Euvolaemic Hyponatraemia

Euvolaemic hyponatraemia is hypotonic hyponatraemia (serum sodium under 135 mmol/L and osmolality under 275 mosmol/kg) with a normal extracellular volume and no oedema. The commonest cause is the syndrome of inappropriate antidiuresis.

Other causes are:

• Glucocorticoid deficiency (secondary adrenal insufficiency from pituitary disease or after steroid withdrawal).
• Severe hypothyroidism.
• Low solute intake (beer potomania, tea and toast diet, severe malnutrition, anorexia).
• Primary polydipsia.
• Thiazide diuretics (can present as euvolaemic).
• Exercise, and reset osmostat.

Inappropriate antidiuresis arises from:

• Malignancy (small cell lung cancer in 10 to 15%, head and neck, pancreas, thymus).
• Lung disease (pneumonia, tuberculosis, asthma, positive pressure ventilation).
• Central nervous system disease (stroke, haemorrhage, trauma, meningitis, tumour).
• Drugs (selective serotonin reuptake inhibitors, venlafaxine, carbamazepine, oxcarbazepine, cyclophosphamide, vincristine, opioids, MDMA, desmopressin).
• Post-operative pain and nausea, HIV infection, and idiopathic causes in older adults.

A genetic gain of function variant in the vasopressin receptor V2 (nephrogenic syndrome of inappropriate antidiuresis, AVPR2) occurs rarely.

Pathophysiology. Antidiuretic hormone released independent of osmolality causes water retention. Extracellular volume expansion of about 1 to 2 litres triggers natriuresis. Total body sodium is therefore slightly low, but clinical volume remains normal. Urine is concentrated despite hypotonic plasma.

Four patterns exist: erratic release, reset osmostat, failure to suppress at low osmolality, and no detectable hormone with V2 activating variants.

• Often subtle: unsteady gait, falls, inattention, poor concentration, nausea, headache, cramps.
• Severe: confusion, seizures, coma (usually when sodium is under 120 mmol/L or the fall is rapid).
• No oedema, normal or mildly raised blood pressure, no postural hypotension, moist mucous membranes.
• Features of the cause: cough, haemoptysis, weight loss, smoking history (lung cancer); headache, head injury; constipation, cold intolerance (hypothyroidism); drug start dates.

Red flags

• Sodium under 120 mmol/L, seizures, confusion.
• New hyponatraemia with weight loss and lung mass.
• Hypotension, hypoglycaemia or hyperkalaemia (adrenal insufficiency).
• Overcorrection risk factors: hypokalaemia, malnutrition, alcoholism.

• Essential criteria for inappropriate antidiuresis: plasma osmolality under 275 mosmol/kg; urine osmolality over 100 mosmol/kg; clinical euvolaemia.
• Further essential criteria: urine sodium over 30 mmol/L on normal salt and water intake; normal thyroid, adrenal and renal function; no recent diuretic use.
• Supportive: uric acid under 240 micromol/L, urea under 3.6 mmol/L, fractional uric acid excretion over 12%, failure to correct with isotonic saline (sodium falls or no change), abnormal water load test, plasma copeptin (not routine).
• Exclude: morning cortisol (under 100 nmol/L needs synacthen test), thyroid stimulating hormone, free thyroxine, glucose, potassium, creatinine, lipids, protein.
• Cause: chest radiograph, CT chest, abdomen and pelvis, CT or MR brain, medication review, HIV test, tuberculosis assessment.
• Reset osmostat is suggested by stable mild hyponatraemia (125 to 134 mmol/L) with good urine dilution after a water load.

Differential diagnosis

• Hypovolaemic hyponatraemia (diuretics, cerebral salt wasting), hypervolaemic states (heart failure, cirrhosis), adrenal insufficiency, hypothyroidism, primary polydipsia, low solute states, pseudohyponatraemia.

Treat the cause

• Stop or substitute the offending drug. Treat infection, pain and nausea.
• Treat malignancy. Hyponatraemia resolves with response to chemotherapy in many.
• Hypothyroidism: levothyroxine 25 to 50 microg daily, increased by 25 microg every 2 to 4 weeks to 1.6 microg/kg daily.
• Adrenal insufficiency: hydrocortisone 15 to 25 mg daily in divided doses (or 100 mg intravenously then 200 mg over 24 hours in crisis).
• Limits of correction: raise sodium by 8 to 10 mmol/L in any 24 hours (4 to 6 mmol/L in the first 24 hours for those at high risk).

Severe or moderately severe symptoms

• 3% sodium chloride 150 mL intravenously over 20 minutes, repeated up to two further times to a 5 mmol/L rise or symptom resolution.
• Check sodium 20 minutes after each bolus and every 2 hours afterwards. Stop saline when symptoms improve.
• Do not use 0.9% sodium chloride when urine osmolality is over about 500 mosmol/kg, as it can worsen hyponatraemia.
• Consider furosemide 20 to 40 mg intravenously with saline if urine osmolality is over 350 mosmol/kg.

Mild to moderate, chronic

• Fluid restriction to under 800 to 1000 mL daily (or under the urine volume). It fails when the electrolyte ratio ((urine sodium plus urine potassium) divided by plasma sodium) is over 1 or urine osmolality over 500 mosmol/kg.
• Increase solute intake: urea 15 to 30 g daily (with food or juice), or sodium chloride tablets 3 to 6 g daily with furosemide 20 to 40 mg daily.
• Tolvaptan 15 mg daily, increased at 24 hour intervals to 30 mg and then 60 mg. Start in hospital without fluid restriction, with sodium checks at 6, 12 and 24 hours. Avoid with liver disease; maximum 30 days.
• Empagliflozin 25 mg daily is used in some patients (limited evidence).
• Demeclocycline 600 to 1200 mg daily (monitor creatinine) is a third line option.
• Low solute states (beer potomania): sodium rises rapidly as solute is given. Check sodium every 4 hours and prepare desmopressin 2 microg intravenously and 5% glucose if sodium rises too fast.

Overcorrection. Stop active treatment, give desmopressin 2 microg intravenously every 8 hours with 5% glucose 3 mL/kg over 1 hour, and recheck sodium hourly.

Monitoring. Sodium at 1 week, 1 month and every 3 to 6 months once stable. Review the drug list. Maintain tumour surveillance for unexplained inappropriate antidiuresis (repeat imaging at 6 and 12 months).

Referral and escalation. Endocrinology for adrenal and pituitary causes; oncology for malignancy; nephrology for refractory hyponatraemia; neurology for demyelination. Refer urgently for sodium under 120 mmol/L or neurological features.

Special groups

• Older adults: idiopathic inappropriate antidiuresis is common; avoid selective serotonin reuptake inhibitors where possible and use lower doses of urea; check falls and bone density.
• Post-operative patients: stop hypotonic fluids and treat pain and nausea.
• Pregnancy: avoid tolvaptan and urea; use fluid restriction, treat the cause.
• Children: avoid hypotonic fluids; for inappropriate antidiuresis restrict fluid to two thirds of maintenance.