Approach

Hyponatraemia is essentially a laboratory diagnosis, defined as a serum sodium concentration of <135 mmol/L.​[2][3]​ History and physical examination establish volume status and are used to determine if the patient is hypovolaemic, hypervolaemic, or euvolaemic. A thorough review of any underlying medical conditions and medications should be undertaken. The cause of the hyponatraemia is often apparent from the history and examination; however, some causes can only be identified with appropriate investigations. Patients with asymptomatic, mild hyponatraemia (130-135 mmol/L) may be managed initially in a community setting.[41]​ Initial assessment should also include glycaemic status, to establish whether there is a hyperglycaemic-induced hyponatraemia, and the exclusion of pseudohyponatraemia caused by excessive plasma lipids or proteins. Patients with onset of hyponatraemia in <48 hours, or those with symptoms, require urgent assessment.

History

Hyponatraemia can be present on admission to hospital, or it can develop (or worsen) during the hospital stay as a result of several factors including organ failure, medications, or the post-operative state.[2][11][24]

Patients should be asked about fluid intake.

Hypovolaemic hyponatraemia:

  • Recent excessive fluid losses should be noted (e.g., severe diarrhoea or vomiting), which may point to hypovolaemic hyponatraemia. Third spacing of fluids (e.g., in pancreatitis or severe hypoalbuminaemia) may also lead to hypovolaemic hyponatraemia. A history of diabetes mellitus should be sought.

Hypervolaemic hyponatraemia:

  • Typically associated with congestive heart failure, cirrhosis, nephrotic syndrome, or acute kidney injury/chronic kidney disease.

Euvolaemic hyponatraemia:

  • May result from excessive fluid intake, as might occur during high-intensity physical exercise (e.g., marathon running, military training, wilderness exploration).[16][40]​​ Such intake may be associated with acute, symptomatic hyponatraemia.[40]​

  • Potomania is caused by high fluid intake in the setting of very low solute and electrolyte intake. Maximal urinary dilution may be impaired by very low protein intake, and it also reduces with advancing age. It can occur in association with inadequate diets (i.e., very low-calorie diets with high fluid intake, such as the ‘tea and toast’ diet), crash diets and alcohol use disorder with a high intake of beer. If a history of alcohol use disorder is present or suspected, the CAGE questionnaire can be used. MDCalc: CAGE questions for alcohol use Opens in new window A score >2 is considered indicative of probable excessive alcohol intake.

  • Although less common, euvolaemic hyponatraemia related to excessive fluids can occur in the setting of surgery or medical testing such as cardiac catheterisation or colonoscopy.

Pseudohyponatraemia:

  • Suspected in settings such as history of multiple myeloma (due to high serum protein levels) or severe hyperlipidaemia.

A drug history should be taken, since a number of medications are associated with hyponatraemia including:

  • Vasopressin analogs: desmopressin, oxytocin

  • Medications that stimulate vasopressin release or potentiate the effects of vasopressin: selective serotonin-reuptake inhibitors and most other antidepressants,​​ morphine and other opioids[18][19]​​

  • Medications that impair urinary dilution: thiazide diuretics​[12][15][20]​​

  • Medications that cause hyponatraemia by an uncertain mechanism of action: carbamazepine or its analogs, vincristine, nicotine, antipsychotics, chlorpropamide, cyclophosphamide, non-steroidal anti-inflammatory drugs[17]

  • Illicit drugs: methylenedioxy-methamfetamine (MDMA or ecstasy) causes vasopressin release, and has been associated with acute, life-threatening hyponatraemia

Syndrome of inappropriate antidiuretic hormone (SIADH) is a common cause of euvolaemic hyponatraemia, and is a diagnosis of exclusion. Hypothyroidism and adrenal insufficiency must be excluded for a diagnosis of SIADH to be made.[4]​ SIADH is associated with many lung diseases, particularly those resulting from infection such as pneumonia; central nervous system diseases, such as subarachnoid haemorrhage, meningitis, or encephalitis; or malignancies, most commonly small cell lung cancer, or gastrointestinal tract cancers.[4]​ It can also be due to other non-specific causes (e.g., medications, pain, nausea, stress, general anaesthesia), and an idiopathic form of SIADH that is associated with aging may occur.[23][31]​ At times, SIADH may be the presenting finding of a malignancy, or it may precede the malignancy diagnosis. If there is no identifiable cause, the patient can be diagnosed as having idiopathic SIADH.[4]

If hyponatraemia develops acutely (i.e., <48 hours), the brain does not have time to adapt and cerebral oedema occurs, leading to symptoms including nausea, vomiting, altered mental status, and eventually seizures and/or brain herniation and death. This is a medical emergency requiring hypertonic 3% saline for management.[5]​ With more chronic hyponatraemia, brain adaptation occurs with the loss of intracellular osmolytes, returning brain volume to normal after approximately 48 hours. These patients are generally asymptomatic or present with only mild cognitive symptoms (e.g., confusion, balance difficulties).

If a patient presents with acute hyponatraemia and a history of altered mental status (e.g., schizophrenia or psychotic depression) with seizures, a diagnosis of primary polydipsia should be considered.

Physical examination

The patient should be examined to determine volume status, looking for signs of dehydration or volume overload.[3]

Signs of volume depletion include:

  • Low urine output

  • Weight loss

  • Orthostatic hypotension

  • Decreased jugular venous pressure

  • Poor skin turgor

  • Dry mucous membranes

  • Absence of axillary sweat

  • Absence of oedema

Signs of volume overload include:

  • Oedema and/or ascites

  • Rales or crackles on lung auscultation

  • Significant weight gain

  • Raised jugular venous pressure

Polyuria is most common in primary polydipsia.

At times the physical examination and vital signs may be normal in patients with hypovolaemic hyponatraemia; therefore, the cause may not initially be clear.[3]​ Further investigations (e.g., urine electrolytes, fractional excretion of sodium) aid diagnosis. Patients with hypervolaemic hyponatraemia typically have signs and symptoms that point to a diagnosis of heart failure, cirrhosis, or nephrotic syndrome, although kidney disease should also be considered.

Exclusion of hypertonic hyponatraemia or pseudohyponatraemia

Serum glucose (random or fasting) should be checked to exclude hyperglycaemia-associated hyponatraemia. If the patient is hyperglycaemic, a sodium correction formula should be used if the glucose level is >5.5 mmol/L (100 mg/dL).

The most accurate correction formula is:

This formula should be used to determine if true hyponatraemia is present.[42] It is important to remember that even in the setting of hyperglycaemia, true hyponatraemia may occur. The corrected sodium level may be low (hypotonic hyponatraemia), normal (isotonic hyponatraemia), or high (hypertonic hyponatraemia). For example, in diabetic ketoacidosis, urine losses may be isotonic and water intake may be high leading to an underlying hypotonic hyponatraemia that is unmasked once glucose levels are lowered with insulin. Similarly, a patient with uncontrolled diabetes mellitus and congestive heart failure may have a low serum sodium concentration once the hyperglycaemia is corrected.

To exclude the possibility of pseudohyponatraemia, blood lipids and proteins should be measured before proceeding with further investigations. Serum osmolality will be normal in patients with pseudohyponatraemia (i.e., total body sodium and water are unchanged, with no shift of fluid between intracellular and extracellular compartments). The use of ion-specific electrodes to measure sodium directly may help reduce the incidence of pseudohyponatraemia.

Investigations

[Figure caption and citation for the preceding image starts]: Algorithm for the diagnosis of hypotonic hyponatraemia. SIADH, syndrome of inappropriate antidiuretic hormoneCreated by BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@568620ad

A full serum electrolyte panel with glucose, urea, and creatinine should be ordered in all patients. A serum sodium concentration <135 mmol/L (corrected for hyperglycaemia) confirms the presence of hyponatraemia.

The following tests should also be ordered in all patients (preferably before the administration of intravenous fluids) to help establish the underlying aetiology:

  • Serum osmolality

  • Urine sodium and creatinine concentrations

  • Urine osmolality

Serum osmolality

Serum osmolality can differentiate between hypotonic, hypertonic, and isotonic hyponatraemia:​[2][3] [ Osmolality Estimator (serum) Opens in new window ] ​​​​​​​

  • Serum osmolality <275 mmol/kg: indicates hypotonic hyponatraemia

  • Serum osmolality >295 mmol/kg: indicates hypertonic hyponatraemia

  • Serum osmolality normal: indicates isotonic hyponatraemia (pseudohyponatraemia)

Hypertonic hyponatraemia is due to either hyperglycaemia or the administration of hypertonic fluids (e.g., mannitol, sorbitol). Isotonic hyponatraemia indicates pseudohyponatraemia. Hypotonic hyponatraemia has a wider range of causes, and can be further classified as:

  • Hypovolaemic: clinical features of volume depletion present

  • Hypervolaemic: clinical features of fluid overload present

  • Euvolaemic: absence of signs of volume depletion or overload

Urine sodium concentration

It may be difficult to distinguish between hypovolaemia and euvolaemia on physical examination. A spot urine test allows urinary sodium concentration to be measured quickly and conveniently and may help confirm the presence of hypovolaemia or euvolaemia.

The urine sodium concentration, in combination with the volume status of the patient from examination, can provide further clues to the classification and aetiology.

[Figure caption and citation for the preceding image starts]: Aetiologies of hypotonic hyponatraemia (serum osmolality <275 mmol/kg). SIADH, syndrome of inappropriate antidiuretic hormoneProduced by the BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@105788b

Hypovolaemic hyponatraemia:

  • Urine sodium concentration >20 mmol/L: indicates renal sodium losses (e.g., diuretics)

  • Urine sodium concentration ≤20 mmol/L: indicates hypovolaemia with non-renal sodium losses (e.g., gastrointestinal losses)

Hypervolaemic hyponatraemia:

  • Urine sodium concentration >20 mmol/L: indicates acute kidney injury/chronic kidney disease or diuretic use

  • Urine sodium concentration ≤20 mmol/L: indicates congestive heart failure, cirrhosis, or nephrotic syndrome

Euvolaemic hyponatraemia:

  • Urine sodium concentration is >20 mmol/L in most patients with euvolaemic hyponatraemia; however, patients with a concomitant low sodium intake may have a low urinary sodium.

Although a spot urine sodium test can be helpful if the result is very low, the fractional excretion of sodium provides a more accurate assessment of volume status as it corrects for the effect of variations in urine volume on the urine sodium. [ Fractional Excretion of Sodium (SI units) Opens in new window ] ​​​​ The fractional excretion of sodium is calculated using the following formula:

A value of <1% usually indicates pre-renal causes of hyponatraemia.

Urine osmolality

Urine osmolality can be used to further evaluate the cause of hyponatraemia in patients, especially those with euvolaemic hyponatraemia. Urine osmolality is high (i.e., ≥300 mmol/kg) in patients with hypovolaemic or hypervolaemic hyponatraemia, but can be variable in patients with euvolaemic hyponatraemia:[5]

  • High (≥300 mmol/kg): indicates SIADH due to the inappropriate dilution of plasma as a result of pathological vasopressin release, or may be due to drug-related effects.[2]

  • Intermediate (150-300 mmol/kg): indicates potomania or a partial effect of medications or mild SIADH in conjunction with high fluid intake.

  • Low (≤100-150 mmol/kg): indicates primary polydipsia.

Urine osmolality can be variable in hyponatraemia due to prolonged physical exercise with high fluid intake. This is because it reflects vasopressin release with high urine osmolality initially, followed by low urine osmolality as self-correction and aquaresis (loss of water) occur.

Electrolyte-free water excretion

Urine electrolytes and urine flow rate are used to calculate the electrolyte-free water excretion (also known as electrolyte-free water clearance). This value helps to determine the treatment plan by determining ongoing water gains or losses.

It should be calculated in patients with hyponatraemia using the following formula:

  • Electrolyte-free water excretion = V × [1 - (UNa + UK)/(PNa)]

Where V is the urine flow rate, UNa is the urine concentration of sodium (mmol/L), UK is the urine concentration of potassium (mmol/L), and PNa is the plasma concentration of sodium (mmol/L).

The resulting value indicates how much electrolyte-free water is being lost through the urine at any given time (e.g., per hour, per day). This formula can be used to help determine if water is being retained (a negative value) as in SIADH, or excreted (positive value) as in polydipsia or potomania.[43][44]

Other investigations

Thyroid function tests should be ordered to exclude hypothyroidism, and serum cortisol level adrenocorticotrophic hormone testing to exclude adrenal insufficiency in patients with euvolaemic hyponatraemia. Hypothyroidism and adrenal insufficiency must be excluded for a diagnosis of SIADH to be made.[4]

A computed tomography scan of the brain, chest, and/or abdomen/pelvis should be ordered to identify potential causes of SIADH and should be guided by history and physical examination.[4]​ At times, SIADH may be the presenting finding of a malignancy, or it may precede the malignancy diagnosis.

Other tests targeted at diagnosing the underlying cause may be required.

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