What is Syndrome of Inappropriate Antidiuretic Hormone (SIADH)?

What is SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)?

SIADH is a disorder characterized by excessive release of antidiuretic hormone (ADH) causing the kidneys to retain too much water, leading to dilutional hyponatremia (low blood sodium) despite normal kidney, thyroid, and adrenal function. 1

Diagnostic Criteria

To diagnose SIADH, you must confirm all five cardinal features: 1, 2

• Hypotonic hyponatremia: Serum sodium <134-135 mEq/L with plasma osmolality <275 mosm/kg 1, 2
• Inappropriately concentrated urine: Urine osmolality >500 mosm/kg (or >100 mosm/kg at minimum) despite low plasma osmolality 1, 3
• Elevated urinary sodium: Urine sodium concentration >20 mEq/L (typically >40 mEq/L) 1, 3
• Clinical euvolemia: No signs of volume depletion (orthostatic hypotension, dry mucous membranes, poor skin turgor) or volume overload (edema, ascites, jugular venous distention) 1, 2
• Normal renal, thyroid, and adrenal function: Must exclude hypothyroidism, adrenal insufficiency, and renal failure 1, 2

Additional Supportive Laboratory Findings

• Serum uric acid <4 mg/dL has a 73-100% positive predictive value for SIADH 1
• Central venous pressure 6-10 cm H₂O helps distinguish SIADH from cerebral salt wasting (CVP <6 cm H₂O) 1, 4

Pathophysiology

The core problem is persistent, detectable ADH secretion despite low plasma osmolality, which normally should suppress ADH release. 2 This inappropriate ADH activity causes:

• Water retention through V2 receptor activation in distal renal tubules 5
• Impaired urinary dilution preventing excretion of ingested water 3
• Physiologic natriuresis to maintain fluid balance, paradoxically increasing urinary sodium loss despite hyponatremia 3

Four Patterns of ADH Secretion in SIADH

The disorder manifests in four distinct patterns: 2

1. Erratic AVP release: Random, unpredictable ADH secretion
2. Reset osmostat: ADH regulation occurs but at a lower sodium threshold
3. Persistent AVP release: Continuous ADH secretion even at low plasma osmolality
4. Normal osmoregulated AVP secretion: ADH regulation appears normal but hyponatremia persists

Common Causes

SIADH develops from four major categories of conditions: 2

Malignancy

• Small cell lung cancer is the classic paraneoplastic cause, with SIADH occurring more frequently than other paraneoplastic syndromes 1
• Other cancers can produce ectopic ADH 1

Neurological Disorders

• CNS infections (meningitis is most common in pediatrics) 6, 5
• Subarachnoid hemorrhage and other intracranial pathology 1
• CNS malformations (corpus callosum agenesis) 5
• Head trauma 7

Pulmonary Diseases

• Pneumonia and other lung infections 2, 5
• Various lung pathologies 2

Medications

Numerous drugs induce SIADH, including: 1

• Chemotherapy agents (cisplatin, vincristine, vinblastine)
• Antidepressants
• Antiepileptics (carbamazepine)
• NSAIDs
• Opioids
• Chlorpropamide
• Diuretics 8

Postoperative State

• Inappropriate hypotonic fluid administration postoperatively remains a common iatrogenic cause 2
• Pain and surgical stress trigger ADH release 5

Clinical Presentation

Symptoms correlate with both the absolute serum sodium level and the rate of decline, particularly dangerous if sodium falls >0.5 mmol/L/hour. 2

Severity-Based Symptoms

Mild hyponatremia (126-135 mEq/L): 4

• Often asymptomatic
• Subtle neurocognitive changes
• Increased fall risk

Moderate hyponatremia (120-125 mEq/L): 4, 8

• Anorexia
• Nausea and vomiting
• Headache
• Confusion and lethargy

Severe hyponatremia (<120 mEq/L): 4, 8

• Seizures
• Coma
• Death if untreated

Symptoms are principally neuromuscular and gastrointestinal in nature. 2

Critical Differential Diagnosis

You must distinguish SIADH from cerebral salt wasting (CSW), as they require opposite treatments: 1, 4

Feature	SIADH	Cerebral Salt Wasting
Volume status	Euvolemic	Hypovolemic
CVP	6-10 cm H₂O	<6 cm H₂O
Thirst	Absent	Unquenchable
Treatment	Fluid restriction	Volume/sodium replacement

Using fluid restriction in CSW worsens outcomes and can be fatal. 1, 9

Treatment Approach

Acute Symptomatic Management

For severe symptoms (seizures, coma, confusion): 1, 9

• Transfer to ICU for close monitoring
• Administer 3% hypertonic saline with goal to correct 6 mmol/L over 6 hours or until severe symptoms resolve
• Monitor serum sodium every 2 hours initially
• Never exceed 8 mmol/L correction in 24 hours to prevent osmotic demyelination syndrome 1, 9

For patients with malnutrition, alcoholism, or advanced liver disease, limit correction to 4-6 mmol/L per day due to higher osmotic demyelination risk. 1

Chronic/Asymptomatic Management

For mild symptoms or asymptomatic patients with sodium <120 mEq/L: 1

• Fluid restriction to 1 L/day is the cornerstone of treatment 1, 8, 6, 2
• Add oral sodium chloride 100 mEq three times daily if no response to fluid restriction 9

Pharmacological Options for Refractory Cases

When fluid restriction fails or is poorly tolerated: 1, 8

• Demeclocycline as second-line treatment 1, 8
• Vasopressin V2-receptor antagonists (tolvaptan, conivaptan) for euvolemic or hypervolemic hyponatremia 1, 7, 5
  • Start tolvaptan at 15 mg once daily, can increase to 30 mg then 60 mg at ≥24-hour intervals 7
  • Must initiate in hospital with close sodium monitoring 7
  • Avoid in patients with liver disease due to hepatotoxicity risk 7

Other reported options with limited data: 1, 8

• Urea
• Lithium
• Loop diuretics
• Fludrocortisone (primarily studied in neurosurgical patients) 1

Treating Underlying Cause

Treatment of the underlying malignancy or condition causing SIADH is crucial and often leads to resolution of hyponatremia. 1

Critical Pitfalls to Avoid

Four major errors can cause serious harm: 1, 9

1. Overly rapid correction (>8 mmol/L in 24 hours) causing osmotic demyelination syndrome with dysarthria, dysphagia, quadriparesis, seizures, coma, or death 1, 7
2. Inadequate monitoring during active correction 1
3. Using fluid restriction in cerebral salt wasting instead of SIADH 1
4. Failing to identify and treat the underlying cause 1