Hypocalcaemia

Hypocalcaemia is an albumin corrected serum calcium under 2.20 mmol/L (or ionised calcium under 1.10 mmol/L). It increases neuromuscular excitability and can cause tetany, seizures, laryngospasm, QT prolongation and arrhythmia.

Clinical relevance. Hypocalcaemia is common in hospital patients, especially in critical illness, chronic kidney disease, acute pancreatitis, after neck surgery and with vitamin D deficiency. Hypoparathyroidism after thyroid surgery occurs temporarily in up to 20% of patients and permanently in 1 to 5%.

Physiology. About half of calcium is ionised and active, and the rest is bound to albumin or complexed. Acute alkalosis increases protein binding and lowers the ionised calcium without changing the total. PTH, active vitamin D (calcitriol), phosphate and magnesium maintain calcium.

Classification by severity (corrected calcium).

• Mild: 2.00 to 2.19 mmol/L.
• Moderate: 1.80 to 1.99 mmol/L.
• Severe: under 1.80 mmol/L (or ionised calcium under 0.8 mmol/L).

Classification by mechanism.

• PTH deficiency (hypoparathyroidism): post surgical, autoimmune, genetic (DiGeorge), infiltrative, radiation, hypomagnesaemia.
• PTH resistance: pseudohypoparathyroidism, hypomagnesaemia.
• Vitamin D deficiency or resistance: nutritional, malabsorption, liver disease, kidney disease, anticonvulsants, genetic.
• Calcium chelation or deposition: hyperphosphataemia, acute pancreatitis, rhabdomyolysis, tumour lysis, citrate in transfusion, osteoblastic metastases, hungry bone syndrome, and fluoride poisoning.
• Drugs: bisphosphonates, denosumab, cinacalcet, foscarnet, cisplatin, loop diuretics, phenytoin, phenobarbital, rifampicin, and proton pump inhibitors.

Key distinctions. Spurious hypocalcaemia from low albumin is excluded with the corrected or ionised calcium. A high PTH indicates a vitamin D or kidney cause or PTH resistance, and a low PTH indicates hypoparathyroidism or magnesium deficiency.

History.

• Perioral numbness, tingling of the hands and feet, muscle cramps, spasm, carpopedal spasm, seizures, laryngeal stridor, wheeze, palpitations, depression, irritability, and confusion.
• Neck surgery (thyroid, parathyroid), radiotherapy, autoimmune disease, family history, and congenital heart disease or learning disability (DiGeorge syndrome).
• Diet and sun exposure, malabsorption (coeliac disease, bowel resection, bariatric surgery), liver or kidney disease.
• Drugs that lower calcium (bisphosphonates, denosumab, cinacalcet, foscarnet, cisplatin, loop diuretics, phenytoin, phenobarbital, rifampicin, proton pump inhibitors), recent transfusion, pancreatitis, sepsis, burns, or rhabdomyolysis.
• Chronic features: dry skin, brittle nails, cataracts, dental abnormalities, and basal ganglia calcification.

Examination.

• Chvostek sign (facial twitch on tapping the facial nerve), Trousseau sign (carpopedal spasm after inflating a blood pressure cuff to over systolic pressure for 3 minutes), tetany, hyperreflexia, and stridor.
• Cardiovascular: hypotension, bradycardia, heart failure.
• Neck scar, skin and hair changes, cataracts, papilloedema, and short fourth metacarpal (pseudohypoparathyroidism).
• ECG: prolonged QT interval, ST segment prolongation, T wave inversion.

Red flags.

• Tetany, laryngospasm, stridor, bronchospasm, or seizures.
• QTc over 500 ms, ventricular arrhythmia, or heart block.
• Heart failure or hypotension resistant to treatment.
• Corrected calcium under 1.9 mmol/L or ionised calcium under 0.8 mmol/L.
• Rapid fall in calcium (after neck surgery, massive transfusion, pancreatitis, tumour lysis, or rhabdomyolysis).
• Concurrent hypomagnesaemia, hypokalaemia or digoxin therapy.
• Neonates and young children with seizures.

Special groups. Neonates have early and late hypocalcaemia. Pregnancy and breastfeeding increase calcium demand. Older adults have vitamin D deficiency and malabsorption. Critically ill patients have low ionised calcium without symptoms, which may not need treatment.

Hypoparathyroidism. Post thyroidectomy or parathyroidectomy, autoimmune polyendocrine syndrome, isolated autoimmune hypoparathyroidism, DiGeorge syndrome, infiltration (haemochromatosis, Wilson disease, metastases), radiation, and magnesium related PTH suppression.

PTH resistance. Pseudohypoparathyroidism, hypomagnesaemia, and activating calcium sensing receptor mutations.

Vitamin D disorders. Nutritional deficiency, reduced sun exposure, malabsorption (coeliac disease, inflammatory bowel disease, short bowel, bariatric surgery), liver disease, chronic kidney disease (reduced 1 alpha hydroxylation), nephrotic syndrome (loss), anticonvulsants, rifampicin, and vitamin D dependent rickets.

Calcium deposition and chelation. Hyperphosphataemia (kidney failure, tumour lysis, rhabdomyolysis, phosphate enemas), acute pancreatitis, hungry bone syndrome after parathyroidectomy or thyroidectomy, osteoblastic metastases (prostate, breast), massive blood transfusion (citrate), foscarnet, and EDTA.

Critical illness. Sepsis, burns, shock, and cardiopulmonary bypass.

Drugs. Bisphosphonates and denosumab, cinacalcet, cisplatin, loop diuretics, aminoglycosides, phenytoin, phenobarbital, carbamazepine, proton pump inhibitors, fluoride, and sodium phosphate bowel preparations.

Spurious and functional. Hypoalbuminaemia (corrected calcium normal), alkalosis from hyperventilation (low ionised calcium), and sample contamination with EDTA.

Step 1. Confirm the low calcium with albumin correction (corrected calcium equals measured calcium plus 0.02 multiplied by (40 minus albumin in g/L)) or an ionised calcium. Obtain an ECG immediately.

Step 2. Laboratory tests: magnesium, phosphate, intact PTH, 25 hydroxyvitamin D, creatinine and eGFR, alkaline phosphatase, potassium, glucose, liver tests, amylase or lipase, creatine kinase, blood gas, and full blood count.

Step 3. Interpret the pattern.

• Low calcium, low or inappropriately normal PTH, high phosphate: hypoparathyroidism.
• Low calcium, low PTH, low magnesium: hypomagnesaemia induced PTH suppression.
• Low calcium, high PTH, low phosphate, low 25 hydroxyvitamin D, high alkaline phosphatase: vitamin D deficiency.
• Low calcium, high PTH, high phosphate, raised creatinine: chronic kidney disease.
• Low calcium, high PTH, high phosphate, normal creatinine: pseudohypoparathyroidism.
• Low calcium with raised creatine kinase, potassium and phosphate: rhabdomyolysis. High lipase: pancreatitis.

Step 4. Further tests: urinary calcium (24 hour), thyroid function, coeliac serology, anti-parathyroid antibodies and calcium sensing receptor antibodies, genetic tests (22q11.2 deletion, calcium sensing receptor, GNAS), and imaging (skull radiograph or CT for basal ganglia calcification, bone radiographs for rickets or osteomalacia).

Interpretation. Corrected calcium under 1.9 mmol/L with symptoms needs intravenous calcium. A prolonged QTc and tetany correlate with severity but not accurately.

Limitations. Albumin corrected calcium is unreliable in critical illness, acid base disorders and after contrast. Ionised calcium needs a heparinised blood gas sample. Magnesium level can be normal in total body depletion.

Principles. Treat symptomatic hypocalcaemia, a corrected calcium under 1.9 mmol/L (or ionised calcium under 0.8 mmol/L), or a prolonged QT interval with intravenous calcium and ECG monitoring. Correct magnesium. Mild asymptomatic hypocalcaemia is treated with oral calcium and vitamin D. Do not treat asymptomatic hypocalcaemia from pancreatitis, rhabdomyolysis, tumour lysis or critical illness unless symptomatic or with ECG changes, because of the risk of calcium precipitation and rebound hypercalcaemia.

Emergency treatment (tetany, seizures, laryngospasm, arrhythmia, QTc over 500 ms).

• Calcium gluconate 10% 10 to 20 mL (2.2 to 4.4 mmol of elemental calcium) IV over 10 minutes, with continuous ECG monitoring, through a large vein. Repeat after 10 minutes if symptoms persist. Effect lasts 30 to 60 minutes, so follow with an infusion.
• Calcium chloride 10% 5 to 10 mL (3.4 to 6.8 mmol) IV over 10 minutes through a central vein only, in cardiac arrest or when large doses are needed (tissue necrosis if extravasated).
• Follow with an infusion: calcium gluconate 10% 100 mL (22 mmol) added to 1 litre of 5% glucose or 0.9% saline, infused at 50 to 100 mL/hour (1.1 to 2.2 mmol/hour of elemental calcium, equivalent to about 0.5 to 1.5 mg/kg/hour), adjusted to a corrected calcium of 2.0 to 2.2 mmol/L with checks every 4 to 6 hours (hourly in massive transfusion).
• Cautions: digoxin (arrhythmia, so give slowly with monitoring), extravasation (skin necrosis), do not mix with bicarbonate or phosphate (precipitation), and the solution is hyperosmolar in concentrated form. Maximum infusion concentration through a peripheral vein: 100 mL of 10% calcium gluconate in 1 litre.
• Laryngospasm or stridor: airway support, oxygen, and intravenous calcium at once. Seizures: calcium first, and lorazepam 4 mg IV (0.1 mg/kg, maximum 4 mg, repeated once after 10 minutes); anticonvulsants alone are not effective.
• Alkalosis from hyperventilation: reassure and coach breathing, and correct the cause. Do not give calcium for symptoms caused by anxiety hyperventilation.

Magnesium. If magnesium is under 0.7 mmol/L, give magnesium sulphate 2 g (8 mmol) IV over 20 minutes to 1 hour, then 5 g (20 mmol) IV over 12 hours daily for 2 to 3 days (monitor patellar reflexes, respiratory rate and creatinine; reduce by half in kidney impairment). Calcium will not normalise until magnesium is replaced.

Massive transfusion. Calcium chloride 10% 10 mL IV through a central line (or calcium gluconate 10% 30 mL IV) after each 4 units of red cells or when ionised calcium is under 1.1 mmol/L, to a target ionised calcium over 1.1 mmol/L.

Oral treatment (mild, asymptomatic, or after the acute phase).

• Calcium carbonate 1250 mg tablets (500 mg elemental calcium) 1 to 2 tablets orally two to three times daily with meals (elemental calcium 1 to 3 g daily in divided doses, maximum 4 g daily; calcium citrate if on acid suppression; separate by 2 hours from levothyroxine, quinolones, tetracyclines and iron; monitor calcium, constipation and urinary calcium).
• Active vitamin D: calcitriol 0.25 to 0.5 micrograms orally twice daily (usual maintenance 0.5 to 2 micrograms daily; maximum 3 micrograms daily), or alfacalcidol 0.25 to 1 microgram orally once daily (usual maintenance 0.5 to 2 micrograms daily, up to 3 micrograms daily). These act within days and are needed in hypoparathyroidism and kidney disease. Monitor calcium and creatinine weekly at first, then every 3 months, and 24 hour urine calcium yearly.
• Nutritional vitamin D deficiency: colecalciferol 50,000 IU orally once weekly for 6 to 8 weeks, or 3000 to 6000 IU daily for 8 to 12 weeks, then 800 to 2000 IU daily maintenance (maximum 4000 IU daily without monitoring), after calcium is corrected (monitor calcium, phosphate, and 25 hydroxyvitamin D at 3 months).
• Hypoparathyroidism: target corrected calcium at the lower end of the normal range (2.0 to 2.2 mmol/L) to limit hypercalciuria and kidney stones. Hydrochlorothiazide 25 mg orally once or twice daily (maximum 50 mg daily) can lower urinary calcium (monitor sodium, potassium, magnesium and calcium). Recombinant PTH (1 to 84) 50 micrograms subcutaneously once daily is a specialist option when conventional therapy fails.
• Hyperphosphataemia in kidney disease: phosphate restriction and phosphate binders (calcium acetate 667 mg to 1.3 g with meals three times daily, up to a maximum of 4 g daily; sevelamer carbonate 800 mg with meals three times daily, increased to a maximum of 4.8 g daily), with calcium and vitamin D under nephrology.
• Hungry bone syndrome: IV calcium gluconate infusions (10% 100 mL in 1 litre at 50 to 100 mL/hour, adjusted to the calcium) for days, then oral calcium 2 to 4 g elemental daily in divided doses plus calcitriol 0.5 to 2 micrograms daily, with magnesium and phosphate correction, for weeks to months.

Cause specific. Treat pancreatitis, rhabdomyolysis and sepsis. Stop causative drugs where possible. Pseudohypoparathyroidism needs calcium, calcitriol and TSH monitoring. DiGeorge syndrome needs cardiac, immunology and genetic review.

Monitoring. Continuous ECG during IV treatment. Corrected or ionised calcium every 4 to 6 hours during infusion (every 30 to 60 minutes in massive transfusion), then daily; magnesium, phosphate, potassium and creatinine daily; weekly after discharge until stable, then every 3 to 6 months. Watch for hypercalcaemia with active vitamin D.

Referral and escalation. Critical care or high dependency for arrhythmia, laryngospasm or recurrent seizures. Endocrinology for hypoparathyroidism, pseudohypoparathyroidism and refractory cases. Nephrology for kidney disease. Paediatrics and genetics for DiGeorge syndrome. Surgeons after neck operations.

Admission criteria. Symptomatic hypocalcaemia, corrected calcium under 1.9 mmol/L, QT prolongation, arrhythmia, post neck surgery with a rapid fall, or inability to take oral treatment. Mild asymptomatic hypocalcaemia can be managed in the community.

Discharge and safety netting. Discharge when the corrected calcium is 2.0 mmol/L or more on oral treatment and asymptomatic, with calcium checked in 1 week. Written advice on supplements, dose timing, and symptoms. Patients return for tingling, cramps, muscle spasm, palpitations, fits, or wheeze.