Hyponatraemia: quick reference for work-up and correction

The main clinical rule

Two questions determine the initial management:

1. Does the patient have severe neurological symptoms that may be due to the hyponatraemia?
2. Is the hyponatraemia acute or chronic?

Severe symptoms require immediate treatment with hypertonic sodium chloride, whether the hyponatraemia is acute or chronic. The aim is to relieve the cerebral oedema quickly, not to normalise the plasma sodium. Chronic or minimally symptomatic hyponatraemia must be corrected in a controlled fashion, since too rapid a rise can cause osmotic demyelination syndrome [1,2].

Hyponatraemia is primarily a disorder of water balance. The plasma sodium reflects the ratio between the body's exchangeable sodium and potassium and the total body water. In hypotonic hyponatraemia the amount of water is too great in relation to the amount of dissolved cations [3].

The first five minutes

1. Assess airway, breathing and circulation.
2. Assess the neurological symptoms and at the same time exclude other acute causes, for example hypoglycaemia, poisoning, stroke, meningitis and a postictal state.
3. Check a repeat plasma sodium if the result is unexpected or does not fit the clinical picture.
4. Where possible, take the plasma osmolality, urine osmolality and urine sodium before treatment.
5. With severe symptoms: give hypertonic saline immediately. Do not wait for a complete work-up of the cause or for imaging.
6. Document the starting time, the baseline plasma sodium, the target for the first few hours, and the maximum permitted correction over 24 and 48 hours.
7. Start a fluid balance chart and hourly urine measurement. Sudden polyuria is a warning sign of impending overcorrection.

Grading

Hyponatraemia is defined as a plasma sodium below 135 mmol/L. The biochemical grade alone does not indicate how acute the condition is. A patient with a chronic plasma sodium of 112 mmol/L may be relatively unaffected, while a rapid fall from 140 to 125 mmol/L can cause marked symptoms [4].

The brain adapts to prolonged hypotonicity by extruding electrolytes and organic osmolytes. This adaptation reduces the cerebral oedema but makes the brain sensitive to a rapid increase in extracellular tonicity. This explains why acute hyponatraemia chiefly carries a risk of cerebral oedema, while rapid correction of chronic hyponatraemia carries a risk of demyelination [5].

The severity of the symptoms governs the emergency treatment

Severe symptoms

The following symptoms indicate hyponatraemic encephalopathy and warrant immediate treatment in the absence of another obvious explanation:

• Seizures
• A deeply reduced level of consciousness
• Coma
• Marked drowsiness, for example a Glasgow Coma Scale below 8
• Vomiting together with clear neurological impairment
• Respiratory failure or respiratory arrest
• Clinical signs of raised intracranial pressure or impending herniation

Moderately severe symptoms

• New confusion
• Severe headache
• Persistent nausea
• Moderately reduced consciousness
• Marked gait instability

The specificity of the symptoms is limited. In a patient with moderate symptoms the physician must judge the likelihood that the symptoms really are caused by the hyponatraemia. With severe symptoms and marked hypotonic hyponatraemia, however, treatment must not be delayed [1,3].

Severe symptoms: treat immediately

Hypertonic sodium chloride

Give hypertonic saline 30 mg/mL, 3 per cent, 100 mL intravenously over about 10 to 20 minutes. Check the plasma sodium and the clinical response. The bolus can be repeated, usually up to a total of three boluses, if severe symptoms persist and the initial rise is insufficient [3,6].

European protocols have also used 150 mL per bolus, while American and several more recent reviews use 100 mL. Weight-based dosing of around 2 mL/kg may be considered in patients of very low body weight. Follow the locally established procedure in the first instance, but do not let the difference between 100 and 150 mL delay life-saving treatment [1,6].

The target during the first few hours

• Aim for a rise in plasma sodium of 4 to 6 mmol/L.
• With ongoing seizures or impending herniation, an initial rise of approximately 2 to 4 mmol/L is needed as rapidly as is practicable.
• Stop repeating boluses once the severe symptoms have improved or the plasma sodium has risen by about 5 mmol/L.
• Thereafter continue with cause-directed treatment and controlled correction.

A rise of 4 to 6 mmol/L is usually sufficient to reduce cerebral oedema and intracranial pressure appreciably. Continuing towards a normal plasma sodium during the same treatment session has no established additional acute benefit and increases the risk of overcorrection [5,7].

In the SALSA trial of 178 patients, intermittent bolus treatment caused no more overcorrection than continuous infusion. Bolus treatment more often produced the desired early rise and less often required active relowering of the plasma sodium [6]. A later meta-analysis found no definite difference between bolus and continuous infusion with respect to overcorrection, osmotic demyelination syndrome or mortality, but the evidence base was small [7]. Bolus dosing is practical and consistent with current guidelines.

Monitoring

The patient must be cared for in a setting in which repeated sampling and immediate adjustment of treatment are possible, often an intensive care unit or an equivalent monitored area.

• Check the plasma sodium after every bolus, usually after 20 to 30 minutes.
• Thereafter check the plasma sodium at least every two to four hours until the course is stable.
• Monitor the hourly urine output.
• Check the plasma potassium, plasma glucose and renal function repeatedly.
• With a sudden increase in urine output, for example above 100 mL per hour, the plasma sodium should be checked more frequently.
• Count all sodium and potassium given as potentially contributing to the rise in plasma sodium.

Formulas for the expected rise in sodium can be used as an aid but do not replace measurement. They cannot reliably predict the water diuresis that occurs when vasopressin stimulation suddenly ceases [8].

The rate of correction in chronic or unknown duration

It is important to distinguish between the treatment target and the absolute correction limit. A reasonable target is usually lower than the maximum permitted rise.

The correction limit does not become higher merely because the patient is being cared for in an intensive care unit. Intensive care allows closer monitoring but does not protect the brain from too rapid a change in tonicity [8,9].

Many clinicians use the simpler safety rule of no more than 8 mmol/L over 24 hours in all patients with chronic or unknown duration, particularly when the plasma sodium is below 120 mmol/L. This provides a safety margin for the measurement uncertainty of the laboratory and for an unexpected water diuresis [8].

High risk of osmotic demyelination syndrome

The risk factors are:

• A plasma sodium of 105 mmol/L or lower
• Excessive alcohol consumption
• Malnutrition or a very low solute intake
• Hypokalaemia
• Advanced liver disease
• Very prolonged and marked hyponatraemia

In a systematic review of 96 published cases of osmotic demyelination, the median plasma sodium on admission was 105 mmol/L. Two thirds had been corrected by more than 10 mmol/L in the first 24 hours, but a smaller proportion developed the syndrome despite a lower reported correction. This supports a target of 4 to 6 mmol/L and a limit of 8 mmol/L in high-risk patients [9].

Potassium affects the correction of sodium

Correction of hypokalaemia can raise the plasma sodium and must be counted within the total osmotic correction. This is particularly important in thiazide-induced hyponatraemia, malnutrition and alcohol-related illness. The plasma potassium must be corrected, but with simultaneous close monitoring of the plasma sodium [10].

Overcorrection: slow it down early

The commonest cause of overcorrection is not that too much hypertonic saline has been given. It is more often that the kidney suddenly begins to excrete large volumes of dilute urine when vasopressin stimulation ceases. The plasma sodium can then rise by more than 2 mmol/L per hour [8].

Common situations are:

• Volume replacement in hypovolaemia
• Withdrawal of a thiazide
• Treatment of adrenal insufficiency
• Relief of pain, nausea or hypoxia
• Correction of a low solute intake
• Spontaneous resolution of SIAD
• Treatment of postoperative hyponatraemia

Action in impending or established overcorrection

1. Stop hypertonic or isotonic sodium administration and any other treatment that raises the plasma sodium.
2. Measure the plasma sodium, plasma potassium, urine osmolality and urine volume immediately.
3. Replace the water loss with glucose 50 mg/mL, that is 5 per cent glucose.
4. Consider desmopressin to stop the water diuresis.
5. Contact nephrology, endocrinology or intensive care.
6. Continue plasma sodium measurements every two hours until the course is stable.

A common specialist strategy is desmopressin 2 micrograms intravenously or subcutaneously, with reassessment after 6 to 8 hours. The dose must be individualised, particularly in renal failure. The glucose infusion is titrated against the current urine output and the desired plasma sodium. This should be done in a monitored setting [10,11].

Active relowering should be considered particularly if a high-risk patient has risen by more than 8 mmol/L in less than 24 hours. Experimental data and case series suggest that early relowering can interrupt the process that leads to demyelination [5,8].

Osmotic demyelination syndrome

Osmotic demyelination syndrome usually appears 2 to 6 days after too rapid correction of severe, chronic hyponatraemia. The course is often biphasic: the patient first improves as the hyponatraemia is corrected and then develops new neurological symptoms [8,10].

Typical manifestations are:

• Dysarthria
• Dysphagia
• Aspiration
• Paraparesis or tetraparesis
• Movement disorders
• Confusion or a change in behaviour
• A reduced level of consciousness
• Seizures
• Locked-in syndrome

The condition is serious and can cause permanent disability or death, but it is not always irreversible. Substantial recovery does occur. MRI can be normal when the symptoms begin, and radiological changes may appear only later. The diagnosis is therefore clinical and must not be dismissed on the basis of an early normal MRI alone [5,8].

Work-up: the diagnostic triad of tests

Where possible, take the following three tests before fluid or drug treatment is started:

1. Plasma osmolality
2. Urine osmolality
3. Urine sodium

This triad is usually more reliable than clinical assessment of volume status alone. Volume status is nevertheless important and must be assessed in parallel [12,13].

Important limitations

• Ongoing diuretic therapy can make the urine sodium hard to interpret.
• Recent fluid administration can alter both the urine sodium and the urine osmolality.
• In vomiting, the urine sodium may be higher than expected because of bicarbonaturia. Urine chloride may then be more informative.
• In renal failure the kidney cannot regulate the osmolality or the sodium content of the urine normally.
• A urine sodium below 30 mmol/L also occurs in heart failure, cirrhosis and nephrotic syndrome, even though the patient has an increased total extracellular fluid volume.
• SIAD can occur together with moderate hypovolaemia, a drug effect or a low solute intake.
• The cause can sometimes still be established after a bag of intravenous fluid, but the interpretation becomes more difficult. The claim that the cause can never be established after fluid has been given is too categorical.

Stepwise diagnosis

Step 1: is the hyponatraemia hypotonic?

Measure the plasma osmolality and the plasma glucose. Only hypotonic hyponatraemia is managed according to the usual algorithm with urine osmolality and urine sodium.

Pseudohyponatraemia

Pseudohyponatraemia can be seen in marked hypertriglyceridaemia or paraproteinaemia when sodium is measured with an indirect ion-selective electrode. The plasma osmolality and the physiological tonicity are then normal. Confirm where necessary with direct sodium measurement, for example on a blood gas analyser [3,4].

Hyperglycaemic, translocational hyponatraemia

Hyperglycaemia does not cause pseudohyponatraemia. Glucose draws water from the intracellular to the extracellular compartment and thereby lowers the measured plasma sodium. The condition is a genuine translocational, and often hypertonic, hyponatraemia.

A practical correction is to add approximately 2.4 mmol/L to the plasma sodium for every 5.6 mmol/L by which the plasma glucose exceeds 5.6 mmol/L. The correction factor varies and may be lower in moderate and higher in extreme hyperglycaemia. In hyperglycaemic hyperosmolar state, treatment must be guided by the effective osmolality and the total fluid deficit, not by the uncorrected plasma sodium alone [4,11].

Mannitol, hypertonic contrast media and certain irrigation fluids can produce a corresponding translocational state.

Step 2: is the urine maximally dilute?

A urine osmolality of 100 mosmol/kg or lower means that the vasopressin effect is suppressed. Consider:

• Primary or psychogenic polydipsia
• A very large water intake
• Beer potomania
• Tea-and-toast syndrome
• Another form of low protein and salt intake
• Recently ceased vasopressin stimulation with an ongoing water diuresis

Even when the urine is maximally dilute, water excretion is limited by the amount of osmoles that can be excreted. A patient with a very low protein and salt intake can therefore develop severe hyponatraemia at a water intake that a well-nourished person would have been able to excrete [14].

Beer potomania and other forms of low solute intake carry a substantial risk of spontaneous overcorrection when food, sodium, potassium or intravenous fluid is given. In a systematic review of 44 published cases, five patients developed osmotic demyelination after rapid correction [15].

Step 3: interpret the urine sodium and the volume status

Urine sodium 30 mmol/L or lower

Consider:

• Vomiting or diarrhoea
• Haemorrhage
• Sweating
• Third-space losses
• Heart failure
• Cirrhosis
• Nephrotic syndrome
• Recently withdrawn diuretic therapy
• A very low sodium intake

Urine sodium above 30 mmol/L

Consider:

• SIAD
• Primary or secondary adrenal insufficiency
• Ongoing thiazide or other natriuretic treatment
• Renal failure
• Salt-wasting renal disease
• Cerebral salt wasting in selected neurological situations

Additional tests and history

Take, or consider taking:

• Plasma potassium
• Plasma creatinine and estimated glomerular filtration rate
• Plasma glucose
• Plasma urea
• TSH and free T4
• Morning cortisol, or an urgent cortisol level where there is clinical suspicion
• Liver function tests
• Full blood count
• Plasma urate and, in difficult cases, the fractional excretion of urate
• Urine potassium
• Acid–base status
• The current weight and previous weight
• Fluid intake, diet and alcohol intake
• Vomiting, diarrhoea, pain and nausea
• The medication list and recently started drugs
• Signs of malignancy, or of pulmonary or central nervous system disease

Adrenal insufficiency is an important and potentially life-threatening differential diagnosis of SIAD. Secondary cortisol deficiency can give an almost identical picture with euvolaemia, a low plasma osmolality, concentrated urine and a high urine sodium. SIAD must therefore not be diagnosed before relevant cortisol deficiency has been excluded [16].

Hypothyroidism, by contrast, is rarely the sole cause of marked hyponatraemia outside myxoedema coma. If a patient with hypothyroidism has a plasma sodium below 130 mmol/L, other causes must be actively sought [17].

Diagnostic criteria for SIAD

SIAD is a diagnosis of exclusion. The typical criteria are:

• Hypotonic hyponatraemia
• A urine osmolality above 100 mosmol/kg despite hypotonicity
• A urine sodium usually above 30 mmol/L with a normal salt intake
• Clinical euvolaemia
• No significant renal failure
• No untreated adrenal insufficiency
• No other clear non-osmotic stimulus to vasopressin
• No recent or ongoing diuretic treatment that fully explains the picture

A low plasma urate and a fractional excretion of urate above about 10 to 12 per cent can support SIAD, particularly when diuretics make the urine sodium hard to interpret. Thiazide-induced hyponatraemia can, however, give a similar urate picture [11].

Common causes of SIAD are:

• Small cell lung cancer and other malignancies
• Pneumonia and other lung disease
• Stroke, haemorrhage, infection or tumour in the central nervous system
• The postoperative state
• Pain and nausea
• Drugs
• Idiopathic SIAD, particularly in older people

Treatment according to the cause

Hypovolaemic hyponatraemia

Isotonic saline is the correct first-line treatment when the hyponatraemia is caused by genuine volume depletion. When the circulation is restored, vasopressin is suppressed and the kidney can begin to excrete large volumes of dilute urine. The plasma sodium can therefore rise rapidly even after a limited amount of fluid [11].

In circulatory shock, adequate resuscitation takes priority. The risk of undertreated shock then outweighs the risk of overcorrection, but the course of correction must be monitored and slowed if necessary.

SIAD

Fluid restriction is the first-line treatment in chronic SIAD without severe symptoms. A common initial prescription is 800 to 1,000 mL of total fluid per 24 hours, including drinks, soups, nutritional supplements and intravenous fluid.

The effect is often limited. In a randomised trial in chronic SIAD, restriction to 1 litre per day produced a median rise in plasma sodium of 3 mmol/L after three days, compared with 1 mmol/L without specific treatment. More than a third still did not reach a plasma sodium of 130 mmol/L [18]. Around half of patients with SIAD respond inadequately to fluid restriction [3].

The likelihood of a poor response is higher with:

• A very high urine osmolality
• A small urine volume
• A urine sodium plus urine potassium that approaches or exceeds the plasma sodium
• Difficulty in adhering to the restriction
• Continued strong vasopressin stimulation

Ensure an adequate protein and salt intake. Fluid restriction without a sufficient solute intake can be ineffective and can worsen nutritional status.

Urea in SIAD

Oral urea increases the excretion of osmotically bound water and may be considered as second-line treatment in consultation with a specialist. In a systematic review of 23 studies including 462 urea-treated patients, the plasma sodium rose on average by about 9.6 mmol/L during treatment and by about 4.9 mmol/L in the first 24 hours. The studies were mainly uncontrolled and the commonest adverse effect was a bad taste [19].

A later meta-analysis also found a clear rise in plasma sodium, but emphasised the high heterogeneity and the absence of randomised trials [20]. Availability, the choice of product and the pattern of use vary within Swedish health care. Treatment should therefore follow local specialist practice.

Vaptans

Vasopressin receptor antagonists, chiefly tolvaptan, raise the plasma sodium by increasing the excretion of electrolyte-free water. They must not be used for the emergency treatment of severe neurological symptoms.

The Cochrane review found that vaptans raised the plasma sodium on average about 4.2 mmol/L more than control treatment, but increased the risk of rapid correction. No definite mortality benefit or improvement in quality of life has been shown [21]. A later meta-analysis specifically in SIAD found a rise of around 4.8 mmol/L after four to five days and an approximately fivefold increase in the risk of overcorrection [22].

Vaptans should therefore be started by, or in close consultation with, a physician experienced in hyponatraemia. They require frequent sampling and free access to water. Their use and reimbursement status in Sweden may differ from international recommendations.

Hypervolaemic hyponatraemia

In heart failure, cirrhosis and nephrotic syndrome the total body sodium is often increased, but the effective arterial circulating volume is low. This stimulates vasopressin and water retention.

Treat the underlying disease and avoid hypotonic fluids. Fluid restriction and loop diuretics are often used. Salt restriction may be warranted by the underlying disease, but excessive salt and protein restriction can reduce solute excretion and impair water elimination. In cirrhosis with marked hyponatraemia, treatment should be individualised together with a hepatologist or nephrologist.

Drug-induced hyponatraemia

Common drug classes are:

• Thiazides
• SSRIs and SNRIs
• Carbamazepine and oxcarbazepine
• Antipsychotics
• Cytotoxic drugs
• Desmopressin
• Proton pump inhibitors
• NSAIDs
• Opioids

Thiazides are the most important drug cause. The risk is greatest during the first weeks after initiation but remains raised thereafter. SSRIs, antipsychotics, antiepileptics and proton pump inhibitors also often cause hyponatraemia close to the start of treatment [23].

Stop the suspected drug where possible, but monitor the plasma sodium closely after withdrawal. When the drug effect ceases, a marked water diuresis can occur.

Isotonic saline in SIAD

Isotonic saline can lower the plasma sodium in SIAD. If the urine is more concentrated than the infused saline, the kidney can excrete sodium and chloride while retaining some of the water, sometimes called desalination. In one registry the plasma sodium fell by more than 2 mmol/L in a small proportion of patients with SIAD after isotonic saline [4].

This does not mean that every patient with possible SIAD is barred from a diagnostically or haemodynamically justified fluid challenge. If hypovolaemia is a reasonable differential diagnosis, a limited amount of isotonic fluid can be given under close monitoring. A clear improvement with increasingly dilute urine supports hypovolaemia, while an unchanged or falling plasma sodium argues for SIAD. Do not, however, give several litres of isotonic saline as a matter of routine to a clinically euvolaemic patient with concentrated urine [24].

Hyponatraemia in older people

Older people are at higher risk because of reduced renal function, a lower total body water, comorbidity, a low solute intake and polypharmacy. Mild chronic hyponatraemia is not always clinically silent. It has been associated with impaired attention, gait instability, falls, osteoporosis and fractures [4,5].

A meta-analysis of 15 studies including a total of 51,879 patients found that hyponatraemia was associated with approximately a doubling of the risk of falls and of hip fracture. The associations are largely observational and do not prove that normalising the plasma sodium eliminates the risk, but they justify actively investigating the cause even in mild hyponatraemia [25].

Special situations

Acute water intoxication

This can be seen in psychogenic polydipsia, endurance sport, MDMA use or the erroneous administration of hypotonic fluid. The risk of cerebral oedema is high, since the brain has not had time to adapt. With severe symptoms, hypertonic saline is given according to the same bolus principle. A spontaneous water diuresis can then produce a very rapid rise in sodium [26].

After pituitary surgery

Delayed SIAD and hyponatraemia often appear several days after the operation, sometimes after discharge. The course can turn into vasopressin deficiency with sudden polyuria. The plasma sodium and fluid balance therefore need to be monitored according to the neuroendocrine protocol [3].

Suspected adrenal crisis

Take cortisol and ACTH if this can be done without delaying treatment. Where an adrenal crisis is clinically suspected, hydrocortisone and circulatory support must be given immediately. The cortisol result must not be awaited. Be prepared for a rapid rise in plasma sodium once cortisol treatment removes the vasopressin stimulus [16].

The need for dialysis

Patients with a very low plasma sodium who also need dialysis are at risk of too rapid correction. Continuous renal replacement therapy or a specially adapted dialysate may be needed. Plan this together with nephrology and intensive care.

Red flags and common pitfalls

• Delaying hypertonic saline in seizures or coma. Severe symptomatic hypotonic hyponatraemia is an acute neurological emergency.
• Trying to normalise the plasma sodium in the first 24 hours. The aim in the acute phase is symptom relief after 4 to 6 mmol/L, not a normal laboratory value.
• Permitting a greater correction merely because the patient is in an intensive care unit. The correction limit is determined by the risk to the brain, not by the level of care.
• Not monitoring the urine output. Sudden polyuria often precedes overcorrection.
• Forgetting that potassium raises the plasma sodium.
• Giving isotonic saline as a matter of routine in SIAD.
• Calling hyperglycaemic hyponatraemia pseudohyponatraemia. It is a translocational hyponatraemia.
• Diagnosing SIAD without excluding cortisol deficiency.
• Attributing marked hyponatraemia to hypothyroidism alone. Outside myxoedema coma, other causes must be sought.
• Correcting a low solute intake aggressively. Food, protein, salt and intravenous fluid can rapidly restore water excretion.
• Trusting calculation formulas blindly. They do not predict a sudden water diuresis.
• Believing that osmotic demyelination syndrome must be visible on MRI straight away.
• Stopping monitoring once the plasma sodium has reached 125 or 130 mmol/L. It is the rate of change and the continuing diuresis that determine the risk.
• Not investigating mild hyponatraemia in older people. Drugs, malnutrition, the risk of falls and occult malignancy may be clinically important.
• Using a vaptan or urea as an emergency substitute for hypertonic saline in seizures or coma.

A practical on-call checklist

With severe symptoms

• Secure airway, breathing and circulation.
• Take the diagnostic triad of tests if this does not delay treatment.
• Give hypertonic saline 3 per cent, 100 mL over 10 to 20 minutes.
• Check the plasma sodium after the bolus.
• Repeat if severe symptoms persist, usually to a maximum of three boluses.
• Stop when the symptoms have improved or the plasma sodium has risen by about 5 mmol/L.
• Monitor the hourly urine output and the plasma sodium at least every two to four hours.
• Define the 24-hour limit from the outset.

In chronic or unknown duration without severe symptoms

• Confirm that the hyponatraemia is hypotonic.
• Take the plasma osmolality, urine osmolality and urine sodium.
• Check the glucose, potassium, creatinine, TSH, free T4 and cortisol.
• Take a careful drug and nutritional history.
• Treat the cause.
• Aim usually for 4 to 6 mmol/L per 24 hours.
• Do not exceed 8 mmol/L per 24 hours in high-risk patients.
• Monitor the urine output and be prepared to give glucose 50 mg/mL and desmopressin.

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