How do I manage a patient with hypercalcemia in the Emergency department?

Emergency Management of Severe Hypercalcemia (Calcium 14.1 mg/dL)

A calcium of 14.1 mg/dL represents severe, life-threatening hypercalcemia requiring immediate aggressive treatment with IV normal saline hydration followed by IV zoledronic acid 4 mg, while simultaneously investigating the underlying cause. 1

Immediate Actions (First 1-2 Hours)

Aggressive IV Hydration

• Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis, targeting urine output of 100-150 mL/hour. 1
• Give boluses of 250-500 mL every 15 minutes until rehydration is achieved, then maintain diuresis >2.5 L/day in adults. 1
• Balanced crystalloids are preferred over 0.9% saline when possible to avoid hyperchloremic metabolic acidosis with large volumes. 1
• Do NOT use loop diuretics (furosemide) until the patient is fully volume-repleted—only use them if renal or cardiac insufficiency develops to prevent fluid overload. 1, 2

Obtain Stat Laboratory Studies

• Measure ionized calcium (more accurate than total calcium), albumin, intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, magnesium, serum creatinine, and BUN. 1
• Check ECG for QT interval prolongation and other cardiac manifestations. 1
• If PTH is suppressed (<20 pg/mL), this indicates malignancy or another non-PTH-mediated cause; if PTH is elevated or normal, consider primary hyperparathyroidism. 3

Assess Clinical Status

• Evaluate for altered mental status, confusion, somnolence, nausea, vomiting, dehydration, polyuria, and cardiac arrhythmias—all common with calcium >14 mg/dL. 3, 4
• Check for signs of malignancy (weight loss, bone pain, lymphadenopathy) or granulomatous disease (pulmonary symptoms suggesting sarcoidosis). 1

Definitive Pharmacologic Treatment (Within 2-4 Hours)

First-Line: IV Bisphosphonate

• Administer zoledronic acid 4 mg IV infused over no less than 15 minutes as the preferred bisphosphonate. 1, 2
• Zoledronic acid normalizes calcium in 50% of patients by day 4 and is superior to pamidronate. 1
• Do NOT exceed 4 mg for initial treatment and do NOT infuse faster than 15 minutes—both increase risk of acute renal failure. 2
• If creatinine clearance is 30-60 mL/min, reduce the dose: 3.5 mg for CrCl 50-60,3.3 mg for CrCl 40-49,3.0 mg for CrCl 30-39. 2
• If creatinine clearance <30 mL/min or severe renal impairment, use denosumab 120 mg subcutaneously instead due to lower renal toxicity. 1

Bridge Therapy: Calcitonin (While Waiting for Bisphosphonate Effect)

• Give calcitonin-salmon 4 Units/kg subcutaneously or intramuscularly every 12 hours for rapid calcium reduction within 4-6 hours. 5
• If response is inadequate after 1-2 days, increase to 8 Units/kg every 12 hours; if still inadequate after 2 more days, increase to maximum 8 Units/kg every 6 hours. 5
• Calcitonin provides only temporary benefit (1-4 hours) with tachyphylaxis developing after 48 hours, but bridges the gap until bisphosphonates take effect (3-4 days). 1

Adjunctive Therapy: Corticosteroids (If Specific Etiologies)

• Use prednisone 20-40 mg/day orally or IV methylprednisolone equivalent if hypercalcemia is due to granulomatous disease (sarcoidosis), vitamin D intoxication, lymphoma, or multiple myeloma. 1
• Corticosteroids reduce excessive intestinal calcium absorption and work within 3-6 days. 1
• Do NOT use corticosteroids empirically without knowing the etiology—they are ineffective for PTH-mediated or most malignancy-related hypercalcemia. 1

Refractory or Special Situations

If Bisphosphonates Fail

• Consider denosumab 120 mg subcutaneously for bisphosphonate-refractory hypercalcemia, which lowers calcium in 64% of patients within 10 days. 1
• Denosumab carries higher risk of severe hypocalcemia, so monitor calcium closely and supplement with oral calcium 500 mg plus vitamin D 400 IU daily. 1

If Severe Renal Failure or Oliguria

• Initiate hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) for severe hypercalcemia complicated by renal insufficiency. 1
• Dialysis effectively removes calcium through diffusive therapy when pharmacologic measures are insufficient. 1

Monitoring During Acute Phase

• Check serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6-12 hours during the acute phase. 1
• Monitor urine output continuously to maintain 100-150 mL/hour. 1
• Reduce IV fluid rate once stable diuresis is achieved and vital signs normalize without tachycardia. 1
• If hypocalcemia, hypophosphatemia, or hypomagnesemia develop during treatment, provide short-term supplementation. 2

Critical Pitfalls to Avoid

• Never delay bisphosphonate administration—start zoledronic acid early without waiting for complete rehydration, as temporary measures like calcitonin provide only 1-4 hours of benefit. 1
• Never use loop diuretics before adequate volume repletion—this worsens dehydration and renal function. 1, 2
• Never infuse zoledronic acid faster than 15 minutes or exceed 4 mg initially—both dramatically increase risk of acute tubular necrosis and renal failure. 2
• Never store undiluted zoledronic acid in a syringe—this risks inadvertent bolus injection causing severe renal toxicity. 2
• Avoid NSAIDs and IV contrast media in this setting, as they worsen renal function. 1
• Discontinue all calcium supplements, vitamin D supplements, and thiazide diuretics immediately. 1

Disposition and Follow-Up

• Admit all patients with calcium >14 mg/dL to a monitored setting for continuous cardiac monitoring and frequent laboratory assessment. 3, 4
• Hypercalcemia of malignancy carries a median survival of approximately 1 month, so early oncology consultation is essential if malignancy is suspected. 1
• If primary hyperparathyroidism is confirmed, refer for parathyroidectomy evaluation once acute crisis resolves. 1
• Continue monitoring calcium levels for 7-10 days, as bisphosphonates have delayed onset but prolonged duration of action. 1