Chronic Hyponatraemia

Chronic hyponatraemia is a serum sodium under 135 mmol/L that has been present for 48 hours or longer. It is the commonest electrolyte disorder, affecting 15 to 30% of hospital inpatients and 5 to 10% of community adults over 65 years.

The brain adapts within 48 hours by losing organic osmolytes, so cerebral oedema is rare. The cost is a vulnerability to osmotic demyelination if sodium is raised too fast.

Despite being called asymptomatic, chronic mild hyponatraemia (125 to 134 mmol/L) causes gait instability, attention deficit, falls, fractures, osteoporosis and higher mortality. Levels under 120 mmol/L cause confusion, nausea, headache, lethargy, and occasionally seizures.

Main causes:

• Syndrome of inappropriate antidiuresis (about 30 to 40%).
• Thiazide diuretics (about 20 to 30%).
• Heart failure, cirrhosis, nephrotic syndrome, advanced chronic kidney disease.
• Adrenal insufficiency and hypothyroidism.
• Low solute intake (beer potomania, tea and toast diet).
• Drugs: selective serotonin reuptake inhibitors, carbamazepine, oxcarbazepine, vincristine, cyclophosphamide, opioids, proton pump inhibitors, desmopressin.

Pathophysiology. Water retention from antidiuretic hormone, or reduced free water excretion because of low solute or low glomerular filtration, dilutes the extracellular sodium. Adaptation (loss of potassium and organic osmolytes from brain cells) protects against swelling but makes rapid correction dangerous.

• Mild to moderate: unsteady gait and falls, inattention, mild cognitive impairment, nausea, malaise, muscle cramps.
• Severe: confusion, lethargy, vomiting, seizures (rare in chronic disease unless sodium is under 115 mmol/L), coma.
• Clues to cause: oedema, ascites, jugular venous distension (hypervolaemia); dry mucous membranes, postural hypotension, weight loss (hypovolaemia); neither (euvolaemia).
• Osmotic demyelination 2 to 6 days after overcorrection: dysarthria, dysphagia, spastic quadriparesis, locked in state, behavioural change, seizures.

Red flags

• Sodium under 120 mmol/L, or any neurological symptom.
• Overcorrection risk factors: sodium under 105 mmol/L, hypokalaemia, alcoholism, malnutrition, advanced liver disease.
• Rapid rise in sodium (over 8 mmol/L in 24 hours) during treatment, especially with brisk dilute diuresis.
• Cortisol deficiency or severe hypothyroidism.

• Sodium (repeat), potassium, chloride, bicarbonate, urea, creatinine, glucose, calcium, magnesium, uric acid (low in inappropriate antidiuresis; under 240 micromol/L), serum osmolality (under 275 mosmol/kg), lipids, protein.
• Urine osmolality (under 100 mosmol/kg: primary polydipsia or low solute; over 100 mosmol/kg: antidiuretic hormone effect), urine sodium (over 30 mmol/L with euvolaemia suggests inappropriate antidiuresis or a diuretic effect; under 30 mmol/L suggests hypovolaemia, heart failure or cirrhosis).
• Morning cortisol (synacthen test if equivocal), thyroid stimulating hormone and free thyroxine, brain natriuretic peptide, liver tests, albumin, urine protein:creatinine ratio.
• Imaging for the cause of inappropriate antidiuresis: CT chest and abdomen when a lung or other malignancy is suspected, CT or MR brain for central causes.
• Fluid restriction responsiveness: urine to plasma electrolyte ratio ((urine sodium plus urine potassium) divided by plasma sodium); a ratio over 1 predicts failure of fluid restriction.

Differential diagnosis

• Pseudohyponatraemia (hyperlipidaemia, paraproteinaemia), hyperglycaemia, cerebral salt wasting, reset osmostat, cortisol deficiency, hypothyroidism, low solute states, mannitol or contrast infusion.

Principles

• Treat the cause first. Assess volume status and urine studies before choosing therapy.
• Correction limits: raise sodium by no more than 8 to 10 mmol/L in any 24 hours. In high risk patients, aim for 4 to 6 mmol/L in the first 24 hours, with a limit of 8 mmol/L.
• Check sodium every 6 hours in severe or symptomatic cases, and every 2 hours when treated with hypertonic saline or tolvaptan.

Mild or asymptomatic (sodium 125 to 134 mmol/L)

• Stop the culprit drug (thiazide, selective serotonin reuptake inhibitor, carbamazepine). Restrict fluid to 800 to 1000 mL daily. Treat the cause. Recheck sodium in 24 to 48 hours.

Moderate or symptomatic (sodium under 125 mmol/L, or any symptoms)

• Admit. For moderately severe symptoms (nausea, confusion), give 3% sodium chloride 150 mL intravenously over 20 minutes, repeated up to two times if needed.
• For severe symptoms (seizure, coma), give the same bolus, repeated up to two further times to a 5 mmol/L rise, with intensive care.
• Hypovolaemia: 0.9% sodium chloride 500 to 1000 mL over 2 to 4 hours with sodium checks every 2 hours. Watch for dilute diuresis once volume is restored.

Syndrome of inappropriate antidiuresis (fluid restriction fails or is not tolerated)

• Oral urea 15 to 30 g daily in divided doses with orange juice (rises in sodium of 3 to 8 mmol/L in 3 to 5 days). Taste can be improved with sweeteners.
• Sodium chloride tablets 3 to 6 g daily with furosemide 20 to 40 mg daily when urine osmolality is over 350 mosmol/kg (loop diuretic reduces urine concentration).
• Tolvaptan 15 mg once daily, increased to 30 mg and then 60 mg at 24 hour intervals to sodium 130 to 135 mmol/L. Start in hospital, stop fluid restriction, and check sodium at 4 to 6 hours and again at 12 and 24 hours.
• Avoid tolvaptan with liver disease and in hypovolaemia. Limit treatment to 30 days.
• Empagliflozin 25 mg daily has been used in outpatients (evidence is limited).
• Demeclocycline 600 to 1200 mg daily in divided doses is a third line option. It is nephrotoxic, so monitor creatinine.

Overcorrection

• If the sodium rises over 10 mmol/L in 24 hours (or 8 mmol/L for high risk patients): stop active therapy. Give desmopressin 2 microg intravenously every 8 hours and 5% glucose 3 mL/kg over 1 hour, repeated according to hourly sodium checks, in a high dependency unit.

Monitoring. Check sodium at 1 week and 1 month after discharge, then every 3 to 6 months. Monitor weight, blood pressure, fluid intake and renal function. Reassess the drug list at each visit.

Referral and escalation. Endocrinology or nephrology for unexplained, recurrent or refractory cases; oncology for malignancy; neurology for suspected osmotic demyelination. Escalate urgently for sodium under 120 mmol/L, neurological signs or overcorrection.

Special groups

• Older adults: avoid thiazides when possible. Check sodium 1 to 2 weeks after starting thiazides, selective serotonin reuptake inhibitors and antiepileptic drugs.
• Alcoholism and malnutrition: high risk of overcorrection as solute intake restores. Give thiamine 100 mg intravenously before feeds, replace potassium, and check sodium every 4 hours.
• Pregnancy: avoid tolvaptan and urea; use fluid restriction and treatment of the cause.
• Children: avoid hypotonic fluids and check sodium on admission.