How is inappropriate antidiuretic hormone (ADH) secretion treated?

Treatment of Inappropriate Antidiuretic Hormone Secretion (SIADH)

For SIADH, fluid restriction to 1 L/day is the cornerstone of treatment for mild to moderate cases, while severe symptomatic hyponatremia requires immediate administration of 3% hypertonic saline with careful monitoring to avoid overcorrection. 1

Diagnostic Confirmation Before Treatment

Before initiating treatment, confirm SIADH diagnosis with the following criteria 2:

• Hyponatremia (serum sodium <134 mEq/L) with hypoosmolality (plasma osmolality <275 mosm/kg) 2
• Inappropriately high urine osmolality (>500 mosm/kg) relative to low plasma osmolality 2
• Urinary sodium >20 mEq/L (typically >40 mEq/L) 2, 3
• Euvolemic status - no edema, no orthostatic hypotension, normal skin turgor, moist mucous membranes 1, 2
• Exclusion of hypothyroidism, adrenal insufficiency, and diuretic use 1, 2

A serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH 2, though this may include cerebral salt wasting cases 1.

Treatment Algorithm Based on Severity

Severe Symptomatic Hyponatremia (Seizures, Coma, Altered Mental Status)

Immediate intervention is required 1:

• Transfer to ICU for continuous monitoring 1
• Administer 3% hypertonic saline with goal to correct 6 mmol/L over 6 hours or until severe symptoms resolve 1
• Monitor serum sodium every 2 hours during initial correction 1
• Total correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 4
• For high-risk patients (advanced liver disease, alcoholism, malnutrition), limit correction to 4-6 mmol/L per day 1, 4

The FDA warns that too rapid correction (>12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, seizures, coma, and death 4.

Mild Symptomatic or Asymptomatic SIADH (Sodium 120-130 mEq/L)

Fluid restriction is first-line therapy 1, 5:

• Restrict fluids to 1 L/day (or <1 L/day for more severe cases) 1, 5
• Avoid fluid restriction during the first 24 hours if using tolvaptan 4
• Add oral sodium chloride 100 mEq three times daily if no response to fluid restriction alone 1
• Monitor serum sodium every 4 hours initially, then daily 1

Fluid restriction alone fails to increase serum sodium by ≥5 mEq/L in 55% of treatment episodes 6, highlighting the need for additional interventions in many cases.

Pharmacological Treatment Options

Second-Line Agents (When Fluid Restriction Fails)

Demeclocycline can be considered as second-line treatment 1, 5, inducing a negative free-water balance by interfering with ADH action on renal tubules 5.

Urea is effective for chronic SIADH management 7, with doses of 40 g in 100-150 mL normal saline every 8 hours reported in neurosurgical patients 7.

Vasopressin Receptor Antagonists (Vaptans)

Tolvaptan is FDA-approved for clinically significant euvolemic hyponatremia (serum sodium <125 mEq/L or symptomatic hyponatremia resistant to fluid restriction) 4:

• Starting dose: 15 mg once daily without regard to meals 4
• Titrate to 30 mg after 24 hours, maximum 60 mg daily as needed 4
• Must initiate and re-initiate in hospital with close serum sodium monitoring 4
• Do not use for more than 30 days to minimize liver injury risk 4
• Produces mean rate of sodium change of 3.0 mEq/L/day (interquartile range 6.0) 6

Tolvaptan is contraindicated in patients unable to sense or respond to thirst, hypovolemic hyponatremia, those taking strong CYP3A inhibitors, and patients with anuria 4.

Treatment of Underlying Cause

Identifying and treating the underlying cause is essential 1, 8:

• Discontinue offending medications (carbamazepine, SSRIs, chlorpropamide, cyclophosphamide, vincristine) 9, 5
• Treat underlying malignancy in paraneoplastic SIADH (particularly small cell lung cancer) 1
• Manage CNS disorders (meningitis, encephalitis, head trauma) 10
• Address pulmonary diseases (pneumonia, tuberculosis) 10

Critical Monitoring Parameters

During active correction 1:

• Serum sodium every 2 hours for severe symptoms 1
• Serum sodium every 4 hours after symptom resolution 1
• Watch for signs of osmotic demyelination syndrome (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 1

If overcorrection occurs (>8 mmol/L in 24 hours) 1:

• Immediately discontinue hypertonic saline and switch to D5W 1
• Consider desmopressin to slow or reverse rapid sodium rise 1

Common Pitfalls to Avoid

• Using fluid restriction in cerebral salt wasting instead of SIADH - this worsens outcomes as CSW requires volume and sodium replacement 1, 7
• Inadequate monitoring during active correction leading to overcorrection 1
• Failing to distinguish SIADH from cerebral salt wasting in neurosurgical patients - assessment of extracellular fluid volume status is critical 1, 2
• Administering isotonic saline for SIADH - this often fails to correct hyponatremia (64% failure rate) and may worsen it by providing free water 1, 6
• Ignoring mild hyponatremia (130-135 mmol/L) - even mild hyponatremia increases fall risk and mortality 7

Comparative Efficacy of Treatment Modalities

Based on registry data of 1,524 patients 6:

• Hypertonic saline: 3.0 mEq/L/day (IQR 6.0) - most rapid correction 6
• Tolvaptan: 3.0 mEq/L/day (IQR 6.0) - equivalent to hypertonic saline 6
• Isotonic saline: 1.5 mEq/L/day (IQR 3.0) - limited efficacy 6
• Fluid restriction: 1.0 mEq/L/day (IQR 2.3) - slowest but safest for chronic management 6

Despite available effective therapies, 75% of patients were discharged with sodium <135 mEq/L and 43% with sodium ≤130 mEq/L, indicating suboptimal management in real-world practice 6.