TREATMENT OF HYPOCALCEMIA

Acute Hypocalcemia

In chronic hypocalcemia, patients can often tolerate severe hypocalcemia and remain asymptomatic. The decision to treat is dependent on presenting symptoms, and the severity and rapidity with which hypocalcemia develops. The patient with acute hypocalcemia may have symptoms of tetany, seizure, or laryngeal spasm requiring aggressive treatment with intravenous calcium administration.

Calcium gluconate is the preferred intravenous calcium type as calcium chloride often causes local irritation. Calcium gluconate contains 90 mg of elemental calcium per 10 mL ampule and usually 1 to 2 ampules (180 mg of elemental calcium) diluted in 50 to 100 mL of 5% dextrose is infused over 10 minutes. This can be repeated until the patient's symptoms have cleared. With persistent hypercalcemia, administration of dilute calcium solution over longer periods of time may be necessary. The goals should be to raise serum calcium by 2 to 3 mg/dL with the administration of 15 mg/kg of elemental calcium over 4 to 6 hours. Calcium should be maintained in the low-normal range. If possible, oral calcium supplementation should be initiated concurrently with 1 to 2 grams of elemental calcium and if warranted, 1,25-dihydroxyvitamin D.

Intravenous administration of calcium is not without problems. Patients taking digitalis may have increased sensitivity to intravenous calcium. Rapid administration could result in arrhythmias so that intravenous calcium administration should be carefully monitored. Local vein irritation can occur with solutions >200 mg/100 mL of elemental calcium. If local extrapolation into soft tissues occurs, calcification with precipitation of calcium phosphate crystals can occur 90. Calcium phosphate deposition can occur in any organ and is more likely to occur if the calcium-phosphate ratio exceeds solubility product. The term "salting out" is used to describe calcium phosphate deposition in the lungs, kidney or other soft tissue and may occur in patients receiving intravenous calcium and the presence of high serum phosphate levels such as in the tumor lysis syndrome 91.

It is essential to measure serum magnesium in any patient who is hypocalcemic as correction of hypomagnesemia must occur to overcome PTH resistance before serum calcium will return to normal. If one were uncertain about the level of magnesium, it would be appropriate to treat with magnesium while awaiting laboratory confirmation of hypomagnesemia.

Chronic Hypocalcemia

Patients who are asymptomatic or with mild symptomatic hypocalcemia can be treated with oral calcium and vitamin D. Oral calcium carbonate is often the most commonly administrated although many different types exist. Oral calcium in the amounts of 1 to 3 grams of elemental calcium in 3 to 4 divided doses with meals insures optimal absorption. Calcium carbonate contains 40% elemental calcium and is relatively inexpensive. Lower amounts of elemental calcium are present in other types of calcium such as calcium lactate (13%), calcium citrate (21%) and calcium gluconate (9%) requiring a larger number of tablets. There are expensive forms of calcium supplements that have relatively few additional advantages. Liquid calcium supplements are available such as calcium glubionate that contains 230 mg of calcium per 10 mL or liquid forms of calcium carbonate. In patients with achlorhydria, a solution of 10% calcium chloride (1- to 30 ml) every 8 hours can also effectively raise calcium levels. Calcium phosphate salts should be avoided.

The overall goal of therapy is to maintain serum calcium in the low-normal range. Serum calcium should be tested very 3 to 6 months. One potential side effect is hypercalciuria with nephrocalcinosis and/or nephrolithiasis. A 24-hour urine calcium should be determined at least annually once a stable dose is established and should be <4 mg/kg/24 hr. Serum levels of calcium are poor modulators of hypercalciuria and nephrocalcinosis 92. The patient should also see an ophthalmologist to screen for cataracts.

For patients with hypoparathyroidism, vitamin D or vitamin D analogues are required. Calcitriol, the active form of vitamin D, is a rapid-acting physiologic treatment and is often used for initial therapy. Where rapid dose adjustment is necessary, such as growing children, this may be the most useful 93. Most patients require 0.25 mg twice daily up to 0.5 mg four times a day of calcitriol. Due to the need for multiple daily doses and expense, other long-acting and less expensive vitamin D preparations are frequently used. Ergocalciferol is the least expensive choice and has a long duration of action. The usual dose is 50,000 to 100,000 IU/day. Administration of therapy is needed acutely, calcitriol should be administered for the first three week but then tapered off as the dose of ergocalciferol becomes effective.

Thiazide diuretics can increase renal calcium absorption in patients with hypoparathyroidism. These may be useful to titrate urinary calcium to <4 mg/kg/day. Furosemide and other loop diuretics can depress serum calcium levels and should be avoided. Other factors that may precipitate hypocalcemia are glucocorticoids that can antagonize the action of vitamin D and its analogues.

Administration or withdrawal of exogenous estrogen can also influence calcium and vitamin D replacement therapy. Estrogen increases calcium absorption at the level of the intestine and indirectly through stimulation of renal 1a-hydroxylase activity. Dose adjustment may be required after changes in estrogen therapy due to alteration in calcium homeostasis. During the pre- and postpartum period in pregnant patients with hypoparathyroidism, doses of vitamin D often need adjustment and are thought to be due to the changing estrogen levels.

In hypoparathyroidism, autotransplantation of parathyroid tissue has been utilized at the time of parathyroidectomy to preserve parathyroid function 94. Using microencapsulated human parathyroid cells, xenotransplantation has also been reported 95. These studies have varying degrees of success 96.

The success of treatment of permanent, chronic hypoparathyroidism has recently been assessed 97. In a cross-sectional, controlled study, 25 women with postsurgical hypoparathyroidism on stable calcium and vitamin D treatment were compared to 25 control subjects with a history of thyroid surgery. Two of 25 and 4 of 25 hypoparathyroid patients had nephrolithiasis and cataracts, respectively, underscoring the need for monitoring and adjusting therapy. Compared to controls, the hypoparathyroid subjects had higher global complaint scores with predominant increases in anxiety and phobic anxiety subscores using validated questionnaires.

In hypoparathyroidism, the ideal replacement would be to replace the hormone itself. Few clinical studies have evaluated parathyroid hormone as a replacement for hypoparathyroidism. In a series of hypoparathyroid patients, once daily administration of PTH (1-34) normalized serum and urine calcium levels, but the action lasted only 12 hours. Twice daily administration preserved normal serum calcium levels in patients with a calcium sensing receptor (CaR) mutation 98.

Acute hypocalcemia can be a life-threatening situation with patients presenting with seizures, tetany, and cardiac arrhythmias. Although intravenous calcium can alleviate symptoms quickly, there are risks associated with this route of administration. For chronic hypocalcemia, calcium homeostasis can be restored with oral supplementation with calcium and vitamin D analogues. With under-replacement, cataracts and symptoms of numbness and tingling can occur. With over-replacement, nephrocalcinosis and nephrolithiasis are attendant risks.

Treatment

Prehospital Care

Standard advanced cardiac life support (ACLS) procedures should be initiated in the patient whose condition is

unstable. No specific therapy, other than supportive care, is recommended.

Emergency Department Care

Most hypocalcemic emergencies are mild and require only supportive treatment and further laboratory evaluation.

On occasion, severe hypocalcemia may result in seizures, tetany, refractory hypotension, or arrhythmias that

require a more aggressive approach.

Mild hypocalcemia (when symptoms are not life threatening) o Confirm ionized hypocalcemia and check other pertinent laboratory tests.

o If the cause is not obvious, send for a PTH level.

o Depending on the PTH level, the endocrinologist may do further laboratory workup, particularly an

evaluation of vitamin D levels.

o Oral repletion may be indicated for outpatient treatment; patients requiring intravenous (IV)

repletion should be admitted. (Recommended dose of elemental calcium in healthy adults is 1-3

g/d.)

Severe hypocalcemia (life-threatening symptoms)

o Supportive treatment often is required prior to directed treatment of hypocalcemia (ie, IV

replacement, oxygen, monitoring). Be aware that severe hypocalcemia often is associated with

other life-threatening conditions.

o Check ionized calcium and other pertinent screening laboratory tests.

o IV replacement is recommended in severe cases. Doses of 100-300 mg of elemental calcium

(calcium gluconate – 10 mL contains 90 mg elemental calcium; calcium chloride – 10 mL contains

272 mg elemental calcium) should be given over 5-10 minutes. This dosage raises the ionized

level to 0.5-1.5 mmol and should last 1-2 hours. Caution should be used when giving CaCl

intravenously (see Medication).

o Calcium infusion drips should be started at 0.5 mg/kg/h and increased to 2 mg/kg/h as needed,

with an arterial line placed for frequent measurement of ionized calcium.

Consultations

Depending on the clinical situation, multiple consultations may be necessary, including internist, endocrinologist,

intensivist, surgeon, oncologist, nephrologist, dietitian, and/or toxicologist.6

Medication

In the ED, magnesium and calcium (in their many different forms) are the only medications necessary to treat

hypocalcemic emergencies. The consulting endocrinologist may choose to prescribe any of the various vitamin D

supplements depending on laboratory workup findings and oral calcium supplementation for outpatient therapy.

Electrolyte supplements

These agents are used to increase blood calcium levels.

Treatment

Medical Care

The treatment of hypocalcemia depends on the cause, the severity, the presence of symptoms, and how rapidly the

hypocalcemia developed.7

Acute hypocalcemia o Promptly correct symptomatic or severe hypocalcemia with cardiac arrhythmias or tetany with

parenteral administration of calcium salts.

Administer 1-2 ampules 10% calcium gluconate (93 mg/10 mL) in 50-100 mL of D5W

over 5-10 minutes. Calcium chloride 10% solution (273 mg/10-mL ampule) delivers

higher amounts of calcium and is advantageous when rapid correction is needed, but it

should be administered via central venous access.

Measure serum calcium every 4-6 hours to maintain serum calcium levels at 8-9 mg/dL.

If low albumin is also present, ionized calcium should be monitored.

o Patients with cardiac arrhythmias or patients on digoxin therapy need continuous ECG monitoring

during calcium replacement because calcium potentiates digitalis toxicity.

o Identify and treat the cause of hypocalcemia and taper the infusion.

o Start oral calcium and vitamin D treatment early. Patients with postparathyroidectomy hungry

bone disease, especially those with osteitis fibrosa cystica, can present with a dramatic picture of

hypocalcemia.

o Treatment with calcium and vitamin D for 1-2 days prior to parathyroid surgery may help prevent

the development of severe hypocalcemia.

Chronic hypocalcemia: Treatment of chronic hypocalcemia depends on the cause of the disorder.

o PTH deficiency: Patients with hypoparathyroidism and pseudohypoparathyroidism can be

managed initially with the oral administration of calcium supplements. The hypercalcemic effects

of thiazide diuretics may offer some additional benefits. In patients with severe

hypoparathyroidism, vitamin D treatment may be required; however, remember that PTH

deficiency impairs the conversion of vitamin D to calcitriol. Therefore, the most efficient

treatment is the addition of 0.5-2 mcg of calcitriol or 1-alpha-hydroxyvitamin D3.

o Hypocalcemia in patients on dialysis: Most patients on hemodialysis will be hypercalcemic.

However, postparathyroidectomy, patients may have considerable difficulty in maintaining

appropriate calcium levels. These levels can be managed several ways. First, oral calcium

supplements should be provided. They must be given between meals; otherwise, they will

primarily act as phosphate binders. Active vitamin D administration (calcitriol) enhances the

absorption of calcium. Finally, the calcium in the dialysate bath can be increased.

o Nutritional vitamin D deficiency from lack of sunlight exposure or poor oral intake of vitamin D:

Ultraviolet light or sunlight exposure can treat these patients.33 Treat nutritional rickets with

vitamin D2. Oral calcium preparations containing 1-2 g of elemental calcium per day can treat

patients with a calcium deficiency. For infants who are breastfed, adjust the dose to 30 mg/kg/d.

Calcitriol may be used, but it has the disadvantages of a higher price and the possibility of

producing hypervitaminosis D with hypercalcemia.

Surgical Care

Parathyroidectomy (subtotal or total) may be indicated in certain patients with severe secondary

hyperparathyroidism and renal osteodystrophy.

Diet

An increase in dietary calcium to greater than 1 g/d is an important part of the treatment of chronic

hypocalcemia, particularly in cases of vitamin D deficiency.

In patients with hypocalcemia and chronic renal failure, the dietary intake of phosphate should be lowered

to 400-800 mg/d to prevent hyperphosphatemia.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Electrolytes

Restores serum calcium levels. Calcium chloride delivers 3 times more elemental calcium than calcium gluconate.

Dairy foods Milk, yogurt, cheese

Leafy green vegetables

Broccoli, kale, spinach

Fruits Oranges

Beans and peas Tofu, peanuts, peas, black beans, baked beans

Fish Salmon, sardines

Miscellaneous Sesame seeds, blackstrap molasses, corn tortillas, almonds, brown sugar