Magnesium

Magnesium is the second most abundant intracellular cation and a cofactor for more than 300 enzymes, including those of ATP use, nucleic acid synthesis, membrane transport and parathyroid hormone secretion. Less than 1% of body magnesium is in serum, and about 70% of this is free or complexed and 30% protein bound. Serum magnesium is measured by xylidyl blue colorimetry or ion selective electrode (ionised magnesium).

Hypomagnesaemia is common in hospital patients (roughly 10 to 15% of inpatients and up to about 60% of those in intensive care) and is easily missed because it is not part of many routine panels. It is the commonest cause of hypokalaemia and hypocalcaemia that fail to correct. Hypermagnesaemia is uncommon and mostly iatrogenic.

Indications. Hypokalaemia or hypocalcaemia that does not correct, arrhythmia (particularly torsades de pointes and a prolonged QT interval), seizures, tetany, tremor, weakness, alcohol dependence, long term diuretic or proton pump inhibitor use, malabsorption, diabetes, cisplatin, amphotericin and calcineurin inhibitor therapy, refeeding risk, acute pancreatitis, kidney failure with magnesium containing medicines, and monitoring of magnesium sulphate therapy in pre-eclampsia.

Specimen. Serum or lithium heparin plasma, separated promptly. Avoid haemolysis, which raises the result because red cells contain about 3 times the plasma concentration, and avoid EDTA or citrate contamination, which lowers it.

Reference range. 0.70 to 1.00 mmol/L (1.7 to 2.4 mg/dL), equal to 1.4 to 2.0 mEq/L. Local ranges take precedence.

Hypomagnesaemia (under 0.70 mmol/L).

• Mild: 0.50 to 0.69 mmol/L. Often asymptomatic.
• Moderate to severe: under 0.50 mmol/L, with neuromuscular irritability (tremor, tetany, positive Chvostek and Trousseau signs), seizures, arrhythmia, and refractory hypokalaemia and hypocalcaemia.
• Under 0.40 mmol/L: high risk of seizures, torsades de pointes and ventricular arrhythmia.

Causes of hypomagnesaemia.

• Gastrointestinal loss and poor intake: diarrhoea, malabsorption, short bowel, bariatric surgery, malnutrition, alcohol dependence, long term proton pump inhibitors, acute pancreatitis.
• Renal loss: loop and thiazide diuretics, cisplatin, aminoglycosides, amphotericin, calcineurin inhibitors, EGFR antibodies (cetuximab, panitumumab), osmotic diuresis in uncontrolled diabetes, hypercalcaemia, post-obstructive and recovery phase kidney injury, inherited disorders (Gitelman syndrome, Bartter syndrome, familial hypomagnesaemia with hypercalciuria, others).
• Redistribution: refeeding, treatment of diabetic ketoacidosis, hungry bone syndrome, insulin therapy, catecholamine excess, acute pancreatitis.

Differentiating renal from non-renal loss. In a patient with hypomagnesaemia and normal kidney function, a fractional excretion of magnesium over 2% indicates renal loss, and under 2% (usually under 0.5%) indicates gastrointestinal loss or poor intake. A 24-hour urinary excretion over about 1 mmol (24 mg) during hypomagnesaemia also indicates renal wasting.

Hypermagnesaemia (over 1.00 mmol/L).

• Symptoms usually start over about 2.0 mmol/L (4 mEq/L): nausea, flushing, drowsiness and hypotension.
• Loss of tendon reflexes occurs at about 3.5 to 5.0 mmol/L, bradycardia and conduction block at higher values, and respiratory paralysis and cardiac arrest at values over 5.0 mmol/L and over 7 mmol/L respectively. These bands are approximate.
• Causes: kidney failure with magnesium containing antacids, laxatives, enemas or infusions, magnesium sulphate therapy, lithium, adrenal insufficiency, hypothyroidism, tumour lysis, rhabdomyolysis, diabetic ketoacidosis, and familial hypocalciuric hypercalcaemia (mildly raised).

Magnesium sulphate therapy in pre-eclampsia. A therapeutic plasma concentration is about 2.0 to 3.5 mmol/L (4 to 7 mEq/L). Monitoring relies on patellar reflexes, respiratory rate and urine output (over 25 to 30 mL/h), with a level checked when kidney function is impaired. Loss of reflexes is the first warning of toxicity.

Critical values and findings needing immediate action.

• Magnesium under 0.40 mmol/L with arrhythmia, seizures or a prolonged QT interval.
• Magnesium over 3.0 mmol/L, or any rise with loss of reflexes, respiratory depression, hypotension or bradycardia.
• A patient receiving magnesium sulphate with falling urine output, absent reflexes or slowing respiration.

Interferences and pitfalls.

• Serum magnesium is a poor indicator of total body or intracellular stores, so a normal result does not exclude deficiency. Where deficiency is strongly suspected and the level is normal, empirical replacement or a magnesium retention test is used.
• Haemolysis, delayed separation and prolonged storage on cells raise the result. EDTA, citrate and oxalate contamination lower it.
• Low albumin lowers total magnesium modestly without changing the ionised fraction.
• Hypomagnesaemia usually accompanies hypokalaemia and hypocalcaemia, and these are measured together.
• Some medicines raise urinary magnesium excretion for days after dosing, so a fractional excretion measured soon after a diuretic dose misleads.
• Ionised magnesium assays are not widely available, and the extra information is limited.

Special groups.

• Neonates: values are about 0.6 to 1.0 mmol/L. Neonatal hypomagnesaemia is found with maternal diabetes and growth restriction, and neonates exposed to maternal magnesium sulphate show hypotonia and respiratory depression.
• Pregnancy: serum magnesium falls modestly, and a level is checked during magnesium sulphate therapy when kidney function is impaired.
• Older adults: reduced intake, diuretics and proton pump inhibitors make deficiency common, and renal impairment predisposes to toxicity from magnesium containing laxatives.
• Chronic kidney disease: magnesium accumulates, so avoid magnesium containing laxatives and antacids.
• Alcohol dependence and refeeding: replace magnesium before or with potassium, phosphate and thiamine.

Follow up tests. Potassium, calcium and phosphate, parathyroid hormone, urea and electrolytes with eGFR, glucose, ECG, urinary magnesium with creatinine for fractional excretion, 24-hour urine magnesium, gut absorption tests (coeliac serology, faecal fat tests), alcohol and drug history, genetic testing for inherited tubular disorders.