SIADH — syndrome of inappropriate antidiuretic hormone secretion

Definition. A euvolaemic, hypotonic hyponatraemia caused by non-osmotic, non-physiological release of antidiuretic hormone (arginine vasopressin), with continued renal water reabsorption despite plasma hypo-osmolality. It is now often called SIAD (syndrome of inappropriate antidiuresis), because a minority of cases are due to a gain-of-function V2 receptor mutation with undetectable circulating ADH.

The four textbook diagnostic features. (i) Inappropriately high urine osmolality for the concomitant plasma hypo-osmolality; (ii) continued renal excretion of sodium; (iii) clinical normovolaemia; and (iv) normal renal, adrenal and thyroid function. All four must be satisfied.

Full Bartter–Schwartz criteria — essential. Hypotonic hyponatraemia (Na <135 mEq/L, effective osmolality <275 mOsm/kg); urine osmolality >100 mOsm/kg; clinical euvolaemia with no oedema and no signs of volume depletion; urine sodium >30–40 mEq/L on normal salt and water intake; normal thyroid and adrenal function; and no recent diuretic use.

Supplemental criteria that strengthen the diagnosis. Low serum uric acid (<4 mg/dL) and low blood urea — both reflect dilution and increased fractional excretion; fractional excretion of urate >12%; fractional excretion of sodium >0.5%; failure to correct with 0.9% saline; and correction with fluid restriction. A normal or high uric acid should make you doubt the diagnosis.

Pathophysiology. Excess ADH drives aquaporin-2 insertion into the collecting duct → water retention → mild volume expansion → suppression of aldosterone and release of natriuretic peptides → secondary natriuresis. The patient therefore remains clinically euvolaemic while the sodium falls, and continues to excrete sodium in the urine. Vasopressin escape limits further water retention and prevents gross oedema — which is why SIADH does not cause oedema.

Ageing itself is a predisposing factor. Infusion of hypertonic saline leads to a greater increase in plasma vasopressin in older compared with younger persons, possibly through impaired baroreceptor input to the supraoptic nucleus. Combined with the reduced diluting capacity of the ageing kidney, this means older adults seem more prone to develop SIADH from any given trigger.

Causes — central nervous system. Stroke, meningitis, subdural haematoma, tumour, intracranial metastases, haemorrhage, head injury and encephalitis. Any acute intracranial event in an older adult should prompt a sodium check.

Causes — pulmonary. Pneumonia (a very common trigger in the elderly), tuberculosis (highly relevant in India), lung abscess, pulmonary metastases and infection, and positive-pressure ventilation.

Causes — malignancy. SIADH is a paraneoplastic condition classically associated with small-cell carcinoma of the lung; also head and neck cancers, thymoma, and others. In an older smoker with unexplained SIADH, image the chest.

Causes — drugs, which are the commonest in geriatric practice. SSRIs and other antidepressants — the risk of antidepressant-induced hyponatraemia increases with age and is associated with female sex, low body weight, renal failure and concurrent drugs that cause hyponatraemia. Also carbamazepine and oxcarbazepine, chlorpropamide, barbiturates (both of which cause this syndrome more frequently in older individuals), thiazides, antipsychotics, NSAIDs, opioids, PPIs, desmopressin, and the chemotherapeutic agents vincristine, vinblastine, ifosfamide and cyclophosphamide.

Other causes. Pain, nausea, surgery and general anaesthesia (all potent non-osmotic ADH stimuli — a frequent cause of postoperative hyponatraemia in the elderly), HIV infection, and idiopathic SIAD of the elderly, a recognised entity in which no cause is found and the hyponatraemia is chronic and recurring.

Clinical features. Symptoms depend on the depth and the rate of development, but elderly patients are more susceptible and may manifest cognitive impairment with mild hyponatraemia. Acute (<48 hours) — headache, nausea, vomiting, confusion, seizures, coma and respiratory arrest from cerebral oedema. Chronic — apparently "asymptomatic", but in reality associated with gait instability, attention and memory deficits, falls, osteoporosis and fracture (chronic hyponatraemia mobilises sodium from bone). In an older adult, chronic hyponatraemia is almost never truly asymptomatic.

Differential diagnosis to exclude before you accept the label. Hypovolaemia; diuretic use, especially thiazides; hypothyroidism; adrenal insufficiency — a 9 a.m. cortisol is mandatory, because glucocorticoid deficiency mimics SIADH exactly; cerebral salt wasting — which is hypovolaemic with a high urine output and negative salt balance, and is treated with salt and fluid, the opposite of SIADH; and low-solute states such as beer potomania and the tea-and-toast diet.

Treatment. Treat the underlying disease — successful therapy for paraneoplastic SIADH requires treatment of the underlying disease by chemotherapy and/or radiotherapy. Acute measures are indicated in symptomatic patients with severe hyponatraemia (plasma sodium <125 mEq/L): the textbook protocol is to initiate and maintain rapid diuresis with intravenous furosemide while restricting free water intake to 500–1000 mL per day, and to replace the sodium and potassium lost in the urine with 0.9% saline infusions with added potassium; current emergency practice is 3% hypertonic saline 100–150 mL over 10–20 minutes, repeated up to three times, targeting a rise of 4–6 mEq/L to abort seizures. This rapid correction should not exceed a 20 mEq/L rise in serum sodium during the first 48 hours (1 mEq/L/h) to avoid neurological damage and central pontine myelinolysis. For chronic SIADH: fluid restriction to 500–1000 mL/day is first line; then increased solute intake (salt and protein, or oral urea 15–30 g/day); a loop diuretic with salt tablets; demeclocycline (demethylchlortetracycline) may be needed in resistant patients — it induces a partial nephrogenic diabetes insipidus and thus corrects the hyponatraemia, and serum creatinine and blood urea must be closely monitored; and vaptans (tolvaptan) with strict inpatient sodium monitoring. Feature SIADH Cerebral salt wasting Adrenal insufficiency Volume status Euvolaemic Hypovolaemic Hypovolaemic Urine sodium >30–40 mEq/L Very high High Urine output Low / normal High (polyuria) Variable Serum uric acid Low Low Normal / high Serum potassium Normal Normal / low High Response to 0.9% saline Worsens or no change Improves Improves Treatment Fluid restriction Salt and fluid replacement Hydrocortisone LATEST UPDATES (2023–PRESENT) — 3 POINTS

Empagliflozin is emerging as a practical new option for chronic SIAD. In a randomised, double-blind, placebo-controlled crossover trial in outpatients with chronic SIAD (JASN 2023), four weeks of empagliflozin 25 mg added to fluid restriction of about 1500 mL/day raised median serum sodium by 4.1 mEq/L versus placebo, an effect achieved by the end of the first week and sustained thereafter. It was well tolerated with no hypoglycaemia, hypotension, overcorrection or acute kidney injury, and produced a small improvement in neurocognitive function, particularly when normonatraemia was restored. This followed an earlier inpatient randomised trial in 88 hospitalised patients (JASN 2020). The mechanism is glucosuria-induced osmotic diuresis with increased electrolyte-free water excretion. Its appeal in older adults is that it is oral, inexpensive, and does not require the intensive monitoring or carry the overcorrection risk of vaptans.

Fluid restriction fails more often than is taught — predict failure and escalate early. The recognised predictors of failure are urine osmolality >500 mOsm/kg, a urine (Na + K) to serum Na ratio ≥1 (the Furst ratio), and a 24-hour urine volume <1500 mL. Current practice is to identify these at the outset and move to second-line therapy rather than persist with an ineffective restriction — which in a frail older person also causes thirst, distress, constipation and delirium. Among second-line agents, oral urea is increasingly favoured over vaptans on grounds of cost, safety and the absence of overcorrection risk; palatability is the limiting factor.

In geriatric practice, deprescribing is the definitive treatment. The commonest reversible cause of SIADH in an older patient is a drug — the SSRI, thiazide, carbamazepine or PPI. A structured medication review using STOPP/START and the AGS Beers criteria, followed by stopping or substituting the culprit, corrects more cases than any pharmacological manoeuvre. The corresponding preventive standard is to recheck serum sodium at 2 and 4 weeks after starting or changing any of these drugs in a person over 65 — a simple intervention that prevents a substantial proportion of hyponatraemic admissions.