Hyponatraemia

Core

Introduction

The plasma sodium concentration is one of the most tightly regulated variables in physiology, normally kept between 135 and 145 mmol/L by the coordinated action of antidiuretic hormone (ADH) and thirst. The serum sodium is in fact a measure of body water rather than total body sodium; if water intake or retention rises faster than sodium intake, the sodium concentration falls.

This article approaches hyponatraemia in the structured way it is taught in UK pre-clinical pharmacology and renal medicine: define it, work out whether it is osmotically real, then classify by volume status to find the cause, then think carefully about how to correct it. The underlying physiology is in Control of Plasma Osmolarity and Control of Plasma Volume.

Definitions and Severity

Hyponatraemia is defined biochemically as serum sodium below 135 mmol/L. It is conventionally graded:

• Mild: 130-134 mmol/L.
• Moderate: 125-129 mmol/L.
• Severe: below 125 mmol/L.

An equally important axis is the rate of fall, which determines the symptom burden:

• Acute: documented to have developed within 48 hours.
• Chronic: present for longer than 48 hours, or duration unknown (always assume chronic if the timeline is not certain).

An acute fall to 125 mmol/L can cause cerebral oedema and seizures, whereas a chronic value of 120 mmol/L may produce only mild lethargy or be entirely asymptomatic. The brain compensates for chronic hypotonicity by extruding intracellular osmolytes (potassium, organic osmolytes such as taurine and myo-inositol) over hours to days; this is why fast correction of chronic hyponatraemia is dangerous: brain volume falls below normal as plasma osmolality is restored before the osmolytes can be put back.

Why Hyponatraemia Matters

Hyponatraemia is common: it is found in up to 20% of hospital inpatients at some point during their admission and is an independent predictor of mortality across many disease groups. It is clinically important for three reasons:

• It causes neurological symptoms: lethargy, confusion, falls, seizures and coma - through osmotic swelling of brain cells.
• It usually points to an important underlying cause: heart failure, cirrhosis, malignancy, adrenal insufficiency, hypothyroidism or diuretic-induced disturbance.
• Its treatment is itself dangerous: too rapid correction can cause irreversible osmotic demyelination, while too slow correction can leave a symptomatic patient with cerebral oedema.

Approach: Tonicity First, Volume Status Second

The classical clinical algorithm has two sequential steps.

1. Measure plasma osmolality to confirm that the hyponatraemia is genuinely hypotonic. Most hyponatraemia is hypotonic, but a small but important group is not, and the wrong treatment in those patients can be harmful.
2. Assess volume status: clinically and biochemically (urine sodium, urine osmolality): to triage the cause into hypovolaemic, euvolaemic or hypervolaemic categories.

Diagram: the standard two-step approach to hyponatraemia. Always confirm the hyponatraemia is hypotonic before assessing volume status; correction must respect the rate ceiling regardless of category.

Non-Hypotonic Hyponatraemia

Hypertonic Hyponatraemia

An additional osmotically active solute in the extracellular fluid (something that does not enter cells) draws water out of cells, diluting plasma sodium. The classical examples are:

• Hyperglycaemia. Each 5 mmol/L rise in plasma glucose above the upper limit of normal lowers measured sodium by approximately 2 mmol/L. The hyponatraemia is real (not artefactual) but the management is to correct the glucose; sodium will rise as water re-enters cells. Always correct measured sodium for glucose before interpreting.
• Mannitol and similar non-permeating solutes, used in raised intracranial pressure or as osmotic diuretics.
• Maltose in concentrated immunoglobulin preparations: an under-recognised cause in hospital practice.

Isotonic (Pseudohyponatraemia)

Pseudohyponatraemia is a laboratory artefact, not a real biochemical change. Older flame-photometric and indirect ion-selective electrode (ISE) methods report sodium as a concentration in total plasma volume, including the lipid and protein fraction. When that fraction is enlarged; in severe hypertriglyceridaemia, hypercholesterolaemia, or paraproteinaemia: the same number of sodium ions are spread across an apparently larger volume and the reported sodium falls.

Clues:

• Normal measured plasma osmolality.
• The patient is asymptomatic and has none of the usual causes.
• The discrepancy resolves when sodium is measured by direct ISE on undiluted plasma or whole blood (e.g. on a blood gas analyser).

Pseudohyponatraemia requires no treatment; the underlying lipid or protein abnormality is treated separately.

Hypotonic Hyponatraemia

Hypotonic hyponatraemia: the ‘real’ hyponatraemia: is then divided by volume status. Volume status is judged clinically (skin turgor, mucous membranes, jugular venous pressure, postural blood pressure, oedema, ascites) and supported by urine sodium and urine osmolality.

Hypovolaemic

Total body water is low; total body sodium is even lower. The patient looks dry. The cause is sodium loss in excess of water loss, with subsequent water retention by ADH (released in response to volume depletion) restoring the volume but at the cost of dilution.

Sub-classify by urine sodium:

• Urine Na⁺ < 20 mmol/L: extra-renal losses, with the kidneys appropriately conserving sodium. Causes include vomiting, diarrhoea, severe burns, third-space sequestration (pancreatitis, ileus), excessive sweating.
• Urine Na⁺ > 20 mmol/L: renal losses, with the kidney inappropriately wasting sodium. Causes include thiazide diuretics (the single most common drug-induced hyponatraemia), acute kidney injury, salt-losing nephropathy, mineralocorticoid deficiency (Addison's disease), and cerebral salt wasting.

The principle of correction is restoration of volume with isotonic saline; once volume is restored, ADH switches off and the kidney excretes the surplus water. Because this can happen abruptly, the rate of rise in serum sodium must still be controlled.

Euvolaemic

Total body sodium is essentially normal but total body water is increased. The patient appears clinically euvolaemic: no oedema, no signs of dehydration. Causes:

• Syndrome of inappropriate antidiuresis (SIADH): covered in detail in the next section.
• Hypothyroidism: severe hypothyroidism reduces cardiac output and increases ADH.
• Glucocorticoid deficiency: loss of the tonic suppression of ADH by cortisol leads to inappropriate water retention. This can be the presenting feature of Addison's disease or, more commonly in hospital practice, of secondary adrenal insufficiency from abrupt steroid withdrawal. See The Adrenal Glands and Adrenal Disorders.
• Primary polydipsia: intake of so much water that even maximally suppressed ADH and a normal kidney cannot keep up. Urine osmolality is appropriately low (< 100 mOsm/kg).
• Beer-drinker's potomania / "tea and toast" diet: inadequate solute intake limits the kidney's ability to excrete free water; the same biochemical picture as primary polydipsia at lower volumes of fluid intake.
• Exercise-associated hyponatraemia: described in marathon runners and military recruits who drink large volumes of hypotonic fluid during prolonged exercise, when ADH is non-osmotically released.

Hypervolaemic

Total body water is increased; total body sodium is also increased, but water retention has outpaced sodium retention. The patient is oedematous. In heart failure and cirrhosis the underlying mechanism is a reduced effective circulating volume sensed by arterial and cardiopulmonary baroreceptors, which drives ADH release despite total body water being supranormal. In advanced renal failure the dominant mechanism is a primary failure to excrete free water.

The principal causes are:

• Heart failure: see Heart Failure.
• Liver cirrhosis with portal hypertension and splanchnic vasodilatation: see Hepatic, Biliary and Pancreatic Pathology.
• Nephrotic syndrome: reduced plasma oncotic pressure shifts fluid into the interstitium.
• Advanced renal failure: failure to excrete water, see Chronic Kidney Disease.

Urine sodium in hypervolaemic states is usually < 20 mmol/L (avid renal sodium retention), except in advanced renal failure where the kidney can no longer respond to aldosterone.

SIADH

The syndrome of inappropriate antidiuresis is the commonest cause of euvolaemic hyponatraemia and is worth knowing in detail. ADH is released despite a normal or low plasma osmolality, with the result that the kidneys cannot excrete free water.

Diagnostic criteria (the modified Bartter and Schwartz criteria) are:

• Plasma osmolality < 275 mOsm/kg (low).
• Urine osmolality > 100 mOsm/kg (inappropriately concentrated).
• Urine sodium > 30 mmol/L on a normal salt and water intake.
• Clinically euvolaemic.
• Normal renal, adrenal and thyroid function.
• No recent diuretic use.

SIADH is a diagnosis of exclusion: thyroid and adrenal causes must be ruled out. The mnemonic SIADH itself is a useful aide-mémoire for the major aetiologies:

S: Small-cell lung cancer (and other malignancies producing ectopic ADH)
I: Infections (pneumonia, meningitis, encephalitis, abscess)
A: intrAcranial pathology (haemorrhage, tumour, trauma, surgery)
D: Drugs (SSRIs, carbamazepine, oxcarbazepine, antipsychotics, MDMA, opioids)
H: Hormonal and pulmonary causes (pneumonia, severe pain, nausea, post-operative state)

Many cases are drug-related and resolve when the offending drug is stopped. SSRIs and carbamazepine are the most frequent culprits in UK hospital practice.

Investigations

The minimum biochemical workup of any new hyponatraemia is:

• Plasma osmolality: confirms hypotonicity.
• Urine osmolality: distinguishes appropriate dilute urine (< 100 mOsm/kg, e.g. primary polydipsia) from inappropriately concentrated urine (> 100 mOsm/kg, all the SIADH-type causes).
• Urine sodium: below 20-30 mmol/L suggests volume depletion or hypervolaemic states with avid retention; above suggests renal losses or SIADH.
• Thyroid function tests.
• 9 am cortisol or short Synacthen test if there is any clinical suspicion of adrenal insufficiency.
• Glucose: correct measured sodium for hyperglycaemia.
• Urea, creatinine, eGFR, full blood count, liver function tests as part of the general work-up.

If SIADH is suspected, further investigations are directed at the underlying cause: chest imaging (looking for malignancy or pneumonia), neurological imaging if indicated, and a careful drug history.

Clinical Features

Symptoms correlate poorly with the absolute sodium concentration but well with the rate of fall:

• Mild / chronic, often asymptomatic, or non-specific lethargy, fatigue, anorexia, headache, falls (a classical presentation in older patients on thiazides or SSRIs).
• Moderate: nausea, confusion, gait disturbance, postural instability, depressed level of consciousness.
• Severe / acute: vomiting, seizures, decreased Glasgow Coma Scale, coma, respiratory arrest from cerebral oedema and brainstem herniation.

Falls and fractures in older patients with chronic mild hyponatraemia are an under-recognised consequence; the same magnitude of biochemical disturbance produces measurable gait disturbance even when the patient says they feel well.

Principles of Management

Treatment depends on the answers to three questions: how severe are the symptoms, what is the underlying cause, and how chronic is the hyponatraemia?

Symptomatic, severe hyponatraemia, for example seizures or depressed consciousness: is a medical emergency. Treatment is with carefully titrated hypertonic saline in a high-dependency setting, with the aim of raising the sodium just enough to relieve cerebral oedema (a few mmol/L over the first few hours) without triggering osmotic demyelination. Vaptans are not appropriate emergency therapy because of overcorrection risk.

For non-emergency cases the treatment is dictated by the volume-status category:

• Hypovolaemic: cautious volume replacement with isotonic saline, with close monitoring of the rate of rise of serum sodium (which can be brisk once ADH switches off).
• Hypervolaemic: fluid and salt restriction, treatment of the underlying cause (heart failure, cirrhosis, nephrotic syndrome) and judicious diuresis. Loop diuretics may help because they impair the medullary concentrating gradient.
• Euvolaemic / SIADH: first-line is fluid restriction plus treatment of the precipitating cause. Second-line specialist options include oral salt and urea (osmotic diuretic). Vaptans (e.g. tolvaptan), competitive V₂-receptor antagonists, are reserved for resistant cases under specialist supervision because they can correct sodium too quickly. Demeclocycline, a tetracycline that induces partial nephrogenic diabetes insipidus, was the older alternative and is rarely used now.

The single most important rule of correction is the rate. The British and European guidelines specify a maximum rise of:

ΔNa⁺  ≤  10 mmol/L in 24 h   and   ≤ 18 mmol/L in 48 h

Patients at higher risk of demyelination: the malnourished, those with chronic alcohol misuse, those with severe chronic hyponatraemia (Na⁺ < 110 mmol/L) and those with concurrent hypokalaemia: should be corrected even more slowly, around 6-8 mmol/L per 24 hours.

If correction overshoots, urgent specialist management is required because the risk of osmotic demyelination rises sharply.

Osmotic demyelination syndrome (ODS): previously called central pontine myelinolysis: is a delayed (typically 2-6 days after correction) catastrophic neurological event in which oligodendrocytes throughout the brain (most prominently in the central pons) undergo demyelination. The clinical picture is dysarthria, dysphagia, quadriparesis, "locked-in" syndrome, behavioural change and, sometimes, death. There is no specific treatment, only prevention.

Summary

• Hyponatraemia (Na⁺ < 135 mmol/L) is almost always a problem of too much water, not too little sodium.
• The first triage step is plasma osmolality: rule out hypertonic (hyperglycaemia, mannitol) and isotonic / pseudo- (lipids, paraprotein) causes before treating.
• Hypotonic hyponatraemia is then classified by volume status: hypovolaemic, euvolaemic or hypervolaemic. Urine sodium and urine osmolality refine this further.
• SIADH is the commonest euvolaemic cause; remember the SIADH mnemonic for aetiology and exclude thyroid and adrenal causes before making the diagnosis.
• Symptoms correlate with the rate of change rather than the absolute value. Acute severe symptoms need hypertonic saline; most chronic cases need treatment of the cause and (for SIADH and hypervolaemic states) fluid restriction.
• Correct no faster than 10 mmol/L in 24 h (8 mmol/L in high-risk patients) and 18 mmol/L in 48 h to avoid osmotic demyelination syndrome.

Reviewed by: Dr. Marcus Judge

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