In hypercalcemia of sufficient severity to produce symptoms, rapid reduction of serum calcium is required. The first steps include rehydration with saline and diuresis with furosemide, although the efficacy of furosemide in this setting has not been proved. Most patients presenting with severe hypercalcemia have a substantial component of prerenal azotemia owing to dehydration, which prevents the kidney from compensating for the rise in serum calcium by excreting more calcium in the urine. Therefore, the initial infusion of 500–1000 mL/h of saline to reverse the dehydration and restore urine flow can by itself substantially lower serum calcium. The addition of a loop diuretic such as furosemide following rehydration enhances urine flow and also inhibits calcium reabsorption in the ascending limb of the loop of Henle (see Chapter 15). Monitoring of central venous pressure is important to forestall the development of heart failure and pulmonary edema in predisposed subjects. In many subjects, saline diuresis suffices to reduce serum calcium to a point at which more definitive diagnosis and treatment of the underlying condition can be achieved. If this is not the case or if more prolonged medical treatment of hypercalcemia is required, the following agents are available (discussed in order of preference).
Pamidronate, 60–90 mg, infused over 2–4 hours, and zoledronate, 4 mg, infused over at least 15 minutes, have been approved for the treatment of hypercalcemia of malignancy and have largely replaced the less effective etidronate for this indication. The bisphosphonate effects generally persist for weeks, but treatment can be repeated after a 7-day interval if necessary and if renal function is not impaired. Some patients experience a self-limited flu-like syndrome after the initial infusion, but subsequent infusions generally do not have this side effect. Repeated doses of these drugs have been linked to renal deterioration and osteonecrosis of the jaw, but this adverse effect is rare.
Calcitonin has proved useful as ancillary treatment in some patients. Calcitonin by itself seldom restores serum calcium to normal, and refractoriness frequently develops. However, its lack of toxicity permits frequent administration at high doses (200 MRC units or more). An effect on serum calcium is observed within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon calcitonin) is available for parenteral and nasal administration.
Gallium nitrate is approved by the FDA for the management of hypercalcemia of malignancy. This drug inhibits bone resorption. At a dosage of 200 mg/m2 body surface area per day given as a continuous intravenous infusion in 5% dextrose for 5 days, gallium nitrate proved superior to calcitonin in reducing serum calcium in cancer patients. Because of potential nephrotoxicity, patients should be well hydrated and have good renal output before starting the infusion.