15.1 Sodium & Water Disorders
Key Takeaways
- Hypotonic hyponatraemia must first be differentiated from pseudohyponatraemia (hyperlipidaemia, paraproteinaemia) and hypertonic hyponatraemia (hyperglycaemia; corrected [Na+] = measured [Na+] + 0.3 × [glucose - 5.5]).
- Clinical volume assessment guides the differential of hypotonic hyponatraemia: hypovolaemic (urinary Na <30 mmol/L indicates extra-renal losses, >30 mmol/L indicates renal losses/Addison's), euvolaemic (SIADH, hypothyroidism, secondary adrenal insufficiency; urinary Na >30 mmol/L, urine osmolality >100 mOsm/kg), and hypervolaemic (heart failure, cirrhosis, nephrotic syndrome vs acute/chronic kidney disease).
- The cornerstone of chronic hyponatraemia management is avoiding Osmotic Demyelination Syndrome (ODS): the safe rate of correction must not exceed 8–10 mmol/L in 24 hours (strictly 4–6 mmol/L/24h in high-risk patients with alcoholism, malnutrition, or advanced cirrhosis).
- Acute severe symptomatic hyponatraemia (presenting with seizures, acute coma, or cardiorespiratory arrest) is an immediate medical emergency requiring a 150 mL bolus of intravenous 3% hypertonic saline over 20 minutes, repeatable up to twice to elevate sodium by 4–6 mmol/L and abort cerebral herniation.
- Hypernatraemia is managed by calculating total body water deficit and rehydrating with 5% dextrose or 0.45% saline, ensuring serum sodium decreases by no more than 10 mmol/L in 24 hours to prevent fatal rebound cerebral oedema.
Water balance is governed by hypothalamic osmoreceptors that modulate thirst and arginine vasopressin (AVP / antidiuretic hormone [ADH]) secretion from the posterior pituitary. Serum osmolality is maintained within narrow physiological limits (275–295 mOsm/kg). Serum sodium concentration is an index of water homeostasis, not total body sodium content. Mastery of the diagnostic algorithms for hyponatraemia, safe sodium correction limits, and hypernatraemia is essential for MRCP(UK) Part 1.
Calculated Serum Osmolality = 2 × [Na+] + [Glucose] + [Urea] (all in mmol/L)
1. Initial Diagnostic Triage: Ruling Out Pseudo- and Hypertonic Hyponatraemia
When confronted with a low serum sodium ([Na+] < 135 mmol/L), the first mandatory step is assessing measured serum osmolality to differentiate true hypotonic hyponatraemia from pseudohyponatraemia and hypertonic hyponatraemia.
Low Serum Sodium (<135 mmol/L)
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Measure Serum Osmolality
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Normal Osmolality High Osmolality Low Osmolality
(275-295 mOsm/kg) (>295 mOsm/kg) (<275 mOsm/kg)
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Pseudohyponatraemia Hypertonic Hyponatraemia True Hypotonic
• Severe hyperlipidaemia • Hyperglycaemia (DKA/HHS) Hyponatraemia
• Paraproteinaemia • Mannitol infusion │
(Myeloma, Waldenström) • Translocational shift Assess Volume
Status
Normal Serum Osmolality (275–295 mOsm/kg): Pseudohyponatraemia
- Pathophysiology: Plasma normally comprises 93% aqueous solution and 7% non-aqueous solid phase (proteins and lipids). Standard laboratory autoanalysers use indirect ion-selective electrodes (ISE), which dilute the sample by a fixed factor before measurement, assuming normal 7% solids.
- In marked hyperlipidaemia (severe hypertriglyceridaemia >15 mmol/L) or profound paraproteinaemia (multiple myeloma, Waldenström's macroglobulinaemia), the non-aqueous solid phase expands to 15–20% of total volume. The aqueous phase sodium concentration is entirely normal, but dilution over-estimates total sample volume, producing an artificially low reported sodium concentration.
- Resolution: Measure sodium using direct ISE (available on point-of-care blood gas analysers), which measures electrolyte activity directly in undiluted plasma water and gives the true normal value.
Elevated Serum Osmolality (>295 mOsm/kg): Hypertonic Hyponatraemia
- Pathophysiology: Osmotically active solutes confined to the extracellular fluid (ECF)—most commonly glucose in diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS), or exogenous mannitol—draw water out of cells into the ECF via osmosis. This translocational water shift dilutes extracellular sodium.
- Correction Formula (Katz / Hillier): Corrected [Na+] = Measured [Na+] + 0.3 × ([Glucose] - 5.5) (In UK practice, for every 10 mmol/L rise in blood glucose above 5.5 mmol/L, serum sodium drops by approximately 3.0 mmol/L). Failure to calculate the corrected sodium can lead to catastrophic mistreatment with hypertonic fluids.
2. True Hypotonic Hyponatraemia: Clinical Volume Assessment
True hypotonic hyponatraemia (<275 mOsm/kg) represents an excess of water relative to sodium. The diagnostic algorithm is organized by bedside clinical assessment of Extracellular Fluid (ECF) volume status combined with spot urinary sodium and urine osmolality:
| Volume Status | Spot Urine Na (mmol/L) | Urine Osmolality (mOsm/kg) | Clinical Etiologies | Pathophysiology & Management |
|---|---|---|---|---|
| Hypovolaemic (Tachycardia, postural drop, dry mucous membranes, flat JVP, reduced skin turgor) | <30 mmol/L | Concentrated (>300–400) | Extra-renal losses: Severe diarrhoea, vomiting, burns, pancreatitis, bowel obstruction ('third-spacing') | Intravascular volume depletion stimulates carotid/aortic baroreceptors, triggering non-osmotic AVP release and maximal renal sodium retention via aldosterone. Treatment: Intravenous 0.9% sodium chloride rehydration. |
| Hypovolaemic | >30 mmol/L | Variable (often <300 or inappropriately concentrated) | Renal losses: Thiazide diuretics, loop diuretics, primary adrenal insufficiency (Addison's), Cerebral Salt Wasting (CSW), salt-losing nephropathy | Inability of the kidney to retain sodium despite hypovolaemia. Thiazides inhibit DCT sodium reabsorption while preserving medullary concentration. Addison's lacks aldosterone, driving renal natriuresis and hyperkalaemia. Treatment: 0.9% sodium chloride; hydrocortisone and fludrocortisone in Addison's. |
| Euvolaemic (No oedema, normal JVP, moist mucous membranes, normal blood pressure) | >30 mmol/L | Concentrated (>100, characteristically >300) | SIADH, severe primary hypothyroidism, secondary adrenal insufficiency (isolated ACTH/cortisol deficiency) | Mild subclinical volume expansion suppresses aldosterone and stimulates ANP/BNP, promoting natriuresis (>30 mmol/L). Inability to excrete free water due to autonomous AVP. Treatment: Fluid restriction (500–1000 mL/day), oral sodium chloride, demeclocycline, vaptans. |
| Euvolaemic | <30 mmol/L (or variable) | Maximally dilute (<100) | Psychogenic polydipsia, beer potomania ('tea and toast' diet / low solute intake) | Massive free water intake (>10–15 L/day) or extremely low solute intake (<200 mOsm/day) overwhelms renal diluting capacity despite complete physiological suppression of AVP. Treatment: Fluid restriction; gradual reintroduction of dietary solutes. |
| Hypervolaemic (Peripheral oedema, raised JVP, pulmonary crackles, ascites) | <30 mmol/L | Concentrated (>300) | Congestive heart failure, decompensated liver cirrhosis, nephrotic syndrome | Severe reduction in effective arterial blood volume (EABV) activates baroreceptors, triggering non-osmotic AVP release and intense renal sodium reabsorption via RAAS. Treatment: Fluid restriction, dietary sodium restriction, loop diuretics (furosemide). |
| Hypervolaemic | >30 mmol/L | Isosthenuric (~300) | Acute kidney injury (oliguric), advanced chronic kidney disease (CKD stage 4–5) | Failing nephrons cannot filter or excrete water or sodium. Loss of both concentrating and diluting capacity. Treatment: Fluid restriction, loop diuretics, renal replacement therapy (haemodialysis). |
3. Syndrome of Inappropriate ADH Secretion (SIADH)
Diagnostic Criteria (Bartter-Schwartz Criteria)
To establish a diagnosis of SIADH, all of the following core criteria must be fulfilled:
- Decreased plasma effective osmolality (<275 mOsm/kg).
- Inappropriate urinary concentration (urine osmolality >100 mOsm/kg, characteristically >300 mOsm/kg).
- Clinical euvolaemia (no orthostatic hypotension, tachycardia, peripheral oedema, or ascites).
- Inappropriate urinary sodium excretion (urinary sodium >30 mmol/L) on normal diet and water intake.
- Exclusion of hypothyroidism, hypocortisolaemia (normal Short Synacthen Test), and recent diuretic therapy.
Etiologies of SIADH
- Malignancy: Small cell lung cancer (SCLC; responsible for ~70% of paraneoplastic SIADH via autonomous ectopic AVP transcription), head and neck squamous cell carcinomas, lymphoma, pancreatic neuroendocrine tumors.
- Central Nervous System (CNS) Disorders: Subarachnoid haemorrhage, subdural haematoma, ischaemic/haemorrhagic stroke, traumatic brain injury, meningitis, encephalitis, brain abscess.
- Pulmonary Disorders: Pneumonia (particularly atypical pneumonia such as Legionella pneumophila), tuberculosis, lung abscess, acute respiratory distress syndrome (ARDS), positive-pressure ventilation.
- Pharmacological Agents: Selective serotonin reuptake inhibitors (SSRIs: citalopram, fluoxetine, sertraline), carbamazepine and oxcarbazepine, proton pump inhibitors (PPIs), antipsychotics (haloperidol, risperidone), tricyclic antidepressants, cyclophosphamide, vincristine, and MDMA ('ecstasy').
Tiered Therapeutic Strategy
- First-Line: Identify and discontinue offending medications; treat underlying chest infection or malignancy. Implement strict fluid restriction to 500–1000 mL/24 hours. (The Furst ratio, [Urine Na + Urine K] / [Serum Na], predicts responsiveness: if >1.0, fluid restriction alone will fail and pharmacological therapy is required).
- Second-Line: Oral sodium chloride tablets (3–6 g/day) combined with oral low-dose furosemide (20–40 mg/day). Furosemide blunts the renal medullary concentrating gradient, promoting free water excretion.
- Third-Line: Demeclocycline (600–1200 mg/day in divided doses): A tetracycline antibiotic derivative that induces reversible nephrogenic diabetes insipidus by blocking adenylyl cyclase activation and cAMP generation in collecting duct principal cells. Contraindicated in liver cirrhosis and advanced renal failure due to severe nephrotoxicity.
- Vasopressin V2 Receptor Antagonists (Vaptans): Tolvaptan (15 mg once daily oral): Selectively antagonizes collecting duct V2 receptors, inducing pure aquaresis (free water excretion without electrolyte wasting). Requires close inpatient electrolyte monitoring due to the risk of uncontrolled rapid overcorrection; contraindicated in acute severe symptomatic hyponatraemia.
4. Sodium Correction Limits & Osmotic Demyelination Syndrome (ODS)
Pathophysiology of Osmotic Demyelination Syndrome
In chronic hyponatraemia (>48 hours), brain cells adapt to hypotonic extracellular fluid to avoid cerebral oedema by extruding intracellular inorganic ions (sodium, potassium) followed by organic osmolytes (myo-inositol, glutamine, taurine, glutamate). When hypotonic hyponatraemia is corrected too rapidly, the extracellular fluid becomes hypertonic relative to brain parenchymal cells before astrocytes can re-accumulate depleted organic osmolytes. This creates a severe transcellular osmotic gradient, driving rapid dehydrating water efflux from astrocytes into the extracellular space. Astrocytic shrinkage triggers blood-brain barrier breakdown, microvascular endothelial injury, release of inflammatory cytokines, and profound, non-inflammatory demyelination of myelin-rich tracts within the basis pontis (Central Pontine Myelinolysis [CPM]) and extrapontine structures (Extrapontine Myelinolysis [EPM]: basal ganglia, thalamus, internal capsule).
Chronic Hyponatraemia (>48h) ──► Astrocytes lose organic osmolytes to prevent swelling
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RAPID INTRAVENOUS REHYDRATION / CORRECTION
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Hypertonic extracellular fluid pulls water from brain cells
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Astrocyte dehydration ──► Blood-brain barrier rupture
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Oligodendrocyte apoptosis & demyelination of basis pontis
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OSMOTIC DEMYELINATION SYNDROME (Locked-in Syndrome, Spastic Quadriparesis)
Clinical Presentation of ODS
Characteristically exhibits a biphasic course: the patient initially improves neurologically as serum sodium rises, but 2 to 6 days later develops progressive, irreversible neurological deterioration: dysarthria, dysphagia, horizontal gaze palsy, spastic quadriparesis, pseudobulbar palsy, and classical 'locked-in' syndrome (complete anarthria and quadriplegia with preserved cognitive awareness and intact vertical eye movements). MRI of the brain (T2/FLAIR) demonstrates classic high signal intensity in the central pons sparing the periphery.
Safe Correction Limits
- Standard Risk: Serum sodium correction must not exceed 8–10 mmol/L in any 24-hour period, and <18 mmol/L in 48 hours.
- High-Risk Patients: Correction must be restricted to 4–6 mmol/L in 24 hours (maximum 8 mmol/L in 24 hours). High-risk factors include: chronic alcohol dependence, severe malnutrition, advanced liver cirrhosis, hypokalaemia, and baseline serum sodium <105 mmol/L.
Rescue Protocol for Accidental Overcorrection
If the sodium correction rate exceeds the safe threshold, therapeutic re-lowering must be initiated immediately:
- Discontinue all sodium-containing intravenous infusions and diuretics.
- Infuse intravenous 5% Dextrose in water (D5W) at 10 mL/kg over 2 hours under hourly sodium monitoring.
- Administer Desmopressin (DDAVP) 1–2 mcg IV or SC every 6 to 8 hours to arrest renal free water clearance and re-clamp serum sodium.
5. Severe Acute Symptomatic Hyponatraemia Protocol
Severe acute hyponatraemia (<48 hours duration or acute presentation with neuro-emergencies) produces massive cerebral oedema because the brain has not had time to extrude organic osmolytes. Manifestations include generalized tonic-clonic seizures, coma (GCS ≤ 8), respiratory arrest, and signs of transtentorial herniation.
- Immediate Emergency Action: Administer an intravenous bolus of 150 mL of 3% Hypertonic Saline (NaCl) over 20 minutes (or 2 mL/kg).
- Re-check serum sodium immediately. If severe neurological symptoms persist, repeat the 150 mL 3% hypertonic saline bolus once or twice (maximum three boluses).
- Target: A rapid elevation of serum sodium by 4–6 mmol/L acutely. This small increment reduces brain volume by ~10%, aborts cerebral herniation, and terminates seizures.
- Once severe symptoms resolve or the 4–6 mmol/L target is reached, cease hypertonic saline and adhere strictly to the 24-hour ceiling (8–10 mmol/L total rise).
6. Hypernatraemia: Water Deficit & Safe Rehydration
Hypernatraemia ([Na+] > 145 mmol/L) always indicates hyperosmolality and a deficit of total body water relative to sodium. Causes include unreplaced insensible fluid losses (sweating, burns, tachypnoea) paired with impaired thirst or impaired access to water (elderly, infants, ventilated ICU patients), central or nephrogenic diabetes insipidus, osmotic diuresis (HHS/DKA, mannitol), and severe osmotic diarrhoea.
Total Body Water Deficit Calculation
Water Deficit (L) = Total Body Water (TBW) × ([Na+] / 140 - 1) TBW = 0.6 × Weight (kg) in adult males (0.5 × Weight in females and elderly)
Safe Rate of Correction
In chronic hypernatraemia (>48 hours), brain cells accumulate idiogenic organic osmolytes to prevent cellular dehydration. Rapid reduction of serum sodium creates an osmotic gradient directing water into brain cells, causing fatal cerebral oedema, brain herniation, and intractable seizures.
- Correction Ceiling: Serum sodium must decrease by no more than 10 mmol/L per 24 hours (target rate ~0.5 mmol/L/hour).
- Fluids: Oral or nasogastric free water is preferred. If intravenous fluids are required, use 5% Dextrose (D5W) or 0.45% Sodium Chloride (half-normal saline).
A 68-year-old man with extensive-stage small cell lung carcinoma is admitted to the medical assessment unit for investigation of progressive lethargy and mild anorexia. He has no headache, nausea, or visual disturbance. Physical examination reveals normal skin turgor, moist oral mucosa, a jugular venous pressure of 2 cm above the sternal notch, and clear lung fields with no peripheral oedema. His lying blood pressure is 134/78 mmHg and standing blood pressure is 132/76 mmHg. Routine biochemistry reveals: serum sodium 118 mmol/L, potassium 4.2 mmol/L, urea 3.1 mmol/L, creatinine 68 mcmol/L, serum osmolality 248 mOsm/kg. Further testing reveals: urine osmolality 510 mOsm/kg, urine sodium 68 mmol/L, normal 09:00 serum cortisol, and normal thyroid-stimulating hormone. What is the most appropriate initial management step for this patient's hyponatraemia?
A 54-year-old woman with chronic alcohol dependence is brought to the emergency department after being found confused and dishevelled in her flat. On admission, her Glasgow Coma Scale score is 14/15. Initial blood tests demonstrate: serum sodium 104 mmol/L, potassium 3.1 mmol/L, urea 2.2 mmol/L, creatinine 52 mcmol/L, serum osmolality 222 mOsm/kg. She is diagnosed with severe chronic hypovolaemic hyponatraemia and commenced on intravenous 0.9% sodium chloride at 125 mL/hour. Eighteen hours later, repeat biochemistry demonstrates: serum sodium 122 mmol/L and potassium 3.6 mmol/L. The patient is alert but complains of mild generalised weakness. Which of the following is the most appropriate immediate action?
A 42-year-old man with poorly controlled type 1 diabetes mellitus presents to the acute medical unit with vomiting, diffuse abdominal pain, and deep sighing respirations. Physical examination demonstrates dry tongue, sunken eyes, skin turgor loss, blood pressure 98/62 mmHg, and heart rate 116 bpm. Fingerprick capillary ketone concentration is 5.4 mmol/L. Venous blood gas analysis reveals: pH 7.18, bicarbonate 10 mmol/L. Laboratory serum biochemistry reports: measured sodium 124 mmol/L, potassium 5.2 mmol/L, urea 12.8 mmol/L, creatinine 142 mcmol/L, venous blood glucose 35.5 mmol/L. What is the patient's corrected serum sodium concentration?