Edited by William Gossman, M.D., Project Medical Director, Clinical Professor, Department of Emergency Medicine, The Chicago Medical School, Mt. Sinai Hospital; Francisco Talavera, Pharm.D., Ph.D., Department of Pharmacy, Creighton University; Jeffrey Arnold, M.D., Associate Professor, Department of Emergency Medicine, Cedars-Sinai Medical Center; John Halamka, M.D., Executive Director, Center for Quality and Value, Instructor, Division of Emergency Medicine, Beth Israel Deaconess Medical Center; and Craig Feied, M.D., Director of Informatics, Associate Professor, Department of Emergency Medicine, Washington Hospital Center

 

Author's Email:	Robin R. Hemphill, M.D.
Editor's Email:	William Gossman, M.D.

 

Author Status		Editor Status
Completed	Updated	Copy	Medical	Pharmacy	Managing	CME	Chief
11/10/1999	11/10/1999 15:24:35	07/04/1998	07/17/1998	10/18/1999	10/03/1998	10/03/1998	10/05/1998

 

INTRODUCTION

Background: Hypercalcemia is a disorder that most commonly results from malignancy or primary hyperparathyroidism. The other causes of elevated calcium are less common and not usually considered until malignancy and parathyroid disease are ruled out.

While hypercalcemic crisis does not have an exact definition, accepted criteria include a marked elevation of the serum calcium, usually above 14 mg/dl, which is associated with acute signs and symptoms that may be reversed with treatment and resolution of the elevated calcium level.

The normal range of serum calcium is 8.7-10.4 mg/dl, with somewhat higher levels seen in children. Approximately 40% of the calcium is bound to protein, primarily albumen, while 50% is ionized and is the physiologic active form. The remaining 10% is complexed to anions.

Pathophysiology: Plasma calcium is maintained within the normal range by a complex interplay of three major hormones: parathyroid hormone (PTH), 1,25 dihydroxyvitamin D and calcitonin. These three hormones act primarily at bone, kidney and small intestine to maintain appropriate calcium levels.

Calcium enters the body through the small intestine and is eventually excreted via the kidney. Bone can act as a storage depot and the entire system is controlled through a feedback loop. The individual hormones respond as needed to increase or decrease the serum calcium concentration.

For hypercalcemia to develop, the system must be overwhelmed by an excess of either PTH, 1,25-dihydroxyvitamin D, a serum factor the can mimic these hormones or a huge calcium load.

Hypercalcemia can result from a multitude of disorders. The more common causes include the following:

PTH-Mediated Hypercalcemia:

Primary hyperparathyroidism was originally the disease of stones, bones and abdominal groans. Non-PTH-Mediated Hypercalcemia:

Hypercalcemia associated with malignancy is commonly the result of breast or lung cancer and is due the result of increased osteoclastic activity within the bone. Granulomatous disorders with high levels of 1,25-dihydroxyvitamin D may be found in patients with sarcoidosis, berylliosis, tuberculosis, leprosy, coccidiomycosis and histoplasmosis. Iatrogenic disorders of calcium levels may increase secondary to the ingestion of many medications.

Frequency:

• In the U.S.: Hypercalcemia is a fairly common metabolic emergency. Between 10-20% of cancer patients develop hypercalcemia at some point in their disease.

  Primary hyperparathyroidism occurs in 25/100,000 persons in the general population and in 75/100,000 of hospitalized patients. It is the most common cause of outpatient, mild hypercalcemia. There are more than 50,000 new cases each year in the U.S.

Mortality/Morbidity:

• The prognosis of hypercalcemia associated with malignancy is poor; the one-year survival is 10-30%. In one study, 50% of patients died within one month of beginning treatment and 75% were dead within three months.
• Hypercalcemia related to hyperparathyroidism and other etiologies has a good prognosis if the underlying cause is treated.

Sex:

• The incidence of primary hyperparathyroidism is considerably higher in women.
• The annual incidence in women over 65 years of age is 250/100,000.
• Elevations related to cancer have no sexual predominance.

Age:

• The incidence of primary hyperparathyroidism increases with age.
• Malignancy rates increase with age. Thus, the associated hypercalcemia is often seen in an older population.

History:

• Symptoms of hypercalcemia depend on the underlying cause of the hypercalcemia, underlying health and the time course over which it develops.
• Mild elevations in calcium usually have few or no symptoms.
• Increased calcium levels may cause nausea, vomiting, alterations of mental status, abdominal pain, constipation, lethargy, depression, weakness, polyuria and headache.
• Severe elevations may cause coma.
• Elderly patients are more susceptible to moderate elevations of calcium
• Hypercalcemia of Malignancy:

• May not have many of the features commonly associated with hypercalcemia from hyperparathyroidism.
• Specifically, kidney stone formation, joint complaints and ulcer disease favor a diagnosis of hyperparathyroidism.

Physical: Hypercalcemia has limited physical examination findings.

• Often, it is the symptoms or signs of the malignancy that brings the patient to attention.

• Patients with malignancy may have lung findings, skin changes, lymphadenopathy and liver or spleen enlargement that suggest the primary malignancy.
• Hypercalcemia is suggested by some of the following findings:
• Hypertension and bradycardia may be noted in the patient with hypercalcemia but this is non-specific. Abdominal examination may suggest pancreatitis or the possibility of an ulcer.

• Patients with arthralgias may have bony tenderness to palpation.

• Patients with long-standing elevation of serum calcium may have proximal muscle weakness that is more prominent in the lower extremities.

• Hyperreflexia and tongue fasiculations may be present.

• Anorexia, nausea

• Polyuria, dehydration

• Lethargy, stupor, coma

• Long-standing hypercalcemia may also cause band keratopathy but this would probably not be noted in the ED unless severe.
• Patients with hyperparathyroidism may have a large number of complaints but no unique findings beyond those listed above.
• Sarcoidosis, vitamin D intoxication and hyperthyroidism can cause elevation of serum calcium and may have physical examination findings suggestive of those diseases.

Causes

• PTH-Mediated Hypercalcemia (Primary Hyperparathyroidism):

  This was originally the disease of stones, bones and abdominal groans. Although less common today, occasionally the work up for a new kidney stone will reveal an elevated calcium level. In the majority of primary hyperparathyroidism cases, the calcium elevation is due to increased intestinal calcium absorption. This is mediated by the PTH-induced 1,25 dihydroxyvitamin D synthesis which enhances calcium absorption. The increase in serum calcium results in an increased filtered load of calcium at the kidney. Due to PTH-mediated absorption of calcium at the distal tubule, however, less calcium is excreted than might be expected. In PTH-mediated hypercalcemia, the bones do not play an active role since most of the PTH-mediated osteoclast activity that breaks down bone is offset by hypercalcemic-induced bone deposition. The hypercalcemia of this disorder may remain mild for long periods of time because some parathyroid adenomas respond to the feedback generated by the elevated calcium levels.

• Non-PTH-Mmediated Hypercalcemia:

• Hypercalcemia Associated with Malignancy:

  Unlike PTH-mediated hypercalcemia, the elevation of calcium that results from malignancy generally worsens in severity until therapy is provided. Hypercalcemia due to malignancy is the result of increased osteoclastic activity within the bone. This results from one or both of the following mechanisms.

  First, extensive localized bone destruction may result from osteolytic metastasis of solid tumors. There is evidence that many malignant cells may release local osteoclastic activating factors.

  A second mechanism of increased calcium resulting from malignancy is from a PTH-related protein. This protein is a humeral factor that acts on the skeleton to increase bone reabsorption and on the kidney to decrease excretion of calcium. The gene that produces this protein is present in many malignant tissues.

• Granulomatous Disorders:

  High levels of 1,25-dihydroxyvitamin D may be found in patients with sarcoidosis and other granulomatous diseases. In these disorders the increased level of 1,25-dihydroxyvitamin D results from production within the macrophages, which constitute a large portion of some granulomas.

• Iatrogenic:

  In some cases, the elevation of calcium is a known side effect of appropriate dosing. In other cases, large ingestions must be taken to induce the increase. Patients who present with hypercalcemia should have a complete review of their current medications. Vitamin use should also be noted.

• Other Causes of Hypercalcemia:
• Neoplasms (Nonparathyroid):

  Metastasis to the bone from breast, multiple myeloma and hematologic malignancies may occur.

  Nonmetastatic (Humoral-Induced):

  Ovary, kidney, lung, head and neck, esophagus, cervix, lymphoproliferative disease, multiple endocrine neoplasia, pheochromocytoma, hepatoma

• Pharmacologic Agents:

  Thiazide, calcium carbonate (antacid), hypervitaminosis D, hypervitaminosis A, lithium, milk-alkali syndrome, theophylline toxicity

• Endocrinopathies (Nonparathyroid):

  Hyperthyroidism, adrenal insufficiency, pheochromocytoma

• Familial hypocalciuric hypercalcemia

• Tertiary Hyperparathyroidism:

  Postrenal transplant and initiation of chronic hemodialysis

• Miscellaneous:

  Immobilization, hypophosphatasia, primary infantile hyperparathyroidism, acquired immunodeficiency syndrome and advanced chronic liver disease

 

DIFFERENTIALS

HIV Infection and AIDS
Hyperparathyroidism
Sarcoidosis
Toxicity, Lithium
Toxicity, Salicylate
Toxicity, Theophylline
Toxicity, Thyroid Hormone
Toxicity, Vitamin
Tuberculosis

Other Problems to be Considered:

Pheochromocytoma

Immobilization

Addison's Disease

Inflammatory Disorders

Rhabdomyolysis

Paget's Disease

Parenteral Nutrition

 

WORKUP

Lab Studies:

• Confirmatory Tests:

  Changes in serum protein concentrations alter the total serum calcium level but do not affect the unbound fraction. The calcium level reported by the laboratory usually represents the bound and unbound calcium. Thus, when the calcium is reported as high or low, it is important to be able to calculate the actual level of calcium. One common formula is as follows:

  Corrected total calcium (mg/dl) = (measured total calcium mg/dl) + 0.8 (4.4 - measured albumin g/dl)

  A value of 4.4 represents the average normal albumin level. The normal corrected value of calcium is approximately 9.0-10.6 mg/dl.

  The corrected calcium value is useful in most situations, however, there can be individual variation. If there is concern that the corrected serum calcium level is still not correct, it is possible to measure the free calcium ion activity (ionized calcium level).

  Other nonspecific laboratory abnormalities commonly seen in patients with hypercalcemia result from disordered renal function. It is not uncommon for patients to have significant azotemia at presentation.

  Electrocardiographic changes may also be seen in patients with hypercalcemia, specifically, QT interval shortening. In some cases the P-R interval is prolonged. At very high levels the QRS interval may lengthen, T waves may flatten or invert and various degrees of heart block may develop. Digoxin effects are amplified.

   

• Diagnostic Tests:

  Once the diagnosis of hypercalcemia is made, the next step is to determine the cause of the hypercalcemia. Since the most common cause of hypercalcemia is malignancy, hyperparathyroidism or hyperthyroidism, the search usually begins here.

   

• Parathyroid Hormone Measurement (PTH):

  The measurement of circulating PTH in the serum is the most direct and sensitive measure of parathyroid function. A normal range is 2-6 mol/L. A non-suppressed PTH level in the presence of hypercalcemia points to a diagnosis of primary hyperparathyroidism. If the PTH level is suppressed in the face of an elevated calcium level hyperparathyroidism is unlikely.

   

• Parathyroid Hormone-Related Peptide Measurement (PTHrP):

  This peptide is thought to mediate the hypercalcemia that develops with many malignancies. Assays to measure this peptide are available.

   

• Vitamin D Metabolites:

  The measurement of 1.25 dihydroxyvitamin D is difficult but can be done. This laboratory value is useful in diagnosing hypercalcemia secondary to a granulomatous disease such as sarcoidosis.

   

• Other Electrolytes:

  Serum phosphate levels tend to be low or normal in both primary hyperparathyroidism and hypercalcemia of malignancy. It is usually elevated in hypercalcemia secondary to vitamin D related disorders and thyrotoxicosis. Serum chloride levels are usually above 102 mEq/L in hyperparathyroidism and below this value in hypercalcemia from other causes. This is a rapid way to support an early diagnosis of hyperparathyroidism as the cause of hypercalcemia.

   

Imaging Studies:

• There are no specific imaging studies that make the diagnosis of hypercalcemia.
• The finding of a lung mass with associated non-specific complaints should lead the clinician to consider hypercalcemia.
• If there is laboratory evidence of primary hyperparathyroidism, CT, MRI, ultrasound or nuclear parathyroid scans may be required in patients with previous neck surgery or prior to re-exploration/

 

TREATMENT

Prehospital Care:

• There is little specific therapy in the prehospital setting.
• If a patient has a history of hypercalcemia and evidence of acute hypercalcemia, IV access should be established and hydration begun.
• Other stabilization measures should be performed as indicated.

Emergency Department Care: The treatment of hypercalcemia varies depending on the source of the elevation.

• In minor to moderate elevations of calcium, there may be few things for the emergency medicine physician to do acutely. An evaluation to help delineate the source of the elevation is appropriate, followed by a timely follow-up.
• The goals of treatment include adequate hydration, increasing urinary calcium excretion, inhibition of osteoclast activity in the bone and treatment of the underlying cause when possible

• In the ED, the greatest focus is on immediate stabilization and lowering of the calcium level. As this is accomplished, more specific therapy can be instituted.

• Hydration:

• The initial step in the care of severely hypercalcemic patients is hydration with saline. Hydration alone helps decrease the calcium level. The expansion of the extracellular volume also increases the renal calcium clearance.

• This therapy is ineffective in patients with kidney failure and the first-line therapy in this group is usually dialysis. The rate of the fluid therapy is based upon the degree of the hypercalcium, the severity of dehydration and the ability of the patient to tolerate fluid loading.

• Loop Diuretics:

   

   

• The use of a loop diuretic, such as furosemide, may be indicated with hydration.

• In contrast to loop diuretics, thiazide diuretics should be avoided because they increase the reabsorption of calcium.

• The use of loop diuretics may also help prevent volume overload during the therapy.

Consultations:

• The patient with renal failure who is presenting with severe elevations of calcium may require urgent dialysis.

• In these cases, a nephrologist should be consulted early in the presentation.

   

• Patients with primary hyperparathyroidism may need surgery to cure the condition but this is not generally done urgently.

• Patients with hypercalcemia secondary to malignancy may have complications of their disease other than elevated calcium levels.

• Each patient should be considered for complications requiring early surgical intervention.

 

MEDICATION

There are several classifications of medications used to treat elevations of serum calcium. Some can be used in acute life-threatening elevations, while others to help control calcium elevations after the acute event has been treated. Agents that help treat hypercalcemia include plicamycin, mithromycin, calcitonin, gallium nitrate, intravenous phosphate and glucocorticoids.

Drug Category: Bisphosphonates - These compounds are analogs of pyrophosphate and act by binding to hydroxyapatite in bone-matrix, thereby inhibiting the dissolution of crystals. These agents prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

Drug Name	Pamidronate (Aredia) - Its mechanism of action is the inhibition of normal and abnormal bone resorption. It appears to inhibit bone resorption without inhibiting bone formation and mineralization. Pamidronate as a potent agent that has several regimens for administration. The side effects of intravenous administration include mild transient increases in temperature, leukopenia and a mild reduction in serum phosphate levels. Oral maintenance therapy is available after the acute event has resolved but it is experimental. In the face of acute hypercalcemia, all of these agents are effective, however, pamidronate may be preferable due to its potency and efficacy.
Adult Dose	Moderate hypercalcemia: Administer the 60 mg dose as an initial iv dose infusion over 4 h. Alternatively, administer the 90 mg dose as an initial single iv dose infusion over 24 h. Severe hypercalcemia: Administer 90 mg as an initial iv dose infusion over 24 h.
Pediatric	Safety and effectiveness in children have not been established.
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those with diagnosed with hypocalcemia.
Interactions	No significant drug interactions have been reported with this medication.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor hypercalcemia-related parameters, such as serum levels of calcium, phosphate, magnesium and potassium once treatment begins. An adequate intake of calcium and vitamin D is necessary to prevent severe hypocalcemia. Exercise caution when administering bisphosphonates in patients with active upper GI problems. Do not administer concomitantly with alendronate for osteoporosis in postmenopausal women.

Drug Name

Clodronate - Is an experimental bisphosphonate used in the treatment of hypercalcemia of malignancy and increased bone resorption due to malignancy. Clodronate can be given as an intravenous infusion divided over three to five days or as a single infusion over two to nine hours. The daily dosing regimen appears to provide longer-lasting control of the calcium levels. Potential harmful effects to the kidney can be minimized by administering the drug as a slow drip. It is less commonly used and will not be discussed further.

Pregnancy

C - Safety for use during pregnancy has not been established.

Drug Name	Etidronate (Didronel) - Reduces bone formation and does not appear to alter renal tubular reabsorption of calcium. In addition, it does not affect hypercalcemia in patients with hyperparathyroidism where increased calcium reabsorption may increase blood calcium levels. Response is generally seen within the first 48 hours. The drug is more effective if the patient is well hydrated when it is started. If the patient responds well before seven days, the therapy can be disontinued. It is generally well tolerated and the most common side effect is a transient elevation of serum creatinine and phosphorous. Oral therapy for lasting control of hypercalcemia is experimental and not always effective.
Adult Dose	Administer 7.5 mg/kg iv over a 4-h period for 3-7 d. Dilute in at least 250 cc of sterile saline. When used beyond three days it may increase the risk of hypocalcemia. Full initial doses may be used in repeat dosing situations if etidronate has not been used in the previous seven days.
Pediatric	Safety and effectiveness in children have not been established.
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those with diagnosed with hypocalcemia and renal impairment.
Interactions	Etidronate absorption occurs when products containing calcium and other multi-valent cations are administered concomitantly.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor hypercalcemia-related parameters, such as serum levels of calcium, phosphate, magnesium and potassium once treatment begins. An adequate intake of calcium and vitamin D is necessary to prevent severe hypocalcemia. Exercise caution when administering bisphosphonates in patients with active upper GI problems. Do not administer concomitantly with alendronate for osteoporosis in postmenopausal women.

Drug Name	Plicamycin (Mithromycin) - Inhibits cellular ribonucleic acid (RNA) and enzymatic RNA synthesis. It possibly blocks the hypercalcemic action of pharmacologic doses of vitamin D and may act on osteoclasts or block the action of parathyroid hormone. Its effect in lowering calcium is not related to its tumoricidal activity. The effects of this drug last from several days to several weeks. This drug has several side effects that may limit its use and has caused it to be used less commonly as other drugs have become available.
Adult Dose	Administer 25 ug/kg iv over 4-6 h. Repeat q 24-48 h prm for 3-4 d. The dose may be repeated at one-week (or more) intervals, if necessary, until a satisfactory response is obtained.
Pediatric	Safety and effectiveness in children have not been established.
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those diagnosed with thrombocytopenia, coagulation disorders or there is impairment of bone marrow function.
Interactions	Glucagon, calcitonin, and etidronate, may increase plicamycin toxicity.
Pregnancy	X - Contraindicated in pregnancy
Precautions	Monitor the platelets, prothrombin and bleeding times periodically during therapy and for several days after the last dose. Discontinue the therapy if a significant prolongation of bleeding times occurs and thrombocytopenia is observed. Correct any electrolyte imbalance (especially hypokalemia, hypocalcemia, and hypophosphatemia) prior to treatment. Avoid salicylates and immunization usage during therapy.

Drug Name	Calcitonin (Miacalcin, Cibacalcin, Calcimar) - This is a naturally occurring hormone that inhibits bone reabsorption and increases the excretion of calcium. Calcitonin has the most rapid onset of action of any other anticalcemic agent. The effects of the drug may be seen within a few hours, with peak response at 12-24 hours. Due to the short duration of action, other more potent but slower acting agents should be started in those patients with severe hypercalcemia. Salmon calcitonin is the form usually given and is more potent that human calcitonin. Although the action of this agent is short-lived, it has a role in the treatment of hypercalcemia. If the elevation of calcium is severe, it is reasonable to administer one to two doses of this agent while fluids and lasix are being given. The drug should provide a rapid, although limited, lowering of the calcium level that may stabilize the patient.
Adult Dose	sc, im: Administer 2-8 U/kg q6-12h.
Pediatric	Safety and effectiveness in children have not been established.
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products.
Interactions	No significant drug interactions have been reported with this medication.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Calcitonin is generally a safe drug with nausea, abdominal cramps and flushing occurring as occasional side effects. Allergy may be present to salmon calcitonin. Hypocalcemia may occur. Periodically examine the urine sediment of patients on prolonged therapy.

Drug Name	Gallium Nitrate (Ganite) - Exerts a hypocalcemic effect possibly by reducing bone resorption. The drug has performed well against other anticalcium agents but has a slow onset of action.
Adult Dose	Severe hypercalcemia: Administer 200 mg/m2 iv for 5 d in 1 L of NS or D5W. Mild hypercalcemia: Administer 100 mg/m2/d iv for 5 d in 1 L of NS or D5W.
Pediatric	Safety and efficacy in children have not been established
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those with renal failure.
Interactions	The nephrotoxic effects of this drug increase when administered concurrently with amphotericin B, and aminoglycosides.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	The major concern in the use of this agent is nephrotoxicity. The patient's hydration status must be followed carefully during the administration of the drug. Experience with this agent is still limited. Exercise caution when administering to patients diagnosed with renal failure.

Drug Name	Potasium phosphate - The iv preparations are available as sodium or potassium phosphate (K2PO4). Response to iv serum phosphorus supplementation is highly variable and is associated with hyperphosphatemia.
Adult Dose	Initially administer 8 mmol of K2PO4 q6h iv (32 mmol/24h). Aggressive iv replacement: Administer 15 mmol of K2PO4 over 6 h.
Pediatric	Administer 0.25-0.5 mmol/kg over 4-6 h and repeat if necessary.
Contraindications	Do not administer to patients diagnosed with hyperphosphatemia, hypocalcemia, hypomagnesemia, hyperkalemia, and renal failure.
Interactions	Magnesium and aluminum-containing antacids or sucralfate can act as phosphate binders and decrease serum phosphate levels. Potasium-sparing diuretics, ACE inhibitors, and salt substitutes may increase serum phosphate levels.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution in patients with renal insufficiency, and metabolic alkalosis. The admixture of phosphate and calcium in iv fluids can result in calcium phosphate precipitation.

Drug Name	Hydrocortisone (Cortef) - Has mineralocorticoid activity and glucocorticoid effects. Its onset of activity is rapid. There are a significant number of adverse reactions for those on long-term steroids, however, in the acute phase there are few severe reactions of concern.
Adult Dose	Administer 200-300 mg of hydrocortisone iv for 3 d.
Pediatric	Administer 10 mg/kg/d divided qid.
Contraindications	Avoid use in patients with documented hypersensitivity to the drug and patients diagnosed with viral, fungal, or tubercular skin infections.
Interactions	Corticosteroid clearance may decrease when used concurrently with estrogens. In addition, when used concomitantly with digoxin, it may increase digitalis toxicity secondary to hypokalemia.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid live vaccinations in chronic steroid users. Use with caution in patients diagnosed with hyperthyroidism, cirrhosis, nonspecific ulcerative colitis, osteoporosis, peptic ulcer, diabetes, and myasthenia gravis

 

FOLLOW-UP

Further Inpatient Care:

• The serum calcium level generally responds to fluids and lasix, however, this therapy has no effect on the principle pathologic process causing the hypercalcemia. Therefore, additional therapy must be added to the temporizing treatment described above.
• Treatment of the underlying disease must be addressed.

Further Outpatient Care:

• Patients with primary hyperparathyroidism with severe elevations of calcium or moderate elevations with symptoms should be referred for parathyroidectomy. Depending on the severity, this referral may need to be urgent.
• Patients with mild to moderate elevations of calcium and no symptoms may be evaluated on an outpatient basis and usually managed medically. For those patients with malignancy as the cause of their hypercalcemia, a cure may not be possible.

• The ideal scenario is to find a treatable underlying cause for the hypercalcemia and deal with this primary process. If this is accomplished, the patient may not need therapy for the hypercalcemia itself.
• The drug regimen most appropriate for each individual depends on the cause of the elevation and is usually not managed by the emergency physician.
• These patients may require ongoing treatment for the calcium elevation.
• This type of treatment can be frustrating and difficult and is not always successful.

Transfer:

• Transfer may be considered in a number of situations.
• If a patient presents with severe hypercalcemia and renal failure, emergency dialysis is necessary. If this is unavailable at the initial treatment center, transfer should be considered.
• Patients with normal kidney function who are being treated for severe hypercalcemia should be considered for transfer if there is no intensivist available or no physicians familiar with the inpatient treatment of hypercalcemia. This situation, however, is unlikely.

Deterrence:

• Patients who are known to have rapid bone turnover, prolonged bedrest should be avoided.
• In a patient with Paget's disease, elective surgical procedures should be considered after therapy has been initiated for calcium. The patient should be mobilized as quickly as possible.
• For those patients with known metastatic disease who are too ill to ambulate, worsening hypercalcemia should be anticipated before the patient becomes symptomatic.
• Patients at risk for hypercalcemia should have scheduled appointments with ongoing evaluation for the development of hypercalcemia.
• Salt restriction, diuretics and dehydration should be avoided in patients with active or potential hypercalcemia.

Prognosis:

• The prognosis of patients with hypercalcemia depends upon the etiology of the elevation.
• Patients with malignancy that has progressed to the point they develop hypercalcemia generally have a very poor prognosis.
• When the underlying cause is managable and treatment ensues, the hypercalcemia resolves and the overall prognosis of the patient is excellent.

Medical/Legal Pitfalls:

• Failure to consider hypercalcemia in the differential diagnosis of a patient with vague, non-specific complaints may result in delay in diagnosis.

CME Question 1: A 73 year old female with a history of metastatic breast cancer presents with lethargy, vomiting, hypotension and tachycardia. You suspect that she has acute hypercalcemia. What ECG abmornality is most likely to be found?

A: None
B: QT prolongation
C: QT shortening
D: Peaked T-waves
E: QRS interval shortening

CME Question 2: Considering the same patient, which of the following interventions is indicated as a first-line therapy?

A: Pamidronate
B: Hydrocortisone
C: IV hydration
D: Phosphate therapy
E: Mithromycin

Pearl Question 1: What are the most common causes of hypercalcemia?

Pearl Question 2: What is the most important intial intervention for the patient with severe hypercalcemia?

Pearl Question 3: Which type of diuretic should be avoided in patients with hypercalcemia?

Pearl Question 4: What are the most common malignancies responsible for hypercalcemia?

 

BIBLIOGRAPHY

• Aurbach GD, Mallette LE, Patten BM: Hyperparathyroidism: Recent studies. Ann Intern Med 1973; 79: 566-581.
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• Bilezikian JP: Management of acute hypercalcemia. NEJM 1992; 326: 1196-1203.
• Blomqvist CP: Malignant hypercalcemia: A hospital survey. Acta Med Scand 1986; 220: 455-463[Medline].
• Bourke E, Delaney V: Assessment of hypocalcemia and hypercalcemia. Clin in Lab Med 1993; 13: 157-181.
• Dent DM, Miller JL, Klaff L: The incidence and causes of hypercalcaemia. Postgrad Med J 1987; 63: 745-750[Medline].
• Edelson GW, Kleerekoper M: Hypercalcemic crisis. Endocrine Emergen 1995; 79: 79-82.
• Grill V, Ho P, Body JJ: Parathyroid hormone related protien is elevated in both humerol hypercalcemia and in hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab 1991; 73: 1309-1315[Medline].
• Kiang DT, Loken MK, Kennedy BJ: Mechanism of the hypocalcemic effect of mithromycin. J Clin Endocrinol Metab 1979; 48: 341-344[Medline].
• Kinirons MT: Newer agents for the treatment of malignant hypercalcemia. Am J Med Sciences 1993; 305: 403-406.

 

NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this textbook have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this text do not warrant the information in this text is accurate or complete, nor are they responsible for omissions or errors in the text or for the results of using this information. The reader should confirm the information in this text from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.

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