Hypocalcemia

Background

• Hypocalcemia is a common electrolyte abnormality defined as total calcium level (corrected for albumin) or ionized (free) calcium level in serum below the lower limit of normal.
• Common causes of hypocalcemia include vitamin D deficiency, medications, chronic kidney disease, and hypoparathyroidism.
• Clinical presentation of hypocalcemia can vary from an asymptomatic laboratory finding to a severe, life-threatening condition, with symptoms related to both absolute and rate of change of ionized calcium levels or total calcium (corrected for albumin).
• Potential complications of severe acute hypocalcemia include (but are not limited to) tetany, cardiac arrhythmias, laryngospasm, bronchospasm, and/or papilledema.
• Chronic hypocalcemia may often be asymptomatic but may also result in extrapyramidal signs (due to calcification of basal ganglia), cardiomyopathy, heart failure, cataracts, and/or dental abnormalities.

Evaluation

• Perform a thorough patient history, including asking about:
  • family history of genetic conditions associated with hypoparathyroidism or other genetic conditions that cause hypocalcemia (suggests a genetic cause)
  • previous head or neck surgery (suggests an acquired cause)
• Perform a physical exam to assess for:
  • neck scar, which may indicate a remote neck surgery (such as thyroidectomy or parathyroidectomy) not recalled by patient
  • signs of neuromuscular irritability (hallmark of acute hypocalcemia), such as the Trousseau sign or the Chvostek sign.
• Measure total calcium in serum.
  • If total calcium level is low, repeat measurement of total calcium and measure albumin. If serum albumin < 4 g/dL, correct total calcium for hypoalbuminemia.
    • Most common correction formula:
      • corrected total calcium (mg/dL) = {(4 - serum albumin [in g/dL]) × 0.8} + measured total calcium [in mg/dL]
      • corrected total calcium (mmol/L) = {(40 - serum albumin [in g/L]) × 0.02} + measured total calcium [in mmol/L]
  • Ionized (free) calcium level may be more reliable, particularly in patients who are critically ill (ionized calcium generally not altered by albumin levels) or who have acid-base and electrolyte disorders.
• Perform electrocardiography (ECG) to assess for potential ECG changes associated with hypocalcemia.
• If hypocalcemia is confirmed, initial blood tests to consider to determine underlying cause include:
  • magnesium
  • parathyroid hormone (PTH)
  • phosphate
  • alkaline phosphatase
  • 25-hydroxyvitamin D
  • blood urea nitrogen and creatinine
  • pH
• Consider other blood tests depending on clinical presentation:
  • amylase or lipase for suspected acute pancreatitis
  • adrenocorticotropin, cortisol, and thyroid-stimulating hormone for suspected polyendocrine failure
  • muscle enzymes (such as creatine kinase) for suspected early rhabdomyolysis
• Additional testing may include:
  • urine creatinine:calcium ratio to determine abnormal renal calcium excretion and renal tubular reabsorption
  • fractional excretion of magnesium on spot urine or consider obtaining 24-hour urinary magnesium for patients with hypomagnesemia to help differentiate between renal and gastrointestinal losses
  • radiographic imaging
    • in children, consider x-ray of metaphysis of a long bone to identify unsuspected pathology, such as rickets or osteoporosis.
    • if pseudohypoparathyroidism type 1a is suspected, consider evaluating for shortened fourth and fifth metacarpals
    • if hypoparathyroidism is confirmed in a patient with chronic hypocalcemia, consider performing skull x-ray to assess for intracerebral calcifications (such as basal ganglia calcifications)
  • genetic testing if genetic condition is suspected (such as patient presents at young age, has family history of calcium disorder, and/or multiple gland failure); examples of genetic conditions include pseudohypoparathyroidism and activating mutation of the calcium-sensing receptor

Management

• Management goals include:
  • increase and maintain calcium levels in low normal range or slightly below normal range (for example, no more than 0.5 mg/dL [0.1 mmol/L] below normal) for patients with hypoparathyroidism
  • control symptoms
  • remove or treat the underlying cause where possible
• For patients with symptomatic hypocalcemia and/or severe hypocalcemia and/or who require rapid correction or have persistent hypocalcemia, administer IV calcium.
  • Calcium salt options include calcium gluconate (preferred) or calcium chloride.
  • Protocols vary, but one protocol for IV calcium administration is
    • 10% calcium gluconate by bolus
      • give 2-3 IV bolus injections of 10% calcium gluconate (1-2 g [10-20 mL]) in 50-100 mL of 5% dextrose over 10 minutes (each 1 g [10 mL] of 10% calcium gluconate contains 93 mg of elemental calcium)
      • repeat bolus until life-threatening symptoms resolve
      • calcium chloride 10% solution bolus can be used as an alternative to calcium gluconate, but should only be given via a central line to avoid extravasation and tissue necrosis
    • after completing IV boluses
      • continuous infusion: 10 g calcium gluconate (930 mg elemental calcium) in 1 L of 5 % dextrose or 0.9% sodium chloride at 50-100 mL/hour (46-93 mg elemental calcium/hour)
      • titrate infusion rate to achieve normal calcium levels
      • continue infusion until treatment of underlying cause has taken effect
  • If patient has hypomagnesemia, correct magnesium concurrently, since hypocalcemia is refractory until magnesium deficiency is corrected.
    • cardiac monitoring required due to possible arrhythmias with too rapid correction, particularly in patients taking digoxin
    • assess calcium levels every 4-8 hours, as individual responses to IV calcium vary
    • evaluate infusion site for reaction (subsequent scarring of skin and subcutaneous tissue may occur)
    • introduce oral calcium as soon as possible, along with vitamin D and its analogs (if warranted); continue IV calcium infusion (at decreasing doses) until stable oral calcium regimen achieved
• For patients with asymptomatic or with mild-moderate symptomatic hypocalcemia receiving enteral nutrition or who can tolerate oral medications, restoring calcium homeostasis with oral calcium is suggested.
  • Oral calcium supplements of choice are calcium carbonate (taken with meals) and calcium citrate (taken with or without meals).
  • The recommended daily dose of oral elemental calcium is 1-2 g/day in 3-4 divided doses. For optimal absorption, each dose of elemental calcium should be ≤ 500 mg.
• For patients with either vitamin D deficiency or hypoparathyroidism, consider vitamin D supplement or vitamin D analogs.
• Consider additional medications based on underlying condition.
• Follow-up:
  • for patients with chronic hypocalcemia, test serum calcium every 3-6 months or when medical regimen changes occur
  • for patients with hypoparathyroidism
    • test serum calcium, creatinine, and phosphorus
      • weekly to monthly during initial dose adjustments
      • every 3-6 months once therapy protocol has stabilized
    • test 24-hour urine calcium and creatinine at least annually due to increased risk of hypercalciuria; serum calcium level is a poor indicator of hypercalciuria and nephrocalcinosis
  • for women starting or stopping estrogen therapy, calcium and/or vitamin D supplementation might require dose adjustments