AUTHOR INFORMATION

Section 1 of 11

Authored by Robin R Hemphill, MD, MPH, Associate Professor, Director, Disaster Preparedness, Department of Emergency Medicine, Vanderbilt University Medical Center

Robin R Hemphill, MD, MPH, is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Edited by Erik D Schraga, MD, Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital

Author's Email:	Robin R Hemphill, MD, MPH
Editor's Email:	Erik D Schraga, MD

eMedicine Journal, May 1 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

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

Hypercalcemic crisis does not have an exact definition, although marked elevation of serum calcium, usually more than 14 mg/dL, is associated with acute signs and symptoms of hypercalcemia. Treatment of the elevated calcium level may resolve the crisis.

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

Pathophysiology: Plasma calcium is maintained within the reference range by a complex interplay of 3 major hormones, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (ie, calcitriol), and calcitonin. These 3 hormones act primarily at bone, kidney, and small intestine sites to maintain appropriate calcium levels.

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

For hypercalcemia to develop, the normal calcium regulation system must be overwhelmed by an excess of PTH, calcitriol, some other serum factor that can mimic these hormones, or a huge calcium load.

Hypercalcemia can result from a multitude of disorders. The causes are divided into PTH-mediated hypercalcemia and non–PTH-mediated hypercalcemia.

PTH-mediated hypercalcemia

Primary hyperparathyroidism originally was the disease of "stones, bones, and abdominal groans." In most primary hyperparathyroidism cases, the calcium elevation is caused by increased intestinal calcium absorption. This is mediated by the PTH-induced calcitriol synthesis that enhances calcium absorption. The increase in serum calcium results in an increase in calcium filtration at the kidney. Because of PTH-mediated absorption of calcium at the distal tubule, less calcium is excreted than might be expected. In PTH-mediated hypercalcemia, bones do not play an active role because most of the PTH-mediated osteoclast activity that breaks down bone is offset by hypercalcemic-induced bone deposition. Hypercalcemia of this disorder may remain mild for long periods because some parathyroid adenomas respond to the feedback generated by the elevated calcium levels.

Non–PTH-mediated hypercalcemia

Hypercalcemia associated with malignancy commonly is the result of multiple myeloma or breast or lung cancer and is caused by increased osteoclastic activity within the bone. Granulomatous disorders with high levels of calcitriol may be found in patients with sarcoidosis, berylliosis, tuberculosis, leprosy, coccidioidomycosis, and histoplasmosis. Iatrogenic disorders of calcium levels may increase secondary to the ingestion of many medications.

Frequency:

• In the US: Hypercalcemia is a fairly common metabolic emergency. Between 20 and 30% of patients with cancer develop hypercalcemia at some point in their disease (this may be decreasing with the use of bisphosphates, but data are lacking). Primary hyperparathyroidism occurs in 25 per 100,000 persons in the general population and in 75 per 100,000 hospitalized patients. This condition is the most common cause of mild hypercalcemia, which can be treated on an outpatient basis. In the US, more than 50,000 new cases occur each year.

Mortality/Morbidity:

• Prognosis of hypercalcemia associated with malignancy is poor; the 1-year survival rate is 10-30%. In one study, 50% of patients died within 30 days of beginning treatment; 75% died within 3 months.

Sex:

• The incidence of primary hyperparathyroidism is considerably higher in women. The annual incidence in women older than 65 years is 250 per 100,000.

• Elevations in calcium levels related to cancer have no sex predominance.

Age:

• The incidence of primary hyperparathyroidism increases with age.

• The rate of malignancy and, thus, of malignancy-associated hypercalcemia increases with age.

CLINICAL

Section 3 of 11

History:

• Symptoms of hypercalcemia depend on the underlying cause of the disease, the time over which it develops, and the overall physical health of the patient.

• Mild elevations in calcium levels usually have few or no symptoms.

• Increased calcium levels may cause the following:

• Nausea

• Vomiting

• Alterations of mental status

• Abdominal or flank pain (The workup of patients with a new kidney stone occasionally reveals an elevated calcium level.)

• Constipation

• Lethargy

• Depression

• Weakness and vague muscle/joint aches

• Polyuria

• Headache

• Severe elevations in calcium levels may cause coma.

• Elderly patients are more likely to be symptomatic from moderate elevations of calcium levels.

• Hypercalcemia of malignancy may lack many of the features commonly associated with hypercalcemia caused by hyperparathyroidism. In addition, the symptoms of elevated calcium level may overlap with the symptoms of the patient's malignancy.

• Hypercalcemia associated with renal calculi, joint complaints, and ulcer disease is more likely to be caused by hyperparathyroidism.

Physical: Hypercalcemia has few physical examination findings specific to its diagnosis.

• Often it is the symptoms or signs of underlying malignancy that bring the patient with hypercalcemia to seek medical attention.

• The primary malignancy may be suggested by lung findings, skin changes, lymphadenopathy, or liver or spleen enlargement.

• Hypercalcemia can produce a number of nonspecific findings, as follows:

• Hypertension and bradycardia may be noted in patients with hypercalcemia, but this is nonspecific.

• Abdominal examination may suggest pancreatitis or the possibility of an ulcer.

• Patients with long-standing elevation of serum calcium may have proximal muscle weakness that is more prominent in the lower extremities; they also may have bony tenderness to palpation.

• Hyperreflexia and tongue fasciculations may be present.

• Anorexia or nausea may occur.

• Polyuria and dehydration are common.

• Lethargy, stupor, or even coma may be observed.

• Long-standing hypercalcemia may cause band keratopathy, but this is rarely recognized in the ED.

• If hypercalcemia is caused by sarcoidosis, vitamin D intoxication, or hyperthyroidism, patients may have physical examination findings suggestive of those diseases.

Causes: Hypercalcemia is divided into PTH-mediated hypercalcemia (primary hyperparathyroidism) and non–PTH-mediated hypercalcemia.

• PTH-mediated hypercalcemia is related to increased calcium absorption from the intestine.

• Non–PTH-mediated hypercalcemia includes the following:

• Hypercalcemia associated with malignancy: Unlike PTH-mediated hypercalcemia, the elevation of calcium that results from malignancy generally worsens until therapy is provided. Hypercalcemia caused by malignancy is the result of increased osteoclastic activity within the bone. This results from one or both of the mechanisms that follow:
  • Extensive localized bone destruction may result from osteolytic metastasis of solid tumors. Evidence indicates that many malignant cells may release local osteoclastic activating factors.

  • Increased calcium levels resulting from malignancy caused by a PTH-related protein is a second mechanism. This protein is a humeral factor that acts on the skeleton to increase bone reabsorption; it acts 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 calcitriol may be found in patients with sarcoidosis and other granulomatous diseases. In these disorders, the increased level of calcitriol results from production within the macrophages, which constitute a large portion of some granulomas.

• Iatrogenic: In some cases, elevation of calcium is a known adverse effect of appropriate dosage. In other cases, large ingestions must be taken to induce the increase in calcium levels. Obtain a complete review of current medications for patients presenting with hypercalcemia. Record any vitamin use.

• Other causes of hypercalcemia

• Neoplasms (nonparathyroid) - Metastasis to the bone from breast, multiple myeloma, and hematologic malignancies (Breast cancer is one of the most common malignancies responsible for hypercalcemia.)

• Nonmetastatic (humoral-induced) - Ovary, kidney, lung, head and neck, esophagus, cervix, lymphoproliferative disease, multiple endocrine neoplasia, pheochromocytoma, and hepatoma

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

• Endocrinopathies (nonparathyroid) - Hyperthyroidism, adrenal insufficiency, and pheochromocytoma

• Familial hypocalciuric hypercalcemia

• Tertiary hyperparathyroidism - Postrenal transplant and initiation of chronic hemodialysis

• Miscellaneous - Immobilization, hypophosphatasia, primary infantile hyperparathyroidism, AIDS, and advanced chronic liver disease

DIFFERENTIALS

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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 disease
Inflammatory disorders
Rhabdomyolysis
Paget disease
Parenteral nutrition

WORKUP

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Lab Studies:

• Confirmatory tests: Changes in serum protein concentrations alter the total serum calcium level but do not affect the unbound fraction. Calcium level reported by the laboratory usually represents the bound and unbound calcium. When calcium levels are reported as high or low, the physician must be able to calculate the actual level of calcium. A common formula is as follows:
  Corrected total calcium (mg/dL) = (measured total calcium mg/dL) + 0.8 (4.4 - measured albumin g/dL)

  The average normal albumin level is 4.4. The reference range for corrected value of calcium is approximately 9-10.6 mg/dL.

• The corrected calcium value is useful in most situations, but individual variation can occur.

• If the corrected serum calcium level still is not accurate, it is possible to measure the free calcium ion activity (ie, ionized calcium level).

• Other nonspecific laboratory abnormalities commonly found in patients with hypercalcemia result from disordered renal function. Patients commonly have significant azotemia at presentation.

• Hypercalcemia may produce ECG abnormalities related to altered trans-membrane potentials that affect conduction time. QT interval shortening is common, and, in some cases, the PR interval is prolonged. At very high levels, the QRS interval may lengthen, T waves may flatten or invert, and a variable degree of heart block may develop. Digoxin effects are amplified.

• After a diagnosis of hypercalcemia is established, the next step is to determine the cause. Initial testing is directed at malignancy, hyperparathyroidism, and hyperthyroidism, the most common causes of hypercalcemia.

• The measurement of circulating PTH in the serum is the most direct and sensitive measure of parathyroid function. A reference range is 2-6 mol/L. A nonsuppressed PTH level in the presence of hypercalcemia suggests 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 (PTHrP) is thought to mediate the hypercalcemia that develops with many malignancies. Assays to measure this peptide are available.

• Measurement of calcitriol is difficult but can be accomplished. This laboratory value is useful in diagnosing hypercalcemia secondary to a granulomatous disease such as sarcoidosis.

• Other electrolytes also may be disturbed in hypercalcemia. Serum phosphate levels tend to be low or normal in primary hyperparathyroidism and hypercalcemia of malignancy. Phospate levels are elevated in hypercalcemia secondary to vitamin D–related disorders or thyrotoxicosis. Serum chloride levels usually are higher than 102 mEq/L in hyperparathyroidism and less than this value in other forms of hypercalcemia.

Imaging Studies:

• No imaging studies definitively diagnose hypercalcemia.

• Consider hypercalcemia in patients with multiple nonspecific complaints and an associated lung mass.

• If laboratory evidence of primary hyperparathyroidism is present, CT scan of the head, MRI, ultrasound, or nuclear parathyroid scans may be helpful. Preoperative diagnostic imaging is essential in patients with previous neck surgery.

TREATMENT

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Prehospital Care: Prehospital care is primarily supportive. If a patient has a history of hypercalcemia and displays evidence of acute hypercalcemia, immediately begin IV hydration.

Emergency Department Care: The treatment of hypercalcemia depends on the level, the chronicity, and the underlying cause of the problem. In mild-to-moderate elevations of calcium, few treatment options may be available in the ED. A physical evaluation to help delineate the source of the elevation is always appropriate, as is a subsequent timely follow-up visit.

• Initial goals of treatment
  • Stabilization and reduction of the calcium level

  • Adequate hydration

  • Increased urinary calcium excretion

  • Inhibition of osteoclast activity in the bone

  • Discontinuation of pharmacologic agents associated with hypercalcemia

  • Treatment of the underlying cause (when possible)

• The initial step in the care of severely hypercalcemic patients is hydration with saline. Hydration helps decrease the calcium level through dilution. The expansion of extracellular volume also increases the renal calcium clearance. The rate of fluid therapy is based upon the following:

• Degree of hypercalcemia

• Severity of dehydration

• Ability of the patient to tolerate rehydration - Vigilance to prevent volume overload is critical.

• Hydration is ineffective in patients with kidney failure because diuresis is impossible. Dialysis is necessary to correct hypercalcemia in patients with renal failure.

• Loop diuretics

• A loop diuretic (eg, furosemide) may be used with hydration to increase calcium excretion. This may also prevent volume overload during therapy.

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

• Bisphosphates - These agents will inhibit osteoclast activity for up to a month.

Consultations:

• A patient with renal failure who presents with severe elevations of calcium may require urgent dialysis. Consult a nephrologist immediately in this case.

• Patients with primary hyperparathyroidism may require surgery to eliminate the condition, but surgery usually does not need to be performed on an urgent basis.

• Patients with malignancy may require surgery, chemotherapy, or radiation treatment. Appropriate consultation should be undertaken.

MEDICATION

Section 7 of 11

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

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

Drug Name	Pamidronate (Aredia) -- Mechanism of action is inhibition of normal and abnormal bone resorption; appears to inhibit bone resorption without inhibiting bone formation and mineralization. Potent agent that has several regimens for administration. Adverse effects of IV administration include mild transient increases in temperature, leukopenia, and mild reduction in serum phosphate levels. PO maintenance therapy is available after acute event has resolved, but this therapy is experimental. With acute hypercalcemia, all of these agents are effective; pamidronate may be preferable because of its potency and efficacy.
Adult Dose	Moderate hypercalcemia: 60 mg IV infusion over 4 h initial; alternatively, 90 mg IV infusion over 24 h initial Severe hypercalcemia: 90 mg IV infusion over 24 h initial
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypocalcemia
Interactions	None reported
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; adequate intake of calcium and vitamin D is necessary to prevent severe hypocalcemia; caution when administering bisphosphonates in active upper GI problems; do not coadminister with alendronate for osteoporosis in postmenopausal women

Drug Name	Zoledronic acid (Zometa) -- Inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors. Median duration of complete response (maintaining normalized calcium levels) and time to relapse reported as 32 and 30 d, respectively. Indicated for hypercalcemia of malignancy.
Adult Dose	4 mg IV over at least 15 min once qmo; hydrate patient before infusion; may retreat following 7 d if desired response not observed
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Concurrent administration with loop diuretics may increase risk of hypocalcemia, nephrotoxic agents; valacyclovir levels may be increased
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal insufficiency; risk of renal deterioration increased with <15 min IV infusion; flulike syndrome (fever, arthralgias, myalgias, skeletal pain), gastrointestinal reactions, anemia, neutropenia, pancytopenia, insomnia, dyspnea, electrolyte and mineral disturbances, such as low serum phosphate, calcium, magnesium, and potassium may occur

Drug Name	Etidronate (Didronel) -- Reduces bone formation; does not appear to alter renal tubular reabsorption of calcium. Does not affect hypercalcemia in patients with hyperparathyroidism where increased calcium reabsorption may increase blood calcium levels. Response generally observed within first 48 h; more effective if patient is well hydrated before initial dose. If patient responds well before 7 d, therapy can be discontinued. Generally well tolerated; most common adverse effect is a transient elevation of serum creatinine and phosphorous. PO therapy is experimental and not always effective.
Adult Dose	7.5 mg/kg IV over 4 h for 3-7 d; dilute in at least 250 mL of sterile saline; use beyond 3 d may increase risk of hypocalcemia; full initial doses may be used in repeat dosing situations if etidronate has not been used in previous 7 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypocalcemia, renal impairment
Interactions	Coadministration with calcium-containing products and other multivalent cations decrease absorption
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium and potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution in active upper GI problems; do not administer with alendronate for osteoporosis in postmenopausal women

Drug Category: Antidote, hypercalcemia -- Inhibit RNA synthesis in osteoclasts and effective in treatment of hypercalcemia.

Drug Name	Plicamycin (Mithramycin) -- Inhibits cellular RNA and enzymatic RNA synthesis; possibly blocks hypercalcemic action of pharmacologic doses of vitamin D. May act on osteoclasts or block action of parathyroid hormone. Effect in lowering calcium is unrelated to tumoricidal activity. Effects last from several days to several weeks. Several adverse effects may limit use as other drugs become available.
Adult Dose	25 mcg/kg IV over 4-6 h; repeat q24-48h prn for 3-4 d; dose may be repeated at 1-wk (or more) intervals prn until satisfactory response is obtained
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; thrombocytopenia, coagulation disorders, impairment of bone marrow function
Interactions	Coadministration with glucagon, calcitonin, and etidronate, may increase toxicity
Pregnancy	X - Contraindicated in pregnancy
Precautions	Monitor platelets, prothrombin, and bleeding times periodically during therapy and for several days after last dose; discontinue therapy if significant prolongation of bleeding times occurs and thrombocytopenia is observed; correct any electrolyte imbalance (especially hypokalemia, hypocalcemia, and hypophosphatemia) before treatment

Drug Name	Calcitonin (Miacalcin, Cibacalcin, Calcimar) -- A naturally occurring hormone that inhibits bone reabsorption and increases excretion of calcium. Most rapid onset of action of anticalcemic agents. Effects may be observed within a few hours with peak response at 12-24 h; because of short duration of action, other more potent but slower-acting agents should be started in patients with severe hypercalcemia. Salmon calcitonin is used most often and is more potent than human calcitonin. Action of this agent is short-lived. If elevation of calcium is severe, coadminister 1-2 doses with fluids and Lasix to provide a rapid, although limited, reduction of the calcium level.
Adult Dose	2-8 U/kg IM/SC q6-12h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypocalcemia may occur; examine urine sediment during prolonged therapy

Drug Name	Gallium nitrate (Ganite) -- Works by inhibiting bone reabsorption and altering structure of bone crystals. Exerts hypocalcemic effect, possibly by reducing bone resorption; performs well against other anticalcium agents but has slow onset of action.
Adult Dose	Severe hypercalcemia: 200 mg/m2/d IV for 5 d in 1 L of NS or D5W Mild hypercalcemia: 100 mg/m2/d IV for 5 d in 1 L of NS or D5W
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; renal failure
Interactions	Nephrotoxic effects increase when administered with amphotericin B or aminoglycosides
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal failure

Drug Category: Phosphate salts -- Use of IV phosphate is very effective in lowering serum calcium levels most likely because of a precipitation phenomenon. Significant risk exists with use of this agent. This agent is reserved for hypercalcemia unresponsive to other agents.

Drug Name	Potassium phosphate -- 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	Initial: 8 mmol IV q6h (32 mmol/24 h) Aggressive: 15 mmol IV over 6 h
Pediatric Dose	0.25-0.5 mmol/kg IV over 4-6 h; repeat prn
Contraindications	Documented hypersensitivity; hyperphosphatemia, hypocalcemia, hypomagnesemia, hyperkalemia, renal failure
Interactions	Magnesium and aluminum-containing antacids or sucralfate can act as phosphate binders and decrease serum phosphate levels; potassium-sparing diuretics, ACE inhibitors, and salt substitutes may increase serum phosphate levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with renal insufficiency, and metabolic alkalosis; admixture of phosphate and calcium in IV fluids can result in calcium phosphate precipitation

Drug Category: Corticosteroids -- While these agents do not treat hypercalcemia directly, they are useful for treating hypercalcemia caused by vitamin D toxicity, certain malignancies (eg, multiple myeloma, lymphoma), sarcoidosis, and other granulomatous diseases. These agents generally are not effective in patients with solid tumors or primary hyperparathyroidism. Several different glucocorticoids may be used.

Drug Name	Hydrocortisone (Cortef) -- Mineralocorticoid activity and glucocorticoid effects; onset of activity is rapid. Significant number of adverse reactions for those on long-term steroids. In acute phase, few severe reactions present.
Adult Dose	200-300 mg IV for 3 d
Pediatric Dose	10 mg/kg/d IV divided qid
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis

Drug Category: Calcimimetic agent -- Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.

Drug Name	Cinacalcet (Sensipar) -- Directly lowers parathyroid hormone (PTH) levels by increasing sensitivity of calcium sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for hypercalcemia with parathyroid carcinoma.
Adult Dose	30 mg PO qd initially; titrate q2-4wk as needed to normalize calcium levels by sequential doses of 30 mg bid, 60 mg bid, 90 mg bid, and 90 mg tid/qid Take with meals or immediately following; do not crush, chew, or cut tabs
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Strong CYP2D6 inhibitor; may increase serum levels of CYP2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole) may decrease cinacalcet clearance
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2mo (parathyroid carcinoma); do not initiate treatment if serum calcium below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Serum calcium level generally responds to fluids and Lasix; however, this therapy has no effect on the principle pathologic process causing hypercalcemia. 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 who present with symptoms of severe or moderate elevations of calcium levels should be referred for parathyroidectomy. This referral may be urgent, depending on the severity of the hypercalcemia.

• Patients with mild-to-moderate elevations of calcium who have no symptoms may be evaluated on an outpatient basis and usually are treated medically. For those patients with malignancy as the cause of their hypercalcemia, a cure may not be possible.

• The ideal scenario finds a treatable underlying cause for hypercalcemia and allows the physician to attend to 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 usually is not managed by the ED physician.

• Patients may require ongoing treatment for calcium elevation.

• This type of treatment can be frustrating and difficult, and it 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. Consider transfer if this is unavailable at the initial treatment center.

• If no intensivist or physician familiar with the inpatient treatment of hypercalcemia is available, consider transferring patients with normal kidney function who are being treated for severe hypercalcemia.

Deterrence/Prevention:

• Avoid prolonged bedrest for patients known to have rapid bone turnover.

• Consider elective surgical procedures for patients with Paget disease after therapy has been initiated for calcium elevation. Mobilize patients as quickly as possible to minimize bone loss.

• Worsening hypercalcemia is common in patients with known metastatic disease who are too ill to ambulate. This should be anticipated and treated before the patient becomes symptomatic.

• Patients at risk for hypercalcemia should have scheduled appointments with ongoing evaluation to monitor for development or progression of the disease.

• Avoid salt restriction, diuretics, and other causes of volume depletion and dehydration in patients with active or potential hypercalcemia.

Prognosis:

• The prognosis of patients with hypercalcemia depends upon the etiology of the elevation.

• Prognosis is very poor with malignancy that has progressed into development of hypercalcemia.

• Prognosis is excellent when the underlying cause is treatable and treatment is initiated promptly.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to consider hypercalcemia in differential diagnosis of a patient with vague nonspecific complaints may result in delay of diagnosis.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A 73-year-old woman with a history of metastatic breast cancer presents with lethargy, vomiting, hypotension, and tachycardia. The ED physician suspects that she has acute hypercalcemia. Which of the following ECG abnormalities is most likely to be found?

A: QRS interval shortening
B: QT interval prolongation
C: QT interval shortening
D: Peaked T waves
E: None of the above

The correct answer is C: Elevations of calcium cause QT interval shortening. In some cases, the PR interval is prolonged. At very high levels, the QRS interval may lengthen, T waves may flatten or invert, and various degrees of heart blockage may develop. Digoxin effects are amplified.

CME Question 2: A 73-year-old woman with a history of metastatic breast cancer presents with lethargy, vomiting, hypotension, and tachycardia. The ED physician suspects that she has acute hypercalcemia. Which of the following interventions is indicated as a first-line therapy?

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

The correct answer is C: The initial step in care of severely hypercalcemic patients is hydration with saline. Hydration helps decrease the calcium level. Expansion of the extracellular volume also increases renal calcium clearance. This therapy is ineffective in patients with kidney failure, and first-line therapy in this group usually is dialysis. The rate of fluid therapy is based upon the degree of hypercalcium, severity of dehydration, and ability of the patient to tolerate rehydration.

Pearl Question 1 (T/F): Malignancy is one of the most common causes of hypercalcemia.

The correct answer is True: Malignancy and primary hyperparathyroidism are the 2 most common causes of hypercalcemia. Other causes of elevated calcium are less common and usually are not considered until after malignancy and parathyroid disease have been ruled out.

Pearl Question 2 (T/F): Fluid restriction is the most important initial intervention for the patient with severe hypercalcemia.

The correct answer is False: The opposite is true; increased hydration is an important initial intervention for these patients.

Pearl Question 3 (T/F): Any diuretic can be administered to patients with hypercalcemia.

The correct answer is False: Loop diuretics increase calcium excretion, but thiazide diuretics must be avoided because they increase the reabsorption and retention of calcium.

Pearl Question 4 (T/F): Breast cancer is one of the most common malignancies responsible for hypercalcemia.

The correct answer is True: Breast, lung, and kidney malignancies are all associated with hypercalcemia.

BIBLIOGRAPHY

Section 11 of 11

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