Hypercalcaemic Crisis

Hypercalcaemic crisis is severe hypercalcaemia, usually with albumin corrected calcium of 3.5 mmol/L (14 mg/dL) or more, or lower levels with significant symptoms, causing dehydration, renal impairment, neurological dysfunction and cardiac effects. It is a medical emergency.

Epidemiology. Malignancy accounts for most inpatient cases, and primary hyperparathyroidism for most outpatient cases. Hypercalcaemia complicates up to 20 to 30% of cancers. Mortality is high when it is due to malignancy.

Causes and associations.

• Malignancy: parathyroid hormone related peptide (squamous, renal, breast, ovarian), osteolytic metastases, myeloma and calcitriol producing lymphoma.
• Primary hyperparathyroidism, including parathyroid carcinoma and parathyroid crisis.
• Vitamin D intoxication, granulomatous disease (sarcoidosis, tuberculosis) and milk alkali syndrome.
• Drugs: thiazides, lithium, vitamin A, and calcium or vitamin D excess.
• Immobilisation, thyrotoxicosis, adrenal insufficiency and familial hypocalciuric hypercalcaemia.

Pathophysiology. Raised calcium impairs the renal concentrating mechanism and causes nephrogenic diabetes insipidus and natriuresis, so dehydration reduces calcium excretion and calcium rises further. Calcium also affects cardiac conduction, smooth muscle and neurones.

Presentation is polyuria, thirst, dehydration, nausea, vomiting, constipation, abdominal pain, muscle weakness, confusion, drowsiness and coma. Complications are acute kidney injury, pancreatitis, peptic ulcer, short QT interval, bradycardia, heart block and arrhythmia. Bone pain and renal stones suggest longstanding disease.

Red flags.

• Calcium 3.5 mmol/L or more, confusion or coma.
• Acute kidney injury, ECG changes or arrhythmia.
• Known malignancy, myeloma or parathyroid mass.
• Severe dehydration with hypotension, or pancreatitis.

Measure albumin corrected or ionised calcium, phosphate, magnesium, potassium, creatinine, alkaline phosphatase, parathyroid hormone, parathyroid hormone related peptide, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, thyroid function, cortisol, serum and urine protein electrophoresis and urine calcium. Raised or inappropriately normal parathyroid hormone indicates parathyroid mediated disease, while suppressed parathyroid hormone indicates other causes. Do an ECG, with imaging directed by the cause (chest radiograph, CT, parathyroid imaging).

Differential diagnosis.

• Primary hyperparathyroidism versus malignancy.
• Familial hypocalciuric hypercalcaemia.
• Granulomatous disease and vitamin D intoxication.
• Milk alkali syndrome, thyrotoxicosis and drug related causes.

Fluids. 0.9% sodium chloride 200 to 300 mL/h IV after initial resuscitation, titrated to urine output of 100 to 150 mL/h, with a typical first-24-hour volume of 3 to 4 L. Reduce volumes and monitor closely in heart failure or renal failure. Loop diuretics (furosemide 20 to 40 mg IV) only after volume restoration and only to treat overload.

Bisphosphonate (first line anti-resorptive).

• Zoledronic acid 4 mg IV over at least 15 minutes. In renal impairment: 3.5 mg if eGFR 50 to 60 mL/min, 3.3 mg if 40 to 49, 3.0 mg if 30 to 39. Avoid under 30 mL/min unless a specialist decides otherwise.
• Pamidronate 60 to 90 mg IV over 2 to 4 hours (30 to 60 mg in renal impairment).
• Effect begins in 2 to 4 days with a maximum at 4 to 7 days. Monitor creatinine and calcium, and review jaw osteonecrosis risk, with dental review in long term use.

Calcitonin (fast onset). 4 units/kg SC or IM every 12 hours, increased to 8 units/kg every 6 hours if needed. It acts within 4 to 6 hours with tachyphylaxis after 48 hours. Nausea is common.

Denosumab. 120 mg SC for refractory disease or severe renal impairment, repeated on days 8, 15 and 29 for refractory cases, then every 4 weeks. Monitor for severe hypocalcaemia, especially in renal impairment, and give calcium and vitamin D.

Glucocorticoids. For vitamin D-mediated disease, granulomatous disease and lymphoma: prednisolone 40 to 60 mg orally daily, or hydrocortisone 200 to 300 mg IV daily, for 3 to 10 days.

Dialysis. Haemodialysis with low calcium dialysate for renal failure, heart failure or severe neurological compromise.

Cause directed treatment.

• Stop thiazides, lithium, calcium and vitamin D.
• Parathyroidectomy for primary hyperparathyroidism and parathyroid crisis.
• Cinacalcet 30 mg orally twice daily, increased every 2 to 4 weeks to a maximum of 90 mg four times daily, for parathyroid carcinoma or when surgery is not possible. Monitor calcium and QT.
• Treat the cancer where possible.

Monitoring. Calcium every 6 to 12 hours, potassium, magnesium, phosphate, creatinine, ECG, urine output and fluid balance.

Referral and escalation. Endocrinology, oncology, nephrology and intensive care for calcium over 3.5 mmol/L with organ dysfunction, refractory hypercalcaemia or need for dialysis.

Special groups. In pregnancy, parathyroid related disease needs specialist care and bisphosphonates are generally avoided. In renal impairment, reduce bisphosphonate doses and prefer denosumab. In children, management is specialist directed with careful fluid volumes.