ED Management of Hypercalcemia of Malignancy

ED Management of Hypercalcemia of Malignancy

Hypercalcemia in the ED is often times an incidental finding. The clinical presentation, management and treatment of hypercalcemia as it specifically relates to malignancy will be discussed here.

Workup of hypercalcemia

When considering the diagnosis of hypercalcemia, it is important to understand calcium’s distribution in the body. Approximately 50% of calcium is protein bound, primarily to albumin. The remaining 50% of calcium is ionized which is its physiologic form. Ionized calcium should is traditionally obtained from a shock panel.

As calcium is bound to albumin, patients who are hypoalbuminemic will have falsely low calcium value. It is important to correct for low albumin levels with the following equation:

Corrected Calcium = (0.8 * (Normal Albumin – Pt’s Albumin)) + Serum Ca

It is also important to check for potassium, phosphorus, creatinine (to gauge renal function), alkaline phosphatase (to help identify bony invasion) and magnesium.

Obtain an ECG and look for manifestations of hypercalcemia:

Shortened PR interval
Shortened QT

Clinical Presentation of hypercalcemia

Patients can present in a wide variety of ways including but not limited to:

Lethargy
Altered mental status
Nausea/vomiting
Abdominal pain
Constipation
Weakness and vague joint pains

Differential Diagnosis of hypercalcemia

The differential diagnosis can be divided into three categories:

Medications
- Thiazide diuretics
- Calcitriol
- Lithium
- Estrogen
- Theophylline
Endocrine
- Hyperparathyroidism
- Hyperthyroidism
- Myxedema Crisis
- Adrenal Insufficiency
- Pheochromocytoma
Other
- Malignancy
- Granulomatous disease
- Paget’s disease
- Familial hypocalciuric hypercalcemia

Pathophysiology of hypercalcemia of malignancy

Five to 25% of patients with malignancy will have hypercalcemia (3), and approximately 1/3 of all patients who present to the ED with hypercalcemia will be related to malignancy (1). Hypercalcemia of malignancy typically occurs in advanced stages of malignancy.

Hypercalcemia in the setting of malignancy occurs by two mechanisms (2).

Tumor secretion of a humoral factor also known as humoral hypercalcemia of malignancy (HHM) – The humoral factor is usually Parathyroid hormone-related protein (PTHrP) which like its similar protein, Parathyroid Hormone (PTH), increases bone resorption and enhances active calcium resorption in the renal tubules. PTHrP secretion is most commonly associated with squamous cell carcinomas (eg. Non-small cell lung cancers, breast and renal carcinomas). Approximately 80% of patients with solid tumors and hypercalcemia have elevated markers reflecting activation of PTH receptors.
Excessive bone metastasis caused by local osteolytic bone resorption that releases calcium into the blood stream

Treatment (4)

The treatment of hypercalcemia of malignancy in the ED is through the use of anti-hypercalcemia therapy. It has no effect on overall survival but should be viewed as a temporizing measure until definitive therapy for malignancy can be instituted.
Treatment in the ED consists primarily of saline diuresis through fluid hydration to reverse dehydration that was induced by hypercalcemia and increase urinary calcium excretion. Consider normal saline at a rate of 200-300 mL/hr and adjust to adequate urine output.
After adequate volume repletion, consider a loop diuretic (ie furosemide) together with continued hydration to increase calcium excretion. Avoid thiazide diuretics as they decrease urinary calcium excretion.
Bisphosphonates can be considered in the ED but they take 48-72 hours before reaching full therapeutic effect thus limiting their benefit in acute management. Bisphosphonates (ie pamidronate, zoledronic acid, etidronate) work by preventing osteoclast attachment to the bone matrix and interfere with osteoclast recruitment. Pamidronate and zoledronate are the only two bisphosphonates approved by the FDA for hypercalcemia of malignancy. Major et al conducted a randomized, double-blind trial comparing the safety and efficacy of zoledronic acid and pamidronate for the treatment of hypercalcemia in malignancy. 275 patients with confirmed cancer and a baseline calcium >12mg/dL were randomized to receive either zoledronic acid (4 or 8mg) or pamidronate (90mg) while concurrently receiving IV hydration. They found that zoledronic acid (either dose) administered as a single 5 minute IV infusion was superior to 90mg of pamidronate for normalizing the corrected serum calcium levels (2).
Calcitonin works by inhibiting bone reabsorption and increases urinary excretion of calcium. Given its negligible toxicity and peak effect in hours, it is a therapy that can also be used as a temporizing measure in the ED before bisphosphonates take effect (or are initiated as part of inpatient management).
If patient has known lymphoma – consider giving steroids to decrease calcitriol production.
One should avoid administrating phosphorus as it may precipitate into calcium phosphate crystals.

Take home points:

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Lee CT, Yang CC, Lam KK, Kung CT, Tsai CJ, Chen HC. Hypercalcemia in the emergency department. Am J Med Sci. 2006;331(3):119-123.
Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558-567.
Strewler GJ, Nissenson RA. Hypercalcemia in malignancy. Western Journal of Medicine. 1990;153(6):635-640.
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