Approach to the evaluation and treatment of hyponatremia

Definitions. Hyponatremia is serum sodium <135 mEq/L. Clinically significant hyponatremia is <130 mEq/L; severe hyponatremia is <120 mEq/L. Levels of 130–135 mEq/L are usually asymptomatic.

Step 1 — confirm true hypotonic hyponatremia. Measure serum osmolality. True hypo-osmolality is <275 mOsm/kg. This step excludes two traps: Pseudo-hyponatremia — from excess triglycerides or paraproteins (macroglobulinaemia); osmolality is normal. Hyperosmolar (translocational) hyponatremia — from hyperglycaemia or other circulating osmoles; osmolality is high.

Step 2 — take a water intake history. Look for intake that overwhelms renal free water clearance: primary polydipsia (16–20 L/day), beer potomania, and exercise-associated water intoxication in long-distance runners. Without such a history, the cause is water retention, usually with some component of solute loss.

Step 3 — the core panel. Send serum for basic metabolic profile (BMP) and measured osmolality, and urine for osmolality and sodium concentration. The BMP identifies acute renal disease (acute tubular necrosis, obstruction) and hyperglycaemia.

Step 4 — interpret the urine. Urine osmolality >100 mOsm/kg means ADH action is present and inappropriate; it is often higher than serum osmolality. Urine sodium >30–40 mEq/L (sometimes approaching 100) indicates SIADH or renal salt loss. Urine sodium <20 mEq/L, or the presence of orthostatic hypotension, indicates an "appropriate" ADH response to low effective arterial blood volume.

Copeptin — the stable C-terminal fragment of the AVP precursor — used together with the urinary sodium ratio, helps distinguish volume-depleted from normovolemic hyponatremia when clinical assessment is equivocal.

Hypovolemic hyponatremia. Orthostatic hypotension and/or urine sodium <20 mEq/L. Causes: diuretics, gastrointestinal losses. Physiologically, aldosterone and ADH are both appropriately elevated because of low EABV.

Hypervolemic (oedematous) hyponatremia. Two mechanisms: Hypoalbuminaemia with low EABV — cirrhosis, nephrotic syndrome. Reduced carotid baroreceptor perfusion — congestive heart failure, cardiac tamponade, negative inotropic drugs, and poor contractility in hypothyroidism.

Euvolemic hyponatremia — SIADH. Diagnostic set from the textbook algorithm: serum osmolality <275 mOsm/kg, urine osmolality >100 mOsm/kg, urine sodium >40 mEq/L, clinical euvolemia, and normal thyroid and adrenal function.

Step 5 — review every drug. This is mandatory and is the highest-yield reversible cause. Diuretics (commonest overall), SSRIs (elderly are especially sensitive), tricyclics and tetracyclics, phenothiazines and butyrophenones, carbamazepine, oxcarbazepine and valproate, opioids and nicotine, NSAIDs, high-dose co-trimoxazole, vincristine and cyclophosphamide, and MDMA.

Step 6 — exclude endocrine causes. Check TSH for hypothyroidism, and test for primary and secondary adrenal insufficiency by cosyntropin stimulation. Also assess for mineralocorticoid insufficiency and for autonomic dysfunction (Parkinson's disease, multiple system atrophy). Correction of hypothyroidism and hypoadrenalism is mandatory before labelling a patient SIADH.

Causes of true SIADH. Tumours (bronchogenic carcinoma, mesothelioma, thymoma, other non-pulmonary carcinoma); CNS lesions (tumour, trauma, neurosurgery, subarachnoid haemorrhage); pulmonary disease with raised intrathoracic pressure (COPD, positive-pressure ventilation); acute post-operative and post-anaesthetic states; cerebral salt wasting; and HIV–AIDS. In practice, an exhaustive evaluation of 50 elderly inpatients with mild-to-moderate hyponatremia linked it to pneumonia and medication, with 60% remaining idiopathic.

The decision to treat rests on neurocognitive symptoms, not the number. Sodium 130–135 mEq/L is usually asymptomatic and, if chronic, the brain has already adapted — it may need no therapy at all. Sodium 125–130 mEq/L with gait disturbance or cognitive impairment does improve with correction. Withholding causative drugs alone is often sufficient.

Hypovolemic hyponatremia. Give a trial of 1–2 litres of 0.9% saline, withhold diuretics, and consider oral salt 4–12 g/day in divided doses. Restoring EABV suppresses ADH and raises sodium. Fluid restriction is contraindicated here.

Euvolemic and hypervolemic hyponatremia. Fluid restriction 500–1500 mL/24 h is the mainstay. 0.9% saline is usually ineffective and may worsen SIADH — the infused sodium is quantitatively excreted in the urine while the high ADH retains the water.

Severe symptomatic hyponatremia (sodium <120 mEq/L or hyponatremic encephalopathy). Use 3% saline (513 mEq/L). The textbook protocols are: Continuous infusion at 0.5–1.0 mL/kg/hour, adjusted to urine output; or Bolus of 100 mL of 3% saline, with the rate then adjusted. Check serum sodium every 2 hours; stop the infusion if the rise exceeds 0.5 mEq/L/hour. Target a rise of only 4–8 mEq/L over 24 hours — the goal is to remove a calculated portion of the excess free water, not to normalise the sodium.

Osmotic demyelination syndrome (ODS) — the feared complication. Chronic hyponatremia (>48 hours) causes the brain to extrude organic and inorganic osmoles. Correction >8 mEq/L over 24 hours then causes cerebral dehydration and pontine and extrapontine demyelination, which is delayed in onset and carries severe neurological morbidity and mortality. High-risk group: serum sodium <105 mEq/L, hypokalaemia, alcoholism, malnutrition, advanced liver disease. If overcorrected: re-lower with free water (dextrose) ± DDAVP. In the bolus regimen, 14% of patients required this.

Bolus versus continuous infusion. In a historical case-control comparison, a 100 mL bolus of 3% saline was preferable to a slow 20 mL/h infusion, with quicker restoration of the Glasgow Coma Scale. The slow-infusion group showed a trend towards higher mortality (4 of 28 died vs 0 of 22). The textbook conclusion is that it remains unknown which strategy is superior in real-world conditions, or whether reversing overcorrection halts established ODS.

Vaptans (vasopressin V2-receptor antagonists). They reliably raise serum sodium and allow fluid restriction to be stopped, but clinical benefit is modest: Tolvaptan — SALT-1 and SALT-2 (448 subjects): small overall improvement in the SF-12 quality-of-life score (p = 0.02), significant only in the US cohort; benefit greatest when baseline sodium was <130 mEq/L. No change in the physical component. INSIGHT trial (107 patients with SIADH): raising sodium from 129 to 136 mEq/L did not improve the primary composite cognitive endpoint, only a psychomotor speed subdomain. Lixivaptan: raised sodium by 3 mEq/L over control, with no benefit on the Trail Making Test or MOS-6 at 28 days. Systematic review: all vaptans improve serum sodium, with limited evidence of impact on quality of life or mortality.

Prognosis. Hyponatremia carries a poor overall prognosis. There are probably two temporal syndromes in the elderly, often hard to separate: a chronic hyponatremia linked to underlying disease or dementia, and an acute deterioration manifesting as delirium. Ongoing management is to limit thiazides and SSRIs, avoid drugs causing orthostatic hypotension, and moderate antihypertensive intensity.

Numerical Thresholds Parameter Value Normal serum osmolality 285 ± 2 mOsm/kg ADH release threshold 280 mOsm/kg Thirst threshold 5–10 mOsm/kg above the ADH threshold Hyponatremia <135 mEq/L; clinically significant <130; severe <120 True hypo-osmolality <275 mOsm/kg Hypernatremia >145 mEq/L Inappropriately concentrated urine Urine osmolality >100 mOsm/kg Urine sodium in SIADH >40 mEq/L (may approach 100)

Correction Rates — Learn These Verbatim Situation Target Complication if exceeded Hyponatremia Raise Na by 6–8 mEq/L / 24 h (4–8 in the Osmotic demyelination syndrome — acute phase) pontine and extrapontine, delayed onset Hypernatremia Lower Na by <10 mEq/L / 24 h Cerebral oedema Monitoring — hyponatremia Serum Na 2-hourly; stop if rise >0.5 — mEq/L/h Monitoring — hypernatremia Serum Na 4-hourly —

Formulae Serum osmolality = 2[Na] + glucose/18 + BUN/2.8 (mg/dL) Effective serum osmolality = 2[Na] + glucose/18 (urea excluded — freely permeable) Water replacement / 24 h (hypernatremia) = TBW × [(Nagoal/Nacurrent) − 1] + ongoing losses TBW = 0.6 × wt if <75 y; 0.5 × wt if >75 y; Nagoal = Nacurrent − 10 Calculated osmolarity (ESPEN, dehydration screening) = 1.86 × (Na + K) + 1.15 × glucose + urea + 14 (mmol/L)

Fluid Selection Fluid Sodium Use 3% saline 513 mEq/L Severe symptomatic hyponatremia. Bolus 100–150 mL (2–4 mL/kg) over 20–40 min, or infusion 0.5–1.0 mL/kg/h 0.9% saline 154 mEq/L Hypovolemic hyponatremia (1–2 L trial). Worsens SIADH. Does not lower osmolality in hypernatremia 0.45% saline 77 mEq/L Hypernatremia with combined water and solute loss (50% free water) 5% dextrose 0 Hypernatremia from pure water loss; also used to re-lower after overcorrection Oral salt — 4–12 g/day in divided doses, hypovolemic hyponatremia

Named Trials and Landmark Studies Name Message SALT-1 / SALT-2 Tolvaptan in 448 subjects — raised sodium; only a small SF-12 quality-of-life gain, significant in the US cohort only INSIGHT Tolvaptan in 107 SIADH patients — sodium 129 → 136 mEq/L but no improvement in the primary cognitive endpoint Renneboog et al. Mild chronic hyponatremia causes falls, unsteadiness and attention deficits; gait and reaction time improve on correction Verbalis (rat model) Chronic hyponatremia causes osteoporosis via osteoclastic bone resorption SALSA (JAMA Intern Med Bolus vs continuous 3% saline — both safe and effective; bolus needed less relowering therapy 2021) MacMillan (NEJM Evid 2023) 22,858 admissions — ODS only 0.05%; 7 of 12 cases had no rapid correction Seethapathy (NEJM Evid 3,274 patients — slower correction linked to higher mortality and longer stay 2023) Ayus meta-analysis (JAMA 11,811 patients — correction 8–10 mEq/L/24 h: lower in-hospital (OR 0.67) and 30-day (RR 0.55)

One-Line Volume-Status Discriminator Type Clue Urine Na Treatment Hypovolemic Orthostatic hypotension, <20 mEq/L 0.9% saline 1–2 L; oral salt. Never diuretics, GI losses fluid restrict Euvolemic (SIADH) No oedema, no postural drop; >40 mEq/L Fluid restriction 500–1500 mL/day; drugs, pneumonia, CNS or lung urea, vaptan, empagliflozin lesion Hypervolemic Oedema — heart failure, Usually low Fluid restriction + treat underlying cirrhosis, nephrotic syndrome disease; loop diuretic Final Three-Sentence Summary Physiology: ageing brings reduced thirst, reduced urinary concentrating ability, reduced free water excretion and a fall in total body water from 60% to 50% after age 75 — a narrow margin in both directions. Diagnosis: confirm true hypo-osmolality, classify by volume status using urine sodium, then review every drug and exclude hypothyroidism and adrenal insufficiency before diagnosing SIADH. Treatment: correct according to neurocognitive symptoms, not the number — up by 6–8 mEq/L per 24 hours in hyponatremia, down by less than 10 mEq/L per 24 hours in hypernatremia.