What is the recommended treatment for a patient with severe hypercalcemia (serum calcium ≥14 mg/dL or symptomatic)?

Treatment of Severe Hypercalcemia

For severe hypercalcemia (serum calcium ≥14 mg/dL or symptomatic), immediately initiate aggressive intravenous normal saline hydration targeting urine output of 100-150 mL/hour, followed by intravenous zoledronic acid 4 mg infused over at least 15 minutes as first-line definitive therapy. 1, 2

Immediate Management Algorithm

Step 1: Aggressive Hydration (Start Immediately)

• Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis, targeting urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 2
• Continue hydration to maintain diuresis >2.5 L/day in adults while waiting for bisphosphonates to take effect 2
• Avoid loop diuretics (furosemide) until complete volume repletion is achieved—premature use worsens dehydration and can aggravate hypercalcemia 2
• Only add loop diuretics after volume restoration in patients with cardiac or renal insufficiency to prevent fluid overload 1, 2

Step 2: Bisphosphonate Therapy (Initiate Early, Do Not Delay)

Zoledronic acid is superior to pamidronate and should be the preferred agent: 1, 2, 3

• Zoledronic acid 4 mg IV infused over ≥15 minutes normalizes calcium in approximately 50% of patients by day 4 1, 2
• Do not wait for complete rehydration—bisphosphonates can be initiated early to expedite calcium reduction 2
• Dose adjustments required for creatinine clearance <60 mL/min 2
• Measure serum creatinine before each dose; withhold if renal function deteriorates (increase >0.5 mg/dL from normal baseline or >1.0 mg/dL from abnormal baseline) 2, 4

Alternative: Pamidronate (if zoledronic acid unavailable): 4, 3

• Severe hypercalcemia (corrected calcium >13.5 mg/dL): 90 mg IV over 2-24 hours 4
• Moderate hypercalcemia (corrected calcium 12-13.5 mg/dL): 60-90 mg IV over 2-24 hours 4
• Longer infusions (>2 hours) reduce risk of renal toxicity, particularly in patients with preexisting renal insufficiency 4

Step 3: Adjunctive Calcitonin (For Rapid Effect)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid onset within hours but has limited efficacy 2, 5
• Use as a bridge until bisphosphonates take effect (which require 2-4 days) 1, 2
• Tachyphylaxis limits sustained benefit 6

Etiology-Specific Considerations

Malignancy-Associated Hypercalcemia

• Median survival approximately 1 month after detection 1
• Do not delay malignancy work-up—imaging and oncology consultation should proceed simultaneously with calcium-lowering measures 1
• Obtain comprehensive imaging: chest CT, abdominal/pelvic CT or MRI, and PET-CT when available 1
• Most common PTHrP-secreting tumors: squamous cell carcinoma of lung, head-and-neck squamous carcinoma, renal cell carcinoma, breast carcinoma 1

Granulomatous Disease or Vitamin D-Mediated Hypercalcemia

• Glucocorticoids are first-line therapy for hypercalcemia due to excessive intestinal calcium absorption 1, 2, 3
• Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 2
• Effective in sarcoidosis, some lymphomas, vitamin D intoxication, and multiple myeloma 1, 2

Primary Hyperparathyroidism

• Parathyroidectomy is definitive therapy for severe hyperparathyroidism (persistent PTH >800 pg/mL) associated with hypercalcemia refractory to medical therapy 7
• Post-operative monitoring: measure ionized calcium every 4-6 hours for first 48-72 hours to detect "hungry bone syndrome" 7, 1
• If ionized calcium drops below 0.9 mmol/L (≈3.6 mg/dL), initiate IV calcium gluconate infusion at 1-2 mg elemental calcium/kg/hour 7, 1

Renal Failure or Impaired Renal Function

Denosumab is preferred over bisphosphonates in patients with significant renal impairment: 2, 3

• Denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days for bisphosphonate-refractory hypercalcemia 2
• Lower rates of renal toxicity compared to bisphosphonates but higher risk of hypocalcemia—provide calcium/vitamin D supplementation 2
• Dialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1, 2, 5

Critical Monitoring Parameters

Acute Phase (First 48-72 Hours)

• Ionized calcium every 4-6 hours, then twice daily until stable 1, 2
• Serum calcium, phosphorus, potassium, magnesium every 6-12 hours 1, 2
• Serum creatinine and BUN to assess renal function 2
• 12-lead ECG to identify shortened QT interval and arrhythmias 2
• Fluid status monitoring (daily weights, intake/output) to prevent volume overload 2

Target Goals

• Corrected calcium 8.4-9.5 mg/dL, preferably at the lower end of this range 1, 2
• Calcium-phosphorus product <55 mg²/dL² to prevent soft tissue calcification 2
• Urine output maintained at 100-150 mL/hour during acute management 1, 2

Critical Pitfalls to Avoid

• Never use loop diuretics before complete volume repletion—this worsens dehydration and hypercalcemia 2
• Avoid nephrotoxic agents (NSAIDs, iodinated contrast, aminoglycosides) in hypercalcemia-induced renal impairment 2
• Do not delay bisphosphonate therapy—temporary measures like calcitonin provide only 1-4 hours of benefit with rebound hypercalcemia 2
• Discontinue all calcium supplements, vitamin D, and thiazide diuretics immediately 1, 2
• Correct hypocalcemia before initiating bisphosphonate therapy and monitor closely, especially with denosumab 2
• Measure serum creatinine before each bisphosphonate dose; withhold if renal deterioration occurs 2, 4

Medications to Stop Immediately

• All calcium-based phosphate binders 2
• All vitamin D supplements (cholecalciferol, ergocalciferol, calcitriol, paricalcitol) 1, 2
• Thiazide diuretics 2
• Lithium (if applicable) 2

When to Consider Parathyroidectomy

Surgical referral is indicated for: 7, 1

• Persistent PTH >800 pg/mL with hypercalcemia and/or hyperphosphatemia refractory to medical therapy 7
• Tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism despite optimized medical therapy) 2
• Effective surgical options: subtotal parathyroidectomy or total parathyroidectomy with autotransplantation 7