation
Enzymatic co-factor
Membrane and cytoskeletal functions
Secretion
Biomineralization
Low ionized calcium levels are common in critically ill patients with sepsis, renal failure, cardiac
failure, pulmonary failure, post-surgery or burns. Monitoring of ionized calcium is particularly
important in the unconscious or anesthetized patient, in whom unrecognized changes in calcium
homeostasis may result in serious cardiovascular dysfunction with little of no prior warning
signs.
Low ionized calcium values are often seen in renal disease, critically ill patients, or patients
receiving rapid transfusion of citrated whole blood or blood products.
Increased serum ionized calcium concentrations may be seen with primary
hyperparathyroidism, ectopic parathyroid hormone-producing tumors, excess intake of vitamin
D, or various malignancies.
Causes of Hypocalcemia
Decreased Entry of
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Calcium Into the
Circulation
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Hypoparathyroidism (absence of PTH secretion)
o Postoperative
o Autoimmune (isolated or part of polyglandular
autoimmune syndrome)
o Congenital (mutations of CaSR, PTH, and parathyroid
aplasia)
o Pseudohypoparathyroidism, types 1a, 1b and 2
Magnesium depletion
Increased Loss of
Calcium From the
Circulation
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Severe hypermagnesemia
Deficiency of vitamin D
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Hyperphosphatemia
o Renal failure
o Rhabdomyolysis
o Tumor lysis
o Phosphate administration
Acute pancreatitis
Hungry bone syndrome
Chelation
o Citrate
o EDTA
o Lactate
o Foscarnet
Widespread osteoblastic metastases
o Prostate cancer
o Breast cancer
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Other Causes
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Sepsis
Fluoride administration
Surgery
Chemotherapy
o Cisplatin
o 5-Fluorouracil
o Leucovorin
Decreased ionized calcium levels between 3 and 4 mg/dL are usually well tolerated, but the risk
of cardiac arrest increases when ionized calcium levels approach 2.5 mg/dL. An ionized calcium
level below 2.8 mg/dL is a reasonable threshold to begin calcium replacement therapy.
Measurement of ionized calcium may also be helpful in evaluating neonatal hypocalcemia, and
for monitoring hypo- or hypercalcemia associated with malignancy and pancreatitis.
Ionized calcium is valuable in establishing a diagnosis of hyperparathyroidism, especially in
borderline cases where total calcium levels may be normal but ionized calcium increased.
Total calcium is often difficult to interpret or misleading due to decreased albumin and other
proteins, acid-base disturbances, and transfusion of citrated blood. Alterations in serum albumin
during an acute illness may change the total serum calcium by as much as 30%.
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The percentage of protein bound calcium may vary from 30 to 50% during illness. Acute
acidosis decreases protein binding, while acute alkalosis increases it.
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Free fatty acids often increase during illness and after administration of heparin,
isproterenol and insulin. They increase calcium binding to albumin.
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Changes in the concentration of anions such as phosphate, bicarbonate, and citrate also
change ionized calcium levels.
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Transfusion of large numbers of blood components, containing excess citrate, may
chelate calcium. Total calcium levels may only be slightly decreased, even though
ionized calcium levels are markedly decreased.
Hypercalcemia catagorization of causes
The most common causes, categorized according to the results of these tests, are
* High PTH, high phosphorus, and high creatinine: renal failure
* High PTH, low or normal phosphorus, and normal creatinine: vitamin D deficiency or
pancreatitis
* Low PTH, high phosphorus, and normal creatinine: inadequate parathyroid gland function or
hypomagnesemia.
Reference Values
Males
<1 year: not established
1-19 years: 5.1-5.9 mg/dL
> or =20 years: 4.8-5.7 mg/dL
Females
<1 year: not established
1-17 years: 5.1-5.9 mg/dL
> or =18 years: 4.8-5.7 mg/dL
Pediatric ranges derived for GEM method from analytic comparison to reference method in:
Snell J, Greeley C, Colaco A, et al: Pediatric reference ranges for arterial pH, whole blood
electrolytes and glucose. Clin Chem 1993;39:1173.
Specimen Type
Serum
Specimen Required
Container/Tube: Serum gel tube or serum gel MICROTAINER
Specimen Volume: Tube must be full.
Collection Instructions: Allow blood to clot for 30 minutes. Centrifuge with stopper in place for
10 minutes at 3,000 rpm to ensure that the gel barrier separates the serum and cells. Keep
specimen anaerobic (do not transfer).
Reject Due To
Specimens other than
Serum
Anticoagulants other than
Serum gel tube
Hemolysis
Mild OK; Gross reject
Adult
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Adults (whole blood): 4.5-5.6 mg/dL (1.1-1.4 mmol/L) [10]
Adults (plasma): 4.12-4.92 mg/dL (1.03-1.23 mmol/L) [11]
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Neonates,
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Children
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Adults (serum): 4.64-5.28 mg/dL (1.16-1.32 mmol/L) [11]
Adults, 60-90 years (whole blood): 4.64-5.16 mg/dL (1.16-1.29
mmol/L) [11]
Adults, >90 years (whole blood): 4.48-5.28 mg/dL (1.12-1.32 mmol/L)
Neonates, cord blood (serum): 5.2-6.4 mg/dL (1.3-1.6 mmol/L) [11]
Neonates, 2 hours (serum): 4.84-5.84 mg/dL (1.21-1.46 mmol/L) [11]
Neonates, 24 hours (serum): 4.4-5.44 mg/dL (1.1-1.36 mmol/L) [11]
Neonates, 6 to 36 hours (capillary blood): 4.2-5.48 mg/dL (1.05-1.37
mmol/L) [11]
Neonates, 60 to 84 hours (capillary blood): 4.4-5.68 mg/dL (1.1-1.42
mmol/L) [11]
Neonates, 3 days (serum): 4.6-5.68 mg/dL (1.15-1.42 mmol/L) [11]
Neonates, 5 days (serum): 4.88-5.92 mg/dL (1.22-1.48 mmol/L) [11]
Neonates, 108 to 132 hours (capillary blood): 4.8-5.92 mg/dL (1.2-1.48
mmol/L) [11]
Children (serum): 4.8-5.52 mg/dL (1.2-1.38 mmol/L) [11]
Reference
Tietz Textbook of Clinical Chemistry, Edited by CA Burtis, ER Ashwood. Philadelphia, WB
Saunders Company, 1999, chapter 39, pp 1405-1406
Ong GS, Walsh JP, Stuckey BG, Brown SJ, Rossi E, Ng JL, Nguyen HH, Kent GN, Lim EM. The
importance of measuring ionized calcium in characterizing calcium status and diagnosing
primary hyperparathyroidism.J Clin Endocrinol Metab. 2012 Sep;97(9):3138-45.
Bowers GN Jr, Brassard C, Sena SF Measurement of ionized calcium in serum with ion-selective
electrodes: a mature technology that can meet the daily service needs.
Clin Chem. 1986 Aug;32(8):1437-47.
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Serum ionized calcium concentrations 50% below normal result in severely reduced
cardiac stroke work. With moderate to severe hypocalcemia, left ventricular function may
be profoundly depressed.
Ionized calcium values are higher in children and young adults.
Ionized calcium values vary inversely with pH, approximately 0.2 mg/dL per 0.1 pH unit
change.