Introduction¹

Serum sodium concentration is maintained by a homeostatic mechanism that involves thirst, antidiuretic hormone (ADH) secretion, the renin-angiotensin-aldosterone feedback system and the renal handling of sodium. Hyponatraemia is defined as a serum sodium <135 mmol/L.¹ A level <120mmol/L is considered severe. It is postulated that interleukin-6 is responsible for the non-osmotic release of vasopressin in many disease processes and this accounts for the subsequent development of hyponatraemia.²

Falsely low sodium values results can occur with very high circulating levels of lipids or proteins in which the concentration of sodium in the water phase is normal (plasma osmolality normal). This can also occur in severe hyperglycaemia as the high levels of glucose draw intracellular water into the extracellular space.

Epidemiology

Hyponatraemia is the most common electrolyte abnormality encountered in clinical practice.³ An accurate incidence of mild hyponatraemia managed in the community is impossible, as it is rarely reported. A seminal study in 1985 found a daily incidence and prevalence of 0.97% and 2.48% respectively.⁴ A Manchester study reported a prevalence rate as high as 15-30% among patients admitted to acute and intensive care units.⁵ There is no sex predilection. Infants and the elderly are most at risk because they are less likely to be able to express their thirst and autonomously control their own fluid intake. Furthermore, infants with diarrhoea, given tap water instead of electrolyte replacement fluid, and those given watered-down milk formula for reasons of economy are known to be at risk.

Presentation¹

These depend upon severity and are dictated not only by the absolute serum sodium level but also by the rate of fall. Thus, chronic mild hyponatraemia may be asymptomatic whilst a sudden fall to only 125 mmol/L from normal values can result in convulsions (usually from inappropriate intravenous fluids).

Symptoms

The clinical picture can be confusing, because mild hyponatraemia can cause significant symptoms if the drop in sodium level is sudden, whereas severe chronic hyponatraemia can cause no symptoms due to cerebral adaption.³ However, as a rule of thumb, the following may be helpful:

• Mild - anorexia, headache, nausea, vomiting, lethargy.
• Moderate - personality change, muscle cramps and weakness, confusion, ataxia.
• Severe - drowsiness.

Signs

These are again highly variable and depend on the level and rate of fall of the serum sodium. They may include:

• Neurological signs:
  • Decreased level of consciousness.
  • Cognitive impairment (e.g. short-term memory loss, disorientation, confusion, depression).
  • Focal or generalised seizures.
  • Brain stem herniation - seen in severe acute hyponatraemia; signs include coma; fixed, unilateral, dilated pupil, decorticate or decerebrate posturing, respiratory arrest
• Signs of hypovolaemia - dry mucous membranes, tachycardia, diminished skin turgor.
• Signs of hypervolaemia - pulmonary rales, S3 gallop (third heart sound), jugular venous distention, peripheral oedema, ascites.

• Plasma hypo-osmolality proportional to hyponatraemia.
• Patients with SIADH typically have inappropriately concentrated urine, with urine osmolarities in excess of 100mosmol/kg.
• Persistent renal sodium excretion of around 50-70 mmol/L.
• Normal renal, thyroid and adrenal function.

See separate article Syndrome of Inappropriate ADH Secretion.

Causes^1,6

The causes of hyponatraemia can be divided into three groups:

• Hypovolaemic (decreased total body stores of sodium).
• Normovolaemic (normal total body stores of sodium, total body excess of solute-free water).
• Hypervolaemic (increased total body stores of sodium).

Differential diagnosis¹

• Adrenal insufficiency and adrenal crisis.
• Congestive heart failure and pulmonary oedema.
• Gastroenteritis.
• Hypothyroidism and myxoedema.
• Coma.
• Renal failure - acute, chronic and dialysis complications.
• SIADH.
• Cirrhosis.
• Nephrotic syndrome.
• Psychogenic polydipsia.
• Pseudohyponatraemia (falsely low sodium reading due to presence of excessive high weight molecules in the serum, such as lipids or protein or due to analyser error).⁷

Investigations¹

• Serum sodium. Before embarking on other investigations for hyponatraemia, consider whether the sample suffered from dilution by being taken near the site of an infusion, or whether there is any chance of laboratory error. If necessary, repeat the test.
• Serum potassium. If raised, consider Addison's disease.
• Plasma osmolality:
  • Normal (280 to 300 mOsmol/kg) - consider Pseudohyponatraemia.
  • Increased (>300 mOsmol/kg) - likely to be due to hyperglycaemia.
  • Low (<280 mOsmol/kg) - further investigation depends on whether urine sodium is high or low (see 'Causes and Diagnosis of Hyponatraemia' table, above).
• Urine sodium level. If this is >20 mmol/L, a renal cause should be sought.
• Serum thyroid stimulating hormone and free thyroxine level. These should be checked to exclude hypothyroidism.
• Random serum cortisol levels or adrenocorticotropic hormone (ACTH) stimulation test. Either of these should be considered in patients with suspected adrenal suppression (e.g. patients who have recently taken oral steroids).
• Imaging. This may be contributory in some clinical situations. For example, a CXR may be required in suspected congestive cardiac failure, or a CT brain scan in patients with confusion or altered consciousness.

Management¹

No treatment for mild hyponatraemia is usually needed. Correct the underlying cause (e.g. stop thiazide).

In a symptomatic or severe form:

• Hypovolaemic. Volume replacement with isotonic saline is required (intravascular volume expanders to raise blood pressure may be needed).
• Normovolaemic. Fluid restriction to 500 ml/24 hours should be instituted to achieve a serum sodium level of 130 mmol/L. If this proves inadequate, demeclocycline (an antibiotic with ADH antagonist properties) should be used to induce partial nephrogenic diabetes insipidus (this may take two weeks to reach maximum effect). Alternatively, use furosemide + oral sodium chloride 3 g daily.
  
  The vasopressin receptor antagonist tolvaptan may be used to control SIADH. It is available in tablet form. Another drug in this group, conivaptan, available in oral and intravenous form, is used in America but is not currently prescribable in the UK. The exact role which the vaptans, as the group has become known, will play in the management of hyponatraemia, requires further research.⁸
  
  The successful use of oral urea in infants with hyponatraemia secondary to SIADH has been reported.⁹
• Hypervolaemic - use furosemide ± angiotensin-converting enzyme (ACE) inhibitors ± water restriction to <1L/24 hours.

Complications and prognosis¹

Mild hyponatraemia is associated with gait disturbance in the elderly and with falls. It can also cause a reduction in bone mass and this combination of circumstances increases the incidence of fractures.³

A sudden fall in serum sodium concentration over a 24-48 hour period can result in severe cerebral oedema, leading to cerebral herniation and death.

Conversely, too rapid correction of hyponatraemia can cause central pontine myelinolysis (also known as osmotic demyelination syndrome). This is caused by large shifts of intracellular water occurring outside the brainstem as well as in the pons. It is always associated with rapid correction to normal levels (therefore stop at 120 mmol/L and allow more gradual correction subsequently). Symptoms occur 2-4 days later, typically with quadriplegia and pseudobulbar palsy; however, it can take the form of mutism with paralysis ('locked-in' syndrome). Risk factors for this condition are female gender, hypokalaemia, alcoholism and liver transplant.

Chronic hyponatraemia (over more than 48 hours) can result in cerebral oedema but is not associated with brain herniation. Permanent neurological sequelae can arise. Other complications include rhabdomyolysis, seizures and respiratory arrest.

A 2009 study of hospitalised patients found that even a mild degree of hyponatraemia was associated with increased mortality rates.⁵ Patients with cardiovascular disease, metastatic cancer and those undergoing orthopaedic surgery were particularly at risk. Another study, however, concluded that it was the underlying disease process rather than the severity of the hyponatraemia which explained the mortality rate.¹⁰

Document references

1. Craig S; Hyponatremia in Emergency Medicine, Medscape, Apr 2010
2. Swart RM, Hoorn EJ, Betjes MG, et al; Hyponatremia and inflammation: the emerging role of interleukin-6 in Nephron Physiol. 2011;118(2):45-51. Epub 2010 Dec 22. [abstract]
3. Thompson CJ; Hyponatraemia: new associations and new treatments. Eur J Endocrinol. 2010 Jun;162 Suppl 1:S1-3. Epub 2010 Apr 20.
4. Anderson RJ, Chung HM, Kluge R, et al; Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic Ann Intern Med. 1985 Feb;102(2):164-8. [abstract]
5. Mittal R, Sheftel H, Demssie Y; Management of hyponatraemia. Br J Hosp Med (Lond). 2011 Feb;72(2):M22-5. [abstract]
6. Goh KP; Management of hyponatremia. Am Fam Physician. 2004 May 15;69(10):2387-94. [abstract]
7. Fortgens P, Pillay TS; Pseudohyponatremia revisited: a modern-day pitfall. Arch Pathol Lab Med. 2011 Apr;135(4):516-9. [abstract]
8. Gross PA, Wagner A, Decaux G; Vaptans are not the mainstay of treatment in hyponatremia: perhaps not yet. Kidney Int. 2011 Sep;80(6):594-600. doi: 10.1038/ki.2011.78. Epub 2011 Mar 30. [abstract]
9. Chehade H, Rosato L, Girardin E, et al; Inappropriate antidiuretic hormone secretion: long-term successful urea Acta Paediatr. 2011 Jun 14. doi: 10.1111/j.1651-2227.2011.02382.x. [abstract]
10. Chawla A, Sterns RH, Nigwekar SU, et al; Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol. 2011 May;6(5):960-5. Epub 2011 Mar 24. [abstract]

Internet and further reading

• Moritz ML, Ayus JC; New aspects in the pathogenesis, prevention, and treatment of hyponatremic Pediatr Nephrol. 2010 Jul;25(7):1225-38. Epub 2009 Nov 6. [abstract]
• Hyponatraemia in Adults, Guidelines and Audit Implementation Network (2010)
• Hyponatraemia, Prodigy (January 2011)