Hypomagnesaemia

Hypomagnesaemia is a serum magnesium concentration under 0.70 mmol/L. Magnesium is the second commonest intracellular cation and a cofactor for over 300 enzymes, including the sodium potassium pump and parathyroid hormone release. Deficiency is common, under recognised, and a cause of refractory hypokalaemia and hypocalcaemia, ventricular arrhythmia (torsades de pointes) and seizures.

Clinical relevance. Hypomagnesaemia is present in up to 12% of hospital patients and up to 60% in intensive care. It is seen with proton pump inhibitors, diuretics, alcohol use, diarrhoea, diabetes, and chemotherapy. The serum level does not reflect total body stores, which can be depleted with a normal level.

Physiology. About 99% of body magnesium is in bone, muscle and soft tissue, so serum magnesium represents 1%. The gut absorbs 30 to 50% of dietary magnesium. The kidney reabsorbs 95% of filtered magnesium, mostly in the thick ascending limb and the distal tubule, and excretion rises when magnesium is in excess.

Classification by severity.

• Mild: 0.50 to 0.69 mmol/L (usually asymptomatic).
• Moderate: 0.40 to 0.49 mmol/L.
• Severe: under 0.40 mmol/L (often symptomatic, with arrhythmia and seizures).

Classification by mechanism.

• Gastrointestinal loss or reduced absorption: diarrhoea, malabsorption, short bowel, chronic pancreatitis, nasogastric suction, proton pump inhibitors, and genetic defects.
• Renal loss: loop and thiazide diuretics, aminoglycosides, amphotericin B, cisplatin, carboplatin, cetuximab, panitumumab, calcineurin inhibitors, hypercalcaemia, osmotic diuresis, post obstructive diuresis, recovery from acute tubular necrosis, alcohol, and inherited tubular disorders (Gitelman syndrome, familial hypomagnesaemia).
• Reduced intake and redistribution: starvation, alcohol use disorder, parenteral nutrition without magnesium, refeeding, insulin treatment, hungry bone syndrome, acute pancreatitis, burns, and massive transfusion.

Key distinctions. Fractional excretion of magnesium in the urine separates renal from non-renal loss. Hypokalaemia and hypocalcaemia that do not respond to replacement suggest magnesium deficiency.

History.

• Symptoms: weakness, tremor, muscle cramps, tetany, paraesthesia, palpitations, dizziness, fatigue, confusion, depression, and seizures. Many patients are asymptomatic.
• Gastrointestinal: diarrhoea, steatorrhoea, vomiting, bowel surgery, and bariatric surgery.
• Alcohol intake, diet and eating disorders, diabetes, and parenteral nutrition.
• Drugs: proton pump inhibitors (long term use over 1 year), loop and thiazide diuretics, aminoglycosides, amphotericin B, cisplatin, cetuximab, ciclosporin, tacrolimus, digoxin, and laxatives.
• Family history of hypomagnesaemia, hypocalcaemia, or kidney disease.

Examination.

• Muscle: tremor, fasciculations, hyperreflexia, positive Chvostek and Trousseau signs, tetany, ataxia, nystagmus, and weakness.
• Cardiovascular: irregular pulse, hypotension, and signs of heart failure.
• Neurological: confusion, seizures.
• ECG: prolonged QT interval, flat T waves, prominent U waves, ST depression, broad QRS, atrial fibrillation, ventricular ectopics, torsades de pointes.
• Signs of malnutrition, alcohol use disorder, thyrotoxicosis, and malabsorption.

Red flags.

• Torsades de pointes, ventricular arrhythmia, or QTc over 500 ms.
• Seizures, tetany, or laryngospasm.
• Magnesium under 0.4 mmol/L.
• Refractory hypokalaemia or hypocalcaemia.
• Digoxin therapy, acute coronary syndrome, or heart failure.
• Severe diarrhoea or malabsorption, alcohol withdrawal, refeeding, or critical illness.
• Chemotherapy with cisplatin or EGFR antibodies.

Special groups. Pregnancy: low magnesium is associated with cramps and pre-eclampsia, and treated with the same doses in the usual obstetric setting. Older adults on diuretics and proton pump inhibitors are at risk. Children with genetic tubulopathies have growth and neurological features. Patients with kidney failure are at risk of overtreatment.

Gastrointestinal causes. Chronic diarrhoea, inflammatory bowel disease, coeliac disease, bowel resection, bariatric surgery, short bowel syndrome, chronic pancreatitis, steatorrhoea, nasogastric suction, intestinal fistula, and primary intestinal hypomagnesaemia (genetic).

Renal causes.

• Drugs: loop and thiazide diuretics, proton pump inhibitors (impaired absorption), aminoglycosides, cisplatin, carboplatin, EGFR inhibitors (cetuximab, panitumumab), amphotericin B, pentamidine, ciclosporin, tacrolimus, and foscarnet.
• Metabolic: hypercalcaemia, hyperglycaemia and osmotic diuresis, diabetic ketoacidosis, hyperaldosteronism, hyperthyroidism, and SIADH.
• Tubular disorders: Gitelman syndrome, Bartter syndrome, familial hypomagnesaemia with hypercalciuria, and other inherited channelopathies.
• Post obstructive diuresis and the diuretic phase of acute tubular necrosis, and post transplant.

Nutritional and redistribution causes. Alcohol use disorder, malnutrition, parenteral nutrition, refeeding syndrome, insulin therapy, acute pancreatitis, hungry bone syndrome, burns, and sepsis.

Associated disorders to consider. Hypokalaemia, hypocalcaemia, hypophosphataemia, and metabolic alkalosis often occur together, as do vitamin D deficiency and diabetes.

Step 1. Measure serum magnesium in patients with hypokalaemia, hypocalcaemia, arrhythmia, seizures, alcohol use disorder, diarrhoea, malnutrition, and diuretic, proton pump inhibitor, or platinum therapy. Obtain an ECG.

Step 2. Laboratory tests: potassium, calcium (corrected or ionised), phosphate, creatinine, glucose, bicarbonate, PTH, 25 hydroxyvitamin D, thyroid function, liver tests, and urinalysis.

Step 3. Define the mechanism.

• Fractional excretion of magnesium (urine magnesium multiplied by serum creatinine, divided by 0.7 multiplied by serum magnesium and urine creatinine, as a percentage). A value over 2% (or over 4% when kidney function is normal) with hypomagnesaemia indicates renal loss. A value under 2% indicates a gastrointestinal cause or poor intake.
• A 24 hour urinary magnesium over 1 mmol (24 mg) with hypomagnesaemia also indicates renal wasting.

Step 4. Further evaluation when the cause is unclear: faecal fat and malabsorption tests, coeliac serology, genetic testing (Gitelman syndrome, familial hypomagnesaemia), and review of drug exposure.

Interpretation. A normal serum magnesium does not exclude intracellular depletion. A magnesium of 0.5 to 0.69 mmol/L with refractory low potassium or calcium needs replacement.

Limitations. Serum magnesium is a poor indicator of total body magnesium. Magnesium loading tests are impractical. Fractional excretion is unreliable with recent diuretic use.

Principles. Replace magnesium before or with potassium and calcium, monitor reflexes, respiratory rate and renal function, and treat the cause. The total body deficit is 1 to 2 mmol/kg (70 to 140 mmol in adults), and replacement takes days because most infused magnesium is lost in the urine when serum levels rise rapidly.

Emergency treatment (torsades de pointes, seizures, tetany, severe symptoms, magnesium under 0.4 mmol/L).

• Magnesium sulphate 2 g (8 mmol) IV over 15 to 20 minutes (over 1 to 2 minutes in pulseless torsades or cardiac arrest), with continuous ECG monitoring. Repeat once for persisting torsades. Follow with an infusion of 5 g (20 mmol) in 500 mL isotonic saline or 5% glucose over 12 hours, then 5 g (20 mmol) over 12 to 24 hours daily for 3 to 5 days (total about 8 to 12 g in the first 24 hours; maximum 12 g daily in normal kidney function).
• Reduce the dose by 50% when CrCl is 30 to 50 mL/min, and by 50 to 75% when CrCl is under 30 mL/min, or if oliguric, with serum magnesium checked every 6 to 12 hours.
• Monitoring: patellar reflexes (loss of reflexes is the first sign of toxicity), respiratory rate (stop if under 12 breaths/min), urine output (over 25 mL/hour), blood pressure, and ECG. Antidote for toxicity: calcium gluconate 10% 10 mL IV over 10 minutes.
• Seizures in hypomagnesaemia: magnesium sulphate 2 to 4 g IV over 5 to 10 minutes, and lorazepam 4 mg IV (0.1 mg/kg, maximum 4 mg, repeated once after 10 minutes) if seizures continue.
• Dosing for eclampsia and pre-eclampsia is set by obstetric teams and differs from the doses here.

Moderate to mild or asymptomatic hypomagnesaemia (0.40 to 0.69 mmol/L) with normal kidney function.

• Intravenous: magnesium sulphate 2 g (8 mmol) IV over 1 to 2 hours once or twice daily until magnesium is 0.7 mmol/L or more, up to a total of 4 to 8 g (16 to 32 mmol) daily (monitor reflexes, respiratory rate, urine output, and serum magnesium every 12 to 24 hours; reduce in kidney impairment).
• Oral (when asymptomatic, or after IV treatment): magnesium glycerophosphate 4 mmol (97.2 mg elemental) tablets, 1 to 2 tablets two to three times daily (up to 24 mmol daily), or magnesium oxide 400 mg (about 240 mg or 10 mmol elemental) 1 tablet two to three times daily with food (maximum 48 mmol daily), or slow release magnesium chloride 64 mg (2.7 mmol) elemental 2 tablets two to three times daily. Continue for 1 to 4 weeks or until the cause is corrected, with magnesium checked at 1 week. Reduce the dose or change salt if diarrhoea occurs. Avoid in kidney failure (CrCl under 30 mL/min) without monitoring.
• Intramuscular magnesium sulphate 50% 2 mL (4 mmol) is painful and rarely used.
• Separate magnesium from quinolones, tetracyclines, levothyroxine, bisphosphonates and iron by at least 2 hours.

Replace potassium and calcium. Hypokalaemia is corrected with potassium chloride 40 mmol in 1 litre isotonic saline over 4 hours (maximum 10 mmol/hour peripherally, 20 mmol/hour centrally with ECG monitoring; recheck potassium every 4 to 6 hours) together with magnesium. Hypocalcaemia is treated with calcium gluconate 10% 10 to 20 mL IV over 10 minutes if symptomatic, once magnesium replacement has begun.

Cause specific.

• Proton pump inhibitor related: review need, use the lowest effective dose, or change to an H2 receptor antagonist (famotidine 20 mg orally twice daily; reduce in CrCl under 50 mL/min), and supplement magnesium.
• Diuretic related: replace magnesium and add a potassium and magnesium sparing diuretic (amiloride 5 to 10 mg orally once daily, maximum 20 mg daily; monitor potassium and creatinine; avoid in CrCl under 30 mL/min or hyperkalaemia).
• Cisplatin and aminoglycoside related: give magnesium sulphate 2 to 4 g IV before and with treatment, and monitor. EGFR antibodies: IV magnesium sulphate 2 to 4 g weekly or with each dose, and oral supplements.
• Diarrhoea and malabsorption: treat the cause, replace fluids, use oral magnesium in divided small doses or IV when intolerance is limiting.
• Alcohol use disorder and refeeding: thiamine 100 to 300 mg IV or orally once daily (before glucose), replace magnesium, potassium and phosphate, and advance feeding slowly.
• Diabetes: improve glycaemic control.
• Genetic tubulopathies: lifelong high dose magnesium, potassium sparing diuretics, and specialist care.
• Digoxin: keep magnesium at 0.8 mmol/L or more and potassium at 4.0 mmol/L or more.
• Cardiac patients: aim for magnesium of 0.8 mmol/L or more after acute myocardial infarction and in heart failure and arrhythmia.

Monitoring. Magnesium, potassium, calcium and creatinine daily during IV treatment, then weekly until stable, then every 3 months while the cause persists. Continuous ECG in arrhythmia. Check reflexes, respiratory rate and urine output during infusion.

Referral and escalation. Critical care or cardiology for torsades de pointes or refractory arrhythmia. Nephrology for renal magnesium wasting and genetic tubulopathy. Gastroenterology for malabsorption. Endocrinology for associated calcium and diabetes problems. Pharmacy for drug review.

Admission criteria. Magnesium under 0.4 mmol/L, arrhythmia or QT prolongation, seizures, tetany, refractory hypokalaemia or hypocalcaemia, inability to take oral treatment, or a severe underlying illness. Mild asymptomatic hypomagnesaemia can be managed with oral supplements as an outpatient.

Discharge and safety netting. Discharge when magnesium is 0.6 mmol/L or more, symptoms have resolved, and the cause is being addressed, with magnesium, potassium and calcium rechecked in 1 week. Advise taking supplements with food in divided doses and reporting diarrhoea. Patients return for palpitations, fainting, cramps, tingling, seizures, or reduced urine output. Diet advice on magnesium rich foods (green vegetables, nuts, seeds, whole grains, legumes).