What is the etiology, pathophysiology, clinical features, and management of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and Cerebral Salt Wasting Syndrome?

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and Cerebral Salt Wasting Syndrome (CSW)

The management of SIADH requires fluid restriction as first-line treatment for mild/asymptomatic cases and 3% hypertonic saline for severe symptomatic cases, while CSW necessitates volume and sodium replacement with severe cases requiring ICU admission with 3% hypertonic saline and fludrocortisone. 1

Etiology

• SIADH is commonly caused by malignancies (especially small cell lung cancer), neurological disorders, pulmonary diseases, and medications 2
• Approximately 10-45% of small cell lung cancer and 1% of other lung cancers produce arginine vasopressin (ADH), but only 1-5% of lung cancer patients develop symptomatic SIADH 2
• CSW typically occurs in patients with intracranial pathologies such as traumatic brain injury, subarachnoid hemorrhage, and brain surgeries 3
• CSW is more common than SIADH in neurosurgical patients 1

Pathophysiology

SIADH

• Excess ADH activates vasopressin-2 receptors in renal tubules, resulting in increased aquaporins and impaired free water clearance 2
• Persistent detectable or elevated plasma arginine vasopressin concentrations in the presence of continued fluid intake leads to dilutional hyponatremia 4
• Osmoregulated inhibition of thirst fails to curb fluid intake, contributing to water retention 4

CSW

• Characterized by inappropriate natriuresis and volume depletion, leading to hyponatremia 3
• Involves direct neural input to the kidney and/or central elaboration of natriuretic factors (e.g., atrial natriuretic peptide) 5
• Results in negative sodium balance and hypovolemia, unlike the euvolemic state in SIADH 5

Clinical Features

SIADH

• Signs and symptoms are determined by the degree of hyponatremia and acuity of onset 2
• At serum sodium 125-130 mEq/L: general weakness, confusion, headache, and nausea 2
• At serum sodium <120 mEq/L: life-threatening manifestations including seizures, coma, and death 2
• Laboratory findings include:
  • Hyponatremia (serum sodium <134 mEq/L) 2
  • Hypoosmolality (plasma osmolality <275 mosm/kg) 2
  • Inappropriately high urine osmolality (>500 mosm/kg) 2
  • Inappropriately high urinary sodium concentration (>20 mEq/L) 2
  • Absence of hypothyroidism, adrenal insufficiency, or volume depletion 2
  • Serum uric acid <4 mg/dL 2

CSW

• Characterized by hypovolemia rather than euvolemia 6
• Unquenchable thirst is a distinguishing feature 6
• Laboratory findings include:
  • Hyponatremia with high urine sodium excretion 3
  • Signs of volume depletion (tachycardia, hypotension, dry mucous membranes) 3
  • Central venous pressure (CVP) <6 cm H₂O (compared to 6-10 cm H₂O in SIADH) 6
  • Elevated hematocrit and serum albumin due to hemoconcentration 5

Differential Diagnosis

• The key distinguishing factor between SIADH and CSW is volume status: euvolemia in SIADH versus hypovolemia in CSW 5
• Assessment of extracellular fluid volume status with fractional excretion of urate can improve diagnostic accuracy for SIADH to 95% 2
• Other causes of hyponatremia to exclude:
  • Hypovolemic hyponatremia (diuretic use, gastrointestinal losses) 1
  • Hypervolemic hyponatremia (heart failure, cirrhosis) 1
  • Hypothyroidism and adrenal insufficiency 2
  • Polydipsia 6

Management

SIADH

• Fluid restriction (<1 L/day) is first-line treatment for asymptomatic mild SIADH 2, 1
• For life-threatening or acute symptomatic severe hyponatremia (<120 mEq/L), administer 3% hypertonic saline IV 2, 1
• Correction rate should not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1
• For severe symptoms (seizures, coma), correct by 6 mmol/L over 6 hours or until symptoms improve 1
• Pharmacological options include:
  • Demeclocycline (inhibits ADH action) 2
  • Vasopressin-2 receptor antagonists (tolvaptan, conivaptan) 2, 7
  • Lithium (rarely used due to toxicity concerns) 2
• Tolvaptan should be initiated in a hospital setting where serum sodium can be closely monitored 7
• Avoid fluid restriction during the first 24 hours of tolvaptan therapy to prevent overly rapid correction of serum sodium 7

CSW

• Treatment focuses on volume and sodium replacement, not fluid restriction 1, 3
• For severe symptoms, ICU admission with 3% hypertonic saline and fludrocortisone is recommended 1
• Fludrocortisone helps reduce the doses of hypertonic saline required and can maintain serum sodium levels 3
• Using fluid restriction in CSW can worsen outcomes and is contraindicated 1

Common Pitfalls and Caveats

• Overly rapid correction of chronic hyponatremia (>8 mmol/L in 24 hours) can lead to osmotic demyelination syndrome 1
• Inadequate monitoring during active correction of sodium levels 1
• Misdiagnosis between SIADH and CSW leading to inappropriate treatment (fluid restriction in CSW can be hazardous) 1, 8
• Failing to recognize and treat the underlying cause of SIADH or CSW 1
• Using hypertonic saline in hypervolemic hyponatremia without life-threatening symptoms 1
• Tolvaptan should not be used for more than 30 days due to risk of liver injury 7

Monitoring and Follow-up

• For severe symptoms: monitor serum sodium every 2 hours during initial correction 1
• Calculate sodium deficit using formula: Desired increase in Na (mEq/L) × (0.5 × ideal body weight in kg) 1
• Watch for signs of osmotic demyelination syndrome (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 1
• Improvement of hypouricemia and increased fractional excretion of uric acid after correction of hyponatremia may help distinguish SIADH from CSW 5