Calcium Ionized

The average adult stores between 1 and 2 kg of calcium, primarily within the skeleton. Only 1% of calcium is present in extracellular fluid. Adult calcium plasma concentrations are normally between 8.5–10.5 mg/dL (2.2–2.6 mmol/L). Most of this circulating calcium is bound to albumin. Because of this, changes in serum protein concentrations can affect total blood calcium concentrations. Ionized calcium is the biologically active fraction and its concentration is tightly regulated by PTH.

Calcium enters the extracellular fluid through absorption from the gut and resorption from bone. It is removed through secretion into the gastrointestinal tract and urine as well as losses in sweat and deposition in bone.

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.  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.  Patients with hypotension or low cardiac output may require calcium replacement when ionized calcium falls below 3.2 to 3.6 mg/dL. Replacement therapy should be monitored with ionized calcium levels.

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.

In these clinical situations, 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%.  Nomograms and formulas for indirect prediction of free calcium levels are inaccurate and may under-diagnose hypocalcemia (J Clin Endocrinol Metab 1978;46:986 and J Parenteral Enteral Nutrition 2004;28:133). The percentage of protein bound calcium may vary from 30 to 50% during illness.  Acute acidosis decreases protein binding, while acute alkalosis increases it.  Free fatty acids often increase during illness and after administration of heparin, isproterenol and insulin.  They increase calcium binding to albumin. Changes in the concentration of anions such as phosphate, bicarbonate, and citrate also change ionized calcium levels.  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.

Ionized calcium is measured with an ion-specific electrode. Ionized calcium concentration is strongly influenced by pH, because ionized calcium (Ca2+) competes with hydrogen ions (H+) to bind negatively charged proteins and anions. As pH decreases, H+ increases, Ca2+ has more competition for these binding sites and the concentration of circulating free Ca2+ increases. Generally, ionized calcium changes by approximately 0.2 mmol/L for every 0.1 pH unit change. Erroneously low ionized calcium can also occur in vitro from underfilled tubes, or tubes left uncapped before measurement, because the loss of carbon dioxide increases sample pH and increases protein-bound calcium.

 Reference range is 4.5 - 5.3 mg/dL. Critical values are <3.5 mg/dL and >6.5 mg/dL.

Specimen requirement is one SST tube of blood. Tourniquet time should not exceed one minute. The tube must remain capped and should be transported in wet ice.  Hemolysis will falsely lower ionized calcium values. Once collected, the pH of a blood sample may decrease from cell metabolism or increase due to loss of carbon dioxide if the specimen is exposed to air. Ionized calcium values change inversely to pH. The magnitude of change is 0.05 mmol/L per 0.1 pH change. 

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