Sarah Klemencic, MD; Jack Perkins, MD


Western J Emerg Med. 2019;20(2):316-322. 

In This Article

Hypercalcemia of Malignancy

Hypercalcemia is seen in 10–30% of patients with malignancy and is most commonly associated with breast cancer, lung cancer, non-Hodgkin's lymphoma and multiple myeloma, although it may be seen with any malignancy.[48–55] Twenty percent of malignancy-related hypercalcemia is secondary to bony metastases, and it should be noted that the incidence of hypercalcemia increases with advanced disease and portends a poor prognosis.[50] Multiple pathways lead to hypercalcemia of malignancy; however 80% can be attributed to parathyroid-related protein (PTHrP) activity.[51] PTHrP increases bone resorption via osteoclast activity and enhances calcium resorption in the renal tubule.[51] Importantly, an EP should consider malignancy in any patient (without a known diagnosis of malignancy) presenting with hypercalcemia of unclear etiology.[48–50] In these patients, the likelihood of an underlying malignancy rises in direct correlation to the degree of hypercalcemia.[48] Importantly, symptoms are related to the rate of rise of serum calcium and are not solely based on the absolute value.[51]

The symptoms of hypercalcemia are vague and often reflect symptoms associated with significant volume depletion due to the osmotic diuresis associated with hypercalcemia.[51] The most common symptoms are anorexia, nausea, vomiting and constipation, but may include malaise, polyuria, polydipsia, lethargy, confusion, and even coma.[48–52] Laboratory analysis should include both a total calcium and ionized calcium level when possible. If ionized calcium values are unavailable, a corrected calcium value can be calculated as follows: Corrected calcium level = measured calcium level + (0.8 x [4.0 - serum albumin level {g/dl}]) The EP should also send a full CMP, CBC, a magnesium level, and phosphate level. Parathyroid and PTHrP testing are useful for the oncologist, but are not indicated in the emergent setting.[52–55] An ECG may show prolonged PR, widened QRS, shortened QT, and ventricular dysrhythmias.[52–55] Immediate treatment for calcium levels below 12 mg/dl can be deferred. Patients with moderate hypercalcemia with levels of 12–14 mg/dl should be treated based on clinical judgment and symptom control as these levels may have been reached either acutely or subacutely and may even be well tolerated. Nonetheless, any patient with a serum value >14mg/dl is generally symptomatic and should receive an intervention to lower the level.[52,55] Cardiac arrest may occur with levels >15 mg/dl.[49]

Initial emergent management of hypercalcemia involves aggressive IVF administration with an initial bolus of 1000-2000 ml of isotonic fluid followed by an infusion rate of 200–300 ml/hr (milliliters per hour) to achieve urine output of 100–150 ml/hr.[49,52–55] Loop diuretics will decrease serum calcium levels, and studies have shown high doses are required to be effective; therefore, use should only be considered in the euvolemic patient or those with concurrent volume overload.[49,52–55] Bisphosphonates lower calcium levels by inhibiting osteoclasts and stabilize the bone matrix by binding to calcium phosphate. These medications are renally excreted, and the dose will need to be adjusted based on renal function.[49] Complications may include self-limited infusion-related fever or AKI.[49] Calcitonin decreases bone resorption and enhances urinary excretion of calcium and may be employed via intramuscular or IV route.[52–54] The effects are rapid though transient with poor efficacy; therefore, utilization should be considered in adjunct with bisphosphonates when rapid reduction of serum calcium is required.[49]

Glucocorticoids are most effective in patients with Hodgkin's or non-Hodgkin's lymphoma or any malignancy that overproduces calcitriol.[52–53] Glucocorticoids inhibit conversion of 25-hydroxyvitamin D to calcitriol, decreasing gut absorption and renal reabsorption of calcium. These medications have slow onset of action and dosing is uncertain, though a recommended dose is IV hydrocortisone 200–300 mg/day.[52–54] Hemodialysis is reserved for those patients with oliguric renal failure.[52–54] Most patients who have mild symptoms, or are asymptomatic with a serum calcium < 14 mg/dl, are good candidates for outpatient management after discussion with their oncologist.[49,54] Patients in the moderate or severe range of hypercalcemia should be considered for monitored or ICU admission depending on presentation, labs and clinical judgment. Finally, given the significant mortality associated with this presentation, it is important to establish goals of care with the patient and his or her oncologist.