Approach

Hypernatraemia is essentially a laboratory diagnosis, defined as a serum sodium concentration of >145 mmol/L. Severe hypernatraemia has variously been defined as a serum sodium concentration of >152 mmol/L, >155 mmol/L, or >160 mmol/L.[2][3][4]​ However, there is no consensus as to the exact level. Hypernatraemia is hospital acquired in the majority of cases.[11][12]​​[13][15]​ A detailed history and thorough physical examination (including an evaluation of the patient’s volume status and mental status) are important to diagnose the underlying cause.[1]​ Evaluation of urine osmolality and electrolytes is also helpful in determining the underlying cause and aids in formulating a treatment plan.

History

The history should focus on the following three factors:

  • Sources of fluid loss

  • Fluid intake (hypernatraemia typically requires lack of access to water or impaired thirst mechanism)

  • Urine output.

Risk factors for the development of hypernatraemia include:

  • High urine or stool output (e.g., renal dysfunction, Clostridium difficile infection)

  • The inability to drink water/limited access to water (e.g., older/dementia patients, ventilated/intubated patients in intensive care unit, impaired mental status)

  • The inability to concentrate urine (e.g., diabetes insipidus, osmotic diuresis, obstructive uropathy, renal failure).

The patient's age may give a clue to the underlying aetiology:

  • Neonates may develop hypernatraemic dehydration due to inadequate fluid intake, usually related to poor lactation or insufficient maternal milk supply.[69] Neonatal hypernatraemic dehydration​ is associated with a free water deficit.[70] The neonates may present with non-specific features such as jaundice, high temperature, poor oral intake, lethargy and low urine output.[69] Correction of sodium levels in neonates should be undertaken​​ cautiously to avoid adverse effects. There is no consensus as to method or rate of correction, though common recommendations are to correct sodium levels by no more that 0.5 mmol/L/hour with gradual correction over 48 hours.[69][70]​​

  • Infants are at risk of hypernatraemia if they inadvertently ingest a large volume of salt, as they do not often have free access to water. Central diabetes insipidus can be a congenital condition, usually due to a vasopressin (V2) mutation on the X chromosome.[54] Congenital nephrogenic diabetes insipidus is rare.

  • Older patients are particularly at risk of hypernatraemia due to various factors, including an inability to concentrate urine properly, lack of thirst (e.g., due to dementia), an inability to access water (e.g., due to altered mental status from illness, stroke, immobility), and/or increased insensible losses (e.g., due to fever and/or infection). Older patients living in nursing homes are most likely to develop hypovolaemic hypernatraemia due to inadequate free water intake, especially patients with dementia.[2][71]​

A complete medical history, including the presence of any chronic conditions (e.g., poorly controlled diabetes mellitus, renal impairment) or acute conditions (e.g., viral gastroenteritis) should be elicited. A history of traumatic brain injury or any other insult to the brain (e.g., vascular syndromes, infections, tumours, or aggressive surgery for craniopharyngioma, Rathke's cleft cyst, or other hypothalamic tumours) may be suggestive of central diabetes insipidus.[2] Recent extreme heat exposure or exercise, cutaneous burns, fever, or infection may point towards fluid loss as a cause.

A complete medication history should be taken, as the following drugs have been associated with hypernatraemia:

  • Lithium: a mood stabiliser that is commonly associated with nephrogenic diabetes insipidus in adults, usually after chronic administration. This is possibly due to a significant down-regulation of the aquaporin 2 collecting duct (AQP2) gene.[52][54] Patients on chronic lithium therapy have a 50% chance of developing nephrogenic diabetes insipidus,[55] which can sometimes persist even after lithium therapy is stopped.

  • Other drugs reported to cause diabetes insipidus more rarely include: vasopressin receptor antagonists, demeclocycline, ethanol, foscarnet, temozolomide, dexmedetomidine, cisplatin, aminoglycosides, amphotericin B, penicillin derivatives, vitamin A or D excess, colchicine, vinblastine, and phenytoin.[2][53][56][59][60][61]

  • Loop diuretics: cause an increase in free water excretion.

  • Intravenous mannitol: can cause osmotic diuresis.

  • Laxative or bowel cleansing agents: can cause severe diarrhoea.

  • Activated charcoal/sorbitol: hypernatraemia has been reported in patients treated with this drug combination for poisoning due to profuse diarrhoea.[28][29]

  • Sodium polystyrene sulfonate/sorbitol: has been associated with hypernatraemia when used to treat patients with hyperkalaemia.

  • Corticosteroids: increase urea production and are associated with an increased risk of hypernatraemia, particularly when used in high doses e.g., in treatment of sepsis.[56][58]

  • Fosfomycin (when administered intravenously), has been associated with hypernatraemia.[73]

  • Topiramate can cause hypernatraemia.[74]

Iatrogenic causes (e.g., inadvertent administration of hypertonic saline, administration of hypertonic sodium bicarbonate solution in patients with metabolic acidosis) are common in hospitalised patients.[11][12]​​[13][75] Ingestion of large quantities of salt (either intentionally or accidentally) should also be considered, especially in children. Rarely, features of Cushing's syndrome or hyperaldosteronism may be present in mild cases of hypernatraemia.

Symptoms of hypernatraemia are nonspecific and depend on the underlying cause and the severity. If hypernatraemia is acute (generally defined as onset within <48 hours), the higher osmolality in the extracellular space causes water to move out of brain cells causing the brain to shrink. This shrinkage can lead to neurological manifestations, including lethargy, weakness, and irritability. If severe, adverse manifestations can include intracranial haemorrhage, seizures, stupor, coma, and death.[2][66] Severe polyuria, polydipsia, and dilute urine may indicate diabetes insipidus.

Physical examination

Examination should focus on the volume status, particularly noting severe hypovolaemia, which generally needs urgent correction. Hypernatremia that presents on admission to the hospital generally occurs in the setting of hypovolaemia and inadequate free water intake, and is most commonly associated with older dementia patients who have a fever and/or infection.[1][2][12]​​​[23][24][25][26]​​​

Signs of hypovolaemia include:

  • Oliguria

  • Weight loss

  • Orthostatic hypotension

  • Decreased jugular venous pressure

  • Tachycardia

  • Dry mucous membranes.

Diabetes insipidus is characterised by the output of a large volume of dilute urine. The presence of dilute urine in the context of hypernatraemia is diagnostic for diabetes insipidus. Most of these patients never develop hypernatraemia as they have an intact thirst mechanism and, therefore, are able to drink water when necessary. However, in those unable to drink water, severe hypernatraemia can develop rapidly. See Diabetes insipidus.

Adipsia or hypodipsia is a very rare cause of hypovolaemic hypernatremia and can be seen in patients with normal mental status who lack a sense of thirst.[31][32][33]​​[76]

Initial investigations

A full serum electrolyte panel with glucose, urea, and creatinine should be ordered in all patients to assess for the presence of other electrolyte abnormalities, renal impairment, and uncontrolled diabetes mellitus. A serum sodium concentration >145 mmol/L confirms the presence of hypernatraemia.[1]​ Severe hypernatraemia has variously been defined as a serum sodium concentration of >152 mmol/L, >155 mmol/L, or >160 mmol/L.[2][3][4] However,​ no consensus has been reached on the exact level. Extremely high serum sodium levels occur in salt poisoning.

Once hypernatraemia has been confirmed, further investigations should be ordered to help determine the aetiology and formulate a treatment plan, and include:

  • Urine osmolality

  • Urine electrolytes

  • Urine flow rate.

Urine osmolality should be measured in all patients with hypernatremia as it may help determine the underlying aetiology.

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Urine electrolytes and urine flow rate are used to calculate the electrolyte-free water excretion (also known as electrolyte-free water clearance).[Figure caption and citation for the preceding image starts]: Electrolyte-free water excretion formula. V = urine flow rate. UNa = urine concentration of sodium (mmol/L). UK = urine concentration of potassium (mmol/L). PNa = plasma concentration of sodium (mmol/L)Created by the BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@1e8bc1cc​The electrolyte-free water excretion value indicates how much electrolyte-free water is being lost through the urine at any given time.[64][68][77]​​​​ However, it does not provide a value for the total amount of free water needed to correct the hypernatraemia.[78] A low value (<0.5 L/day) suggests inadequate free water intake, a high value (≥1 L/day) suggests large free water losses, while a very high value (>5 L/day) suggests diabetes insipidus.

Other investigations

A desmopressin challenge test should be ordered in patients with suspected diabetes insipidus. The result can be used to differentiate between central diabetes insipidus (where a lack of vasopressin, also known as arginine vasopressin [AVP] or antidiuretic hormone [ADH], responds to exogenous vasopressin administration) and nephrogenic diabetes insipidus. Patients with central diabetes insipidus will respond with decreased urine output and increased urine osmolality. Nephrogenic diabetes insipidus is diagnosed in a patient who is suspected of having diabetes insipidus who does not respond to exogenous vasopressin administration.

A serum AVP level may be useful to help distinguish central diabetes insipidus from nephrogenic diabetes insipidus as the level is low in patients with central diabetes insipidus.

Magnetic resonance imaging or computed tomography of the brain is recommended in patients with central diabetes insipidus to determine the underlying cause.

Other tests may be required, as determined by the history and examination, to evaluate the underlying cause, including serum creatine phosphokinase (CPK) level (may be helpful in hypernatraemia associated with rhabdomyolysis), and renal ultrasound (in patients with renal disease).

Assessing dehydration in older patients

Stand-alone diagnostic tests (including bioelectrical impedance assessment of intracellular or extracellular water, dry mouth, feeling thirsty, fluid intake, heart rate, urine colour, urine specific gravity, and urine volume) should not be relied upon to assess water-loss dehydration in older people.[79] Individual tests lack specificity and/or sensitivity in this population.

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