What is the treatment for severe hypercalcemia in a hospital setting?

Treatment of Severe Hypercalcemia (Calcium 13.2 mg/dL) in the Hospital

Immediately initiate aggressive IV normal saline hydration targeting urine output of 100-150 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes. 1, 2

Immediate Management Algorithm

1. Aggressive Hydration (First-Line, Start Immediately)

• Administer IV normal saline to restore extracellular volume and promote calciuresis, targeting urine output of approximately 2 L/day (100-150 mL/hour). 1, 2
• Vigorous saline hydration is an integral part of hypercalcemia therapy and should be initiated promptly. 2
• Monitor fluid status carefully to avoid volume overload, especially in patients with cardiac or renal insufficiency. 1, 2
• Loop diuretics (furosemide) should only be used after adequate volume repletion has been achieved, not before correction of hypovolemia. 1, 2

2. Bisphosphonate Therapy (Definitive Treatment)

• Administer zoledronic acid 4 mg IV infused over no less than 15 minutes as the preferred bisphosphonate. 1, 2, 3
• Zoledronic acid is superior to pamidronate for hypercalcemia treatment and is the drug of choice. 1, 4
• Check serum creatinine before administration; if creatinine clearance is >60 mL/min, give full 4 mg dose. 2
• For reduced renal function (CrCl 30-60 mL/min), dose-reduce according to FDA guidelines: CrCl 50-60 = 3.5 mg; CrCl 40-49 = 3.3 mg; CrCl 30-39 = 3.0 mg. 2
• Do not use zoledronic acid if serum creatinine >4.5 mg/dL or severe renal impairment is present. 2
• The bisphosphonate effect takes 2-4 days to achieve maximum calcium reduction. 3, 5

3. Bridge Therapy with Calcitonin (If Symptomatic)

• If the patient is symptomatic (confusion, nausea, vomiting), add calcitonin 4 IU/kg subcutaneously or intramuscularly every 12 hours for rapid onset of action within 4-6 hours. 1, 3, 5
• Calcitonin provides only modest calcium reduction (1-2 mg/dL) and tachyphylaxis develops within 48 hours, but it bridges the gap until bisphosphonates take effect. 3, 5
• Calcitonin should not be used as monotherapy but combined with bisphosphonates. 5, 6

Diagnostic Workup (Concurrent with Treatment)

While initiating treatment, obtain the following tests to determine the underlying cause: 1, 3

• Intact parathyroid hormone (PTH): Elevated or normal PTH suggests primary hyperparathyroidism; suppressed PTH (<20 pg/mL) indicates malignancy or other causes. 1, 3
• PTH-related protein (PTHrP) if PTH is suppressed, to identify humoral hypercalcemia of malignancy. 1, 3
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to assess for vitamin D intoxication or granulomatous disease. 1
• Serum albumin, phosphorus, magnesium, creatinine, and BUN to assess renal function and electrolyte status. 1, 2
• Assess for malignancy if PTH is suppressed, as hypercalcemia of malignancy carries poor prognosis with median survival of approximately 1 month. 1

Special Considerations Based on Etiology

If Malignancy-Related Hypercalcemia

• Treat the underlying cancer when possible, as this is essential for long-term control. 1, 7
• Consider adding corticosteroids (prednisone 40-60 mg daily) if hypercalcemia is due to lymphoma, multiple myeloma, or excessive intestinal calcium absorption. 1, 3, 5
• For multiple myeloma specifically, use hydration plus zoledronic acid 4 mg IV every 3-4 weeks, and consider continuing bisphosphonate therapy for up to 2 years. 1

If Severe Renal Impairment or Renal Failure

• Consider hemodialysis with calcium-free or low-calcium dialysate for severe hypercalcemia (calcium >14 mg/dL) complicated by renal insufficiency or oliguria. 1, 5
• Hemodialysis effectively removes calcium through diffusive therapy when bisphosphonates cannot be used. 1, 5
• Denosumab may be considered in patients with renal failure who cannot receive bisphosphonates, though it carries higher risk of hypocalcemia. 3

Monitoring and Follow-Up

• Monitor serum calcium, creatinine, phosphorus, magnesium, and potassium daily until calcium normalizes. 1, 7, 2
• Assess for ECG changes, particularly QT interval prolongation, in patients with severe hypercalcemia. 1
• If serum calcium does not normalize or remains elevated after 7 days, consider retreatment with zoledronic acid 4 mg, ensuring creatinine has returned to within 10% of baseline. 2
• Supplement with oral calcium 500 mg plus vitamin D 400 IU daily after calcium normalizes to prevent rebound hypocalcemia, especially after bisphosphonate therapy. 1, 2

Critical Pitfalls to Avoid

• Never use loop diuretics before adequate volume repletion, as this worsens hypovolemia and hypercalcemia. 2
• Never infuse zoledronic acid faster than 15 minutes or exceed 4 mg single dose, as this significantly increases risk of renal failure. 2
• Avoid nephrotoxic medications (NSAIDs, IV contrast) during treatment to prevent worsening renal function. 1
• Do not restrict calcium intake excessively, as this can worsen bone disease without improving hypercalcemia. 1
• Monitor for osteonecrosis of the jaw (ONJ) risk with bisphosphonates; avoid invasive dental procedures during treatment. 2