General Medical Information

Hypercalcemic Crisis

Jeffrey D. Bunn
Amy R. Coffey
George H. Petti, Jr.

Severe hypercalcemia, or hypercalcemic crisis, predominantly occurs in patients with advanced previously diagnosed malignancy. Serum calcium levels are typically elevated at least to 3.5 mmol/L (14 mg/dL); however, symptom severity also correlates with the rapidity of the calcium elevation. Ionized calcium levels are preferred for diagnosis and follow-up, as this is the physiologically active fraction. Clinical findings in emergent cases include hypovolemia, mental status changes, and gastrointestinal symptoms. Cardiac arrhythmias and renal dysfunction may also complicate the initial course.

Two separate mechanisms for malignancy-associated hypercalcemia are currently accepted. First, many solid tumors secrete a PTH-related protein (PTHrP) that has similar activity to PTH, although its production is unregulated. Squamous cell carcinoma of the lung, head and neck, cervix, esophagus, vulva, and skin, in addition to breast cancer, renal cell, and bladder cancer, are most commonly found to secrete PTHrP. Second, metastatic and hematogenous tumors produce local intercellular mediators that stimulate osteoclast activity. These cytokines (tumor necrosis factor beta, interleukin-6, etc.), once secreted by the tumor cells, act on the local osteoclast population to mediate bone resorption and calcium liberation.

Regardless of the underlying etiology, acute symptomatic hypercalcemia requires aggressive treatment. Initial efforts focus on rehydration. Volume contraction is universal and results from the osmotic diuresis and decreased glomerular filtration rate, which accompany uncontrolled hypercalcemia. Fluid replacement with isotonic saline should be started at 2 to 4 L/day. The use of loop diuretics to stimulate calciuresis is not performed routinely. Bisphosphonates (e.g., pamidronate) are osteoclast inhibitors and are considered first-line therapies for hypercalcemic crisis. Volume expansion and bisphosphonate therapy can normalize most patients’ serum levels. However, the rate of response with the bisphosphonates is 3 to 6 days for calcium normalization. In the critically ill patient, a more rapid response is desired. Calcitonin reduces calcium levels within hours by direct osteoclast inhibition, and its ability enhances renal calcium excretion. Its main drawback is its short-lived effectiveness. Gallium nitrate and plicamycin are no longer considered first-line therapy because the bisphosphonates have significantly better toxicity profiles. Glucocorticoids and dialysis are indicated in specific circumstances.