What is the best treatment approach for a patient presenting to the Emergency Department (ED) with hypercalcemia?

Treatment of Hypercalcemia in the Emergency Department

Initiate aggressive IV normal saline hydration immediately (targeting urine output 100-150 mL/hour) followed by IV zoledronic acid 4 mg infused over at least 15 minutes for moderate to severe hypercalcemia, as this combination represents the cornerstone of ED management. 1

Immediate Assessment and Severity Classification

• Measure ionized calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1
• Classify severity: mild (<12 mg/dL), moderate (12-13.5 mg/dL), or severe (>13.5 mg/dL or >14 mg/dL) 2, 3
• Obtain ECG to assess for QT interval prolongation, which indicates cardiac involvement requiring urgent intervention 1
• Evaluate for symptoms: polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, dehydration, altered mental status, or coma 1, 3

Initial Diagnostic Workup

• Check intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, phosphorus, magnesium, creatinine, and BUN 1
• Calculate corrected calcium: Total calcium (mg/dL) + 0.8 × [4.0 - Serum albumin (g/dL)] 1, 2
• Suppressed PTH (<20 pg/mL) indicates malignancy, granulomatous disease, or medication-induced hypercalcemia rather than primary hyperparathyroidism 3

Treatment Algorithm by Severity

Mild Hypercalcemia (<12 mg/dL, Asymptomatic)

• IV normal saline hydration alone may be sufficient 2, 3
• Avoid overhydration in patients with cardiac failure 2
• Identify and eliminate contributing medications: thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day) 1
• Consider observation without acute pharmacologic intervention if patient is asymptomatic 3

Moderate Hypercalcemia (12-13.5 mg/dL)

• Administer IV pamidronate 60-90 mg as a single dose infused over 2-24 hours, with longer infusions (>2 hours) preferred to reduce renal toxicity 2
• Alternatively, use zoledronic acid 4 mg IV over at least 15 minutes, which normalizes calcium in 50% of patients by day 4 and is superior to pamidronate 1
• Maintain aggressive hydration targeting urine output 100-150 mL/hour throughout treatment 1
• Add calcitonin 100 IU subcutaneously or intramuscularly every 12 hours for rapid onset (within hours) while waiting for bisphosphonates to take effect 1, 3

Severe Hypercalcemia (>13.5 mg/dL or Symptomatic)

• Administer IV pamidronate 90 mg as a single dose infused over 2-24 hours, with longer infusions strongly recommended for renal protection 2
• Zoledronic acid 4 mg IV over at least 15 minutes is preferred due to superior efficacy 1
• Add calcitonin 100 IU subcutaneously or intramuscularly immediately for rapid calcium reduction (onset 1-4 hours, duration 6-8 hours) 1
• Monitor serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6-12 hours during acute phase 1

Special Situations Requiring Modified Approach

Hypercalcemia with Renal Failure

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is the definitive treatment for severe hypercalcemia complicated by renal insufficiency or oliguria 1, 4
• Denosumab 120 mg subcutaneously is preferred over bisphosphonates in patients with creatinine clearance <30 mL/min, as it has lower renal toxicity 1
• Calcium-free hemodialysis can decrease serum calcium from 4.15 mmol/L to 2.15 mmol/L within 2 hours 4

Hypercalcemia with Cardiac Failure

• Avoid aggressive hydration; use loop diuretics (furosemide 40-80 mg IV) after initial volume repletion to prevent fluid overload 1, 2
• Do not use loop diuretics before complete volume repletion, as this worsens hypercalcemia 1

Malignancy-Associated Hypercalcemia

• Bisphosphonates (zoledronic acid or pamidronate) are first-line therapy 1, 3
• For bisphosphonate-refractory cases, denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days 1
• Prognosis is poor with median survival approximately 1 month; focus on symptom control 1

Granulomatous Disease or Vitamin D Intoxication

• Corticosteroids are the primary therapy: prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 1, 3
• Corticosteroids reduce excessive intestinal calcium absorption caused by elevated 1,25-dihydroxyvitamin D 1
• Allow 3-6 months to demonstrate responsiveness before escalating therapy 1

Hematologic Malignancies (Lymphoma, Multiple Myeloma)

• Combine hydration, bisphosphonates (zoledronic acid 4 mg IV preferred), and corticosteroids 1, 2
• Glucocorticoid therapy may be particularly helpful in this population 2

Monitoring and Retreatment

• Allow minimum 7 days before retreating with bisphosphonates to assess full response to initial dose 2
• Bisphosphonates take 2-4 days to achieve maximum effect; calcitonin provides temporary bridge therapy 1, 3
• Check serum creatinine before each bisphosphonate dose and withhold if renal deterioration occurs (increase ≥0.5 mg/dL from normal baseline or ≥1.0 mg/dL from abnormal baseline) 2

Critical Pitfalls to Avoid

• Never delay bisphosphonate therapy in moderate to severe hypercalcemia—temporary measures like calcitonin provide only 1-4 hours of benefit with rebound hypercalcemia 1
• Do not use sodium polystyrene sulfonate (Kayexalate), as it has delayed onset, limited efficacy, and risk of bowel necrosis 1
• Avoid NSAIDs and IV contrast media in patients with renal impairment, as they worsen kidney function 1
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 1
• Calcitonin loses effectiveness after 48 hours due to tachyphylaxis; it is only a temporizing measure 1

Disposition and Follow-up

• Admit patients with severe hypercalcemia (>14 mg/dL), symptomatic hypercalcemia, or hypercalcemia with renal failure 3, 4
• Patients with moderate hypercalcemia may be discharged if asymptomatic after initial treatment, with close outpatient follow-up in 24-48 hours 3
• Identify and treat underlying cause: malignancy workup, parathyroid imaging for suspected primary hyperparathyroidism, or medication review 1, 3