Treatment of hypocalcemia

INTRODUCTION — Hypocalcemia may be associated with a spectrum of clinical manifestations, ranging from few (if any) symptoms if the hypocalcemia is mild and/or chronic to severe life-threatening symptoms if it is severe and/or acute. Thus, the management of hypocalcemia depends upon the severity of symptoms. In patients with acute symptomatic hypocalcemia, intravenous (IV) calcium gluconate is the preferred therapy, whereas chronic hypocalcemia is treated with oral calcium and vitamin D supplements.

The treatment of hypocalcemia will be reviewed here. The etiology, clinical manifestations, and diagnostic approach to hypocalcemia are reviewed separately. (See "Etiology of hypocalcemia in adults" and "Clinical manifestations of hypocalcemia" and "Diagnostic approach to hypocalcemia" and "Hypoparathyroidism".)

INTERPRETATION OF SERUM CALCIUM — Calcium in serum is mainly bound to proteins, principally albumin. As a result, total serum calcium concentrations in patients with low or high serum albumin levels may not accurately reflect the physiologically important ionized (or free) calcium concentration. As a result, ionized calcium remains the gold standard for assessing calcium status, particularly if the diagnosis of hypocalcemia is in doubt, due to hypoalbuminemia, atypical or absent symptoms, or a minimally reduced serum calcium concentration.

However, ionized calcium is not performed routinely, because it is more costly and must be handled carefully and stored under appropriate conditions to preserve a sample pH of 7.4. If a laboratory known to measure ionized calcium reliably is not available, the total calcium should be corrected for any abnormalities in serum albumin, using a calcium correction formula. There are a number of formulas that have been used to correct the total calcium for serum albumin concentrations, but none appears to be universally acceptable when examined for their correlation with ionized calcium. Furthermore, different chemistry laboratories may use different correction formulas.

Traditionally, one of the most widely utilized equations to estimate the total calcium concentration in clinical practice assumes the serum calcium to fall by 0.8 mg/dL (0.2 mmol/L) for every 1 g/dL (10 g/L) fall in the serum albumin concentration [(calculator 1) or for standard units (calculator 2)]. If the measured serum total calcium concentration is 8 mg/dL (2 mmol/L), and the serum albumin concentration is 2 g/dL (20 g/L) below normal, the corrected value will be 9.6 mg/dL (2.4 mmol/L), which is normal. Despite widespread use of this formula in clinical practice over the last several decades, more contemporary studies suggest the accuracy of this estimate is quite poor in a variety of populations, including patients hospitalized with critical illness and patients with advanced-stage chronic kidney disease. (See "Relation between total and ionized serum calcium concentrations", section on 'Hypoalbuminemia'.)

In patients with asymptomatic hypocalcemia, it is important to verify with repeat measurement of ionized calcium or total serum calcium corrected for albumin that there is a true decrease in the calcium concentration.

THERAPEUTIC APPROACH — There are few studies examining the optimal treatment of hypocalcemia. Most recommendations are based upon accepted practice or clinical experience [1-3]. The treatment of hypocalcemia varies with its severity and the underlying cause. The severity of symptoms (paresthesias, carpopedal spasm, laryngospasm, bronchospasm, seizures) and signs (Chvostek's or Trousseau's signs, bradycardia, impaired cardiac contractility, and prolongation of the QT interval) depends upon the absolute level of calcium, as well as the rate of decrease. Patients with acute hypocalcemia will be symptomatic at serum calcium values that would not cause symptoms in patients with chronic hypocalcemia (eg, hypoparathyroidism). Clinical manifestations also vary with other factors such as the arterial pH and the cause of hypocalcemia. (See "Clinical manifestations of hypocalcemia".)

Severe symptomatic and/or acute hypocalcemia — We recommend intravenous (IV) calcium for the treatment of hypocalcemia in patients with (algorithm 1):

●Symptoms (eg, carpopedal spasm, laryngospasm, bronchospasm, seizures)

●A prolonged QT interval

or

●In asymptomatic patients with an acute decrease in serum corrected calcium to ≤7.5 mg/dL (≤1.9 mmol/L), who may develop serious complications if untreated. In an ionized calcium assay with a normal range of 4.8 to 5.6 mg/dL (1.2 to 1.4 mmol/L), the threshold is approximately ≤3 mg/dL (≤0.8 mmol/L). Acute hypocalcemia can occur when there is a rapid and progressive reduction in serum calcium (eg, acute hypoparathyroidism following radical neck dissection for head and neck cancer).

Patients receiving digoxin should be monitored closely, preferably with telemetry, for acute digitalis toxicity, which can develop with IV calcium infusion. However, one retrospective chart review of 23 patients found that IV calcium did not cause malignant dysrhythmias or increased mortality in digoxin-intoxicated patients [4].

IV calcium is not warranted as initial therapy in patients with chronic kidney disease who are asymptomatic or who have chronic stable hypocalcemia with only mild symptoms (eg, paresthesias). In patients with chronic kidney disease, correction of hyperphosphatemia and of low circulating 1,25-dihydroxyvitamin D are usually the primary goals. (See "Management of hyperphosphatemia in adults with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

Intravenous calcium dosing — Initially, IV calcium (1 or 2 g of calcium gluconate, equivalent to 90 or 180 mg elemental calcium, in 50 mL of 5% dextrose or normal saline) can be infused over 10 to 20 minutes. The bolus may be repeated after 10 to 60 minutes, if needed to resolve symptoms. The calcium should not be given more rapidly, because of the risk of serious cardiac dysfunction, including systolic arrest [5]. The bolus dose of calcium gluconate will raise the serum calcium concentration for only two or three hours; as a result, it should be followed by a slow infusion of calcium in patients with persistent hypocalcemia.

A solution of 10% calcium gluconate (90 mg of elemental calcium per 10 mL) can be used to prepare the continuous infusion. Calcium gluconate is preferred to calcium chloride because it is less likely to cause tissue necrosis if extravasated. A solution of 10% calcium chloride (270 mg of elemental calcium per 10 mL) is an alternative if calcium gluconate is unavailable.

An IV solution containing 1 mg/mL of elemental calcium is prepared by adding 11 g of calcium gluconate (equivalent to 1000 mg elemental calcium) to normal saline or 5% dextrose water to provide a final volume of 1000 mL. This solution is administered at an initial infusion rate of 50 mL/hour (equivalent to 50 mg elemental calcium/hour). The dose can be adjusted to maintain the serum calcium concentration at the lower end of the normal range (with the serum calcium corrected for any abnormalities in serum albumin as noted above). Patients typically require 0.5 to 1.5 mg/kg of elemental calcium per hour.

The infusion should be prepared with the following considerations:

●The calcium should be diluted in dextrose and water or saline because concentrated calcium solutions are irritating to veins.

●The IV solution should not contain bicarbonate or phosphate, which can form insoluble calcium salts. If these anions are needed, another IV line (in another limb) should be used.

IV calcium should be continued until the patient is receiving an effective regimen of oral calcium and vitamin D. For patients with acute hypoparathyroidism, calcitriol (in a dose of 0.25 to 0.5 mcg twice daily) and oral calcium (1 to 4 g of elemental calcium carbonate daily in divided doses) should be initiated as soon as possible. Calcitriol is the preferred preparation of vitamin D for patients with severe acute hypocalcemia because of its rapid onset of action (hours). The management of acute and chronic hypoparathyroidism are reviewed in more detail separately. (See "Hypoparathyroidism", section on 'Management'.)

Concurrent hypomagnesemia — Hypomagnesemia is a common cause of hypocalcemia, both by inducing resistance to parathyroid hormone (PTH) and by diminishing its secretion. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

In patients with hypomagnesemia, hypocalcemia is difficult to correct without first normalizing the serum magnesium concentration. Thus, if the serum magnesium concentration is low, 2 g (16 mEq) of magnesium sulfate should be infused as a 10% solution over 10 to 20 minutes, followed by 1 gram (8 mEq) in 100 mL of fluid per hour. Magnesium repletion should be continued as long as the serum magnesium concentration is less than 0.8 mEq/L (1 mg/dL or 0.4 mmol/L). More careful monitoring is required in patients who have impaired renal function and who are therefore at greater risk of developing hypermagnesemia.

Persistent hypomagnesemia, as occurs in some patients with ongoing gastrointestinal (eg, malabsorption) or renal losses, requires supplementation with oral magnesium, typically 300 to 400 mg daily divided into three doses. (See "Hypomagnesemia: Causes of hypomagnesemia" and "Hypomagnesemia: Evaluation and treatment".)

Mildly symptomatic or chronic hypocalcemia — For patients with milder degrees of acute hypocalcemia (serum corrected calcium concentration above 7.5 to 8.0 mg/dL [1.9 to 2.0 mmol/L] or a serum ionized calcium concentration above 3.0 mg/dL [0.8 mmol/L]) or for chronic hypocalcemia, oral calcium supplementation is preferred (algorithm 1). Such patients are typically asymptomatic or, at most, mildly symptomatic (eg, perioral paresthesias). They can be treated initially with 1 to 2 g of elemental calcium given as calcium carbonate or calcium citrate daily, in divided doses. As an example, calcium carbonate is 40 percent elemental calcium, so that 1250 mg of calcium carbonate contains 500 mg of elemental calcium. The dose of elemental calcium is listed on most supplement labels (table 1).

For such patients with milder degrees of acute hypocalcemia and milder symptoms of neuromuscular irritability, who do not have symptomatic improvement with oral calcium supplementation, we switch to IV calcium. IV calcium is also indicated to prevent acute hypocalcemia in patients with milder degrees of hypocalcemia or chronic hypocalcemia (due to hypoparathyroidism) who become unable to take or absorb oral supplements, as may occur after complex surgical procedures requiring prolonged recuperation. (See "Hypoparathyroidism", section on 'Chronic hypoparathyroidism'.)

The role of oral calcium as a phosphate binder in patients with chronic kidney disease is presented elsewhere. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

In addition to calcium, patients with vitamin D deficiency or hypoparathyroidism require vitamin D supplementation, which often permits a lower dose of calcium supplementation. (See "Hypoparathyroidism", section on 'Management' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

DISEASE-SPECIFIC APPROACH

Hypoparathyroidism — Hypoparathyroidism occurs when there is abnormal parathyroid gland development, destruction of the parathyroid glands (autoimmune, surgical), altered regulation of parathyroid hormone (PTH) production, or impaired PTH action. (See "Hypoparathyroidism", section on 'Etiology'.)

When hypoparathyroidism is the cause of hypocalcemia, administration of calcium alone is usually only transiently effective. Long-term management requires the addition of vitamin D. Most patients with hypoparathyroidism require lifelong calcium and vitamin D supplementation (table 2). An exception is the occurrence of transient hypoparathyroidism after thyroidectomy or parathyroidectomy. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Hypoparathyroidism' and "Surgical management of hyperthyroidism", section on 'Hypocalcemia' and "Parathyroid exploration for primary hyperparathyroidism", section on 'Postoperative hypocalcemia'.)

The goals of therapy in patients with hypoparathyroidism are to relieve symptoms and to raise and maintain the serum calcium concentration in the low-normal range, eg, 8.0 to 8.5 mg/dL (2.0 to 2.1 mmol/L). Attainment of higher values is not necessary and is usually limited by the development of hypercalciuria due to the loss of renal calcium-retaining effects of PTH. The management of hypoparathyroidism is reviewed in detail separately. (See "Hypoparathyroidism", section on 'Management'.)

Vitamin D deficiency — When vitamin D deficiency is the cause of hypocalcemia, administration of calcium alone is only transiently effective. Hypocalcemia due to vitamin D deficiency is typically treated with ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3). In the setting of uncomplicated vitamin D deficiency, vitamin D2 or D3 corrects the deficiency and returns the patient's physiology to normal. Vitamin D is available in several doses for oral administration. We typically treat nutritional vitamin D deficiency with 50,000 international units of vitamin D2 or D3 weekly for six to eight weeks. In some countries (not in the United States), vitamin D is also available for parenteral administration. Vitamin D metabolites (calcitriol, dihydrotachysterol, calcidiol) can be used to treat hypocalcemia, particularly when there is abnormal vitamin D metabolism (renal or liver disease). The major advantage of vitamin D over vitamin D metabolites is its low cost, which is approximately 20 percent that of the vitamin D metabolites. Disadvantages include the necessity for hepatic and renal metabolism and slow onset and long duration of action. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Chronic kidney disease — Few patients with chronic kidney disease have symptomatic hypocalcemia. Such asymptomatic patients are often treated with oral calcium to bind intestinal phosphate and to prevent bone disease rather than hypocalcemia per se. The addition of an active form of vitamin D is required in some of these patients. These issues are discussed in detail elsewhere. (See "Management of hyperphosphatemia in adults with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

Chronic liver disease — Vitamin D metabolites can be used to treat hypocalcemia, particularly when there is abnormal vitamin D metabolism (renal or liver disease). Calcidiol (25-hydroxyvitamin D [25(OH)D]) does not require hepatic 25-hydroxylation and is therefore most useful in patients with liver disease. Its action is more rapid and not as prolonged as that of vitamin D, but slower in onset and more prolonged than that of calcitriol. (See "Overview of vitamin D", section on 'Metabolism' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Preparations'.)

Autosomal dominant hypocalcemia — Autosomal dominant hypocalcemia (ADH) is a rare disorder caused by an activating mutation in the calcium-sensing receptor (CaSR) gene (ADH type 1) or by a gain-of-function mutation of G-alpha-11, a key mediator of CASR signaling (ADH type 2). ADH may rarely be accompanied by Bartter syndrome (also called Bartter syndrome type V). Increased activity of CaSR in the renal tubules results in normal or high urinary calcium excretion despite hypocalcemia; raising the patient's serum calcium concentrations with calcium and vitamin D can result in more hypercalciuria, nephrocalcinosis, and renal insufficiency. Fortunately, most patients with this disorder have few, if any, symptoms of hypocalcemia and usually require little or no therapy. Recombinant human PTH, which enhances calcium absorption in the tubules, may be an alternative if therapy is needed. It can raise the serum calcium concentration in this disorder with a low risk of exacerbating hypercalciuria. Alternatively, calcilytics, a class of drugs in development that inhibit the CaSR, may provide a useful therapeutic approach in the future. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Autosomal dominant hypocalcemia'.)

Hypercatabolic state — Unless they are symptomatic from hypocalcemia (eg, tetany or cardiac arrhythmia), patients with acute hypocalcemia and hyperphosphatemia due to a hypercatabolic state such as the tumor lysis syndrome or massive trauma should not be treated with calcium until the hyperphosphatemia is corrected to prevent calcium-phosphate precipitation. Hemodialysis is often indicated in such patients who have symptomatic hypocalcemia. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Treatment of established tumor lysis syndrome'.)

Pseudohypoparathyroidism — Pseudohypoparathyroidism (PHP) refers to a group of heterogeneous disorders defined by target organ (kidney and, perhaps, bone) unresponsiveness to PTH [6]. It is characterized by hypocalcemia, hyperphosphatemia, and, in contrast to hypoparathyroidism, elevated rather than reduced PTH concentrations. The clinical manifestations and diagnosis of this disorder are reviewed elsewhere. (See "Etiology of hypocalcemia in infants and children", section on 'End-organ resistance to PTH (pseudohypoparathyroidism)'.)

The long-term treatment of hypocalcemia in adults with PHP is similar to the treatment of hypocalcemia caused by other forms of hypoparathyroidism. However, patients with PHP infrequently develop hypercalciuria with calcium and vitamin D therapy [6,7]. Therefore, the goal of treatment with calcium and vitamin D is to maintain normocalcemia (rather than low-normal serum calcium as for other forms of hypoparathyroidism). A typical starting dose of calcitriol is 0.25 mcg twice daily. The dose should be increased weekly to achieve a normal serum calcium. Many patients require up to 2 mcg daily [8]. Approximately 1 to 2 g of elemental calcium daily (in divided doses) is recommended.

Patients with PHP may also require screening for other endocrinopathies, particularly hypothyroidism and hypogonadism.

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●Basics topics (see "Patient education: Hypoparathyroidism (The Basics)")

SUMMARY AND RECOMMENDATIONS — The treatment of hypocalcemia varies with its severity and the underlying cause.

●Severe acute hypocalcemia – Patients with hypocalcemia who are severely symptomatic (carpopedal spasm, laryngospasm, bronchospasm, seizures, decreased cardiac function, or prolonged QT interval) require rapid correction of calcium levels with intravenous (IV) calcium therapy (algorithm 1). We also suggest IV calcium therapy in asymptomatic patients with an acute decrease in serum corrected calcium to ≤7.5 mg/dL (≤1.9 mmol/L) or ionized calcium to ≤3 mg/dL (≤0.8 mmol/L). (Grade 2C). (See 'Severe symptomatic and/or acute hypocalcemia' above.)

IV calcium is not warranted as initial therapy in patients with chronic kidney disease who are asymptomatic or who have chronic stable hypocalcemia with only mild symptoms (eg, paresthesias) in whom correction of hyperphosphatemia and of low circulating 1,25-dihydroxyvitamin D are usually the primary goals. (See 'Intravenous calcium dosing' above and 'Chronic kidney disease' above.)

●Mildly symptomatic or chronic hypocalcemia – For those with milder symptoms of neuromuscular irritability (paresthesias) and corrected serum calcium concentrations greater than 7.5 mg/dL (1.9 mmol/L) or a serum ionized calcium concentration greater than 3.0 mg/dL (0.8 mmol/L), initial treatment with oral calcium supplementation is sufficient (algorithm 1) (see 'Mildly symptomatic or chronic hypocalcemia' above). If symptoms do not improve with oral supplementation, IV calcium infusion is required.

IV calcium is also indicated to prevent acute hypocalcemia in patients with milder degrees of hypocalcemia or chronic hypocalcemia (due to hypoparathyroidism) who become unable to take or absorb oral supplements, as may occur after complex surgical procedures requiring prolonged recuperation. (See 'Mildly symptomatic or chronic hypocalcemia' above.)

When hypoparathyroidism (transient or permanent) or vitamin D deficiency are the cause of hypocalcemia, administration of calcium is only transiently effective (as long as the infusion continues), and oral calcium may not be well absorbed. In these cases, successful management requires the addition of vitamin D, which often permits a lower dose of calcium supplementation. (See 'Mildly symptomatic or chronic hypocalcemia' above.)

●Concurrent hypomagnesemia – To effectively treat hypocalcemia in patients with concurrent magnesium deficiency, hypomagnesemia should be corrected first. (See 'Concurrent hypomagnesemia' above.)

●Disease-specific approach

•Hypoparathyroidism – Most patients with hypoparathyroidism require lifelong calcium and vitamin D supplementation (table 2). For patients with permanent hypoparathyroidism, the goals of therapy are to relieve symptoms, raise and maintain the serum calcium concentration in the low-normal range (eg, 8.0 to 8.5 mg/dL [2.0 to 2.1 mmol/L]), and avoid hypercalciuria (maintain 24-hour urinary calcium below 300 mg). (See "Hypoparathyroidism", section on 'Management'.)

•Vitamin D deficiency – Individuals with hypocalcemia due to vitamin D deficiency require vitamin D repletion. Nutritional deficiency (25-hydroxyvitamin D [25(OH)D] <12 ng/mL [30 nmol/L]) requires initial treatment with 50,000 international units of vitamin D2 or D3 orally once per week for six to eight weeks, and then 800 to 1000 international units of vitamin D3 daily thereafter. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)