What is the management approach for a patient with suspected Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

Management of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Diagnostic Criteria

SIADH is diagnosed by the presence of hypotonic hyponatremia (serum sodium <134 mEq/L), plasma osmolality <275 mosm/kg, inappropriately high urine osmolality (>500 mosm/kg), and urine sodium >20 mEq/L in a euvolemic patient with normal thyroid, adrenal, and renal function. 1

• The euvolemic state is critical—look for absence of orthostatic hypotension, normal skin turgor, moist mucous membranes, no edema, and no jugular venous distention 1
• Serum uric acid <4 mg/dL has a 73-100% positive predictive value for SIADH 1
• Exclude hypothyroidism (check TSH) and adrenal insufficiency (check cortisol) as these mimic SIADH 1
• A common pitfall is failing to distinguish SIADH from cerebral salt wasting (CSW) in neurosurgical patients—CSW presents with true hypovolemia (CVP <6 cm H₂O) and requires opposite treatment 1

Treatment Algorithm Based on Symptom Severity

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

Administer 3% hypertonic saline immediately with a target correction of 6 mmol/L over 6 hours or until severe symptoms resolve. 1

• Transfer to ICU for close monitoring 1
• Check serum sodium every 2 hours during initial correction 1
• The absolute maximum correction is 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 2
• If 6 mmol/L is corrected in the first 6 hours, only 2 mmol/L additional correction is allowed in the next 18 hours 1
• Avoid fluid restriction during acute symptomatic treatment—hypertonic saline is the priority 1

Mild to Moderate Symptomatic or Asymptomatic Hyponatremia (Sodium <120 mEq/L)

Fluid restriction to 1 L/day is the cornerstone of treatment for chronic SIADH. 1

• If no response to fluid restriction after 24-48 hours, add oral sodium chloride 100 mEq three times daily 1
• Monitor serum sodium every 24 hours initially, then adjust frequency based on response 1
• Target correction rate: 4-6 mmol/L per day, never exceeding 8 mmol/L in 24 hours 1
• Avoid overly strict fluid restriction in patients with lung cancer undergoing treatment, as it may affect overall clinical status 1

Pharmacological Treatment Options

Vasopressin Receptor Antagonists (Vaptans)

Tolvaptan is FDA-approved for clinically significant euvolemic hyponatremia, starting at 15 mg once daily, titrated to 30 mg after 24 hours, with a maximum of 60 mg daily. 1, 2

• Tolvaptan should be initiated and re-initiated only in a hospital where serum sodium can be monitored closely 2
• The first 24 hours are critical—check serum sodium at 0,6,24, and 48 hours to prevent overly rapid correction 3
• Avoid fluid restriction during the first 24 hours of tolvaptan therapy 2
• Do not administer tolvaptan for more than 30 days to minimize risk of liver injury 2
• Tolvaptan is contraindicated with strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) 2
• In clinical trials, tolvaptan increased serum sodium by 4.0 mEq/L at Day 4 and 6.2 mEq/L at Day 30 compared to placebo 2

Second-Line Pharmacological Options

Demeclocycline can be considered as second-line treatment for chronic SIADH when fluid restriction is ineffective or poorly tolerated. 1

• Demeclocycline induces nephrogenic diabetes insipidus, reducing the kidney's response to ADH 1
• Other options include urea (very effective and safe in recent literature), lithium, and loop diuretics, though these are less commonly used 1
• Urea at 40 g in 100-150 mL normal saline every 8 hours has been effective in neurosurgical patients 1

Special Populations and High-Risk Considerations

Patients with Advanced Liver Disease, Alcoholism, or Malnutrition

These patients require even more cautious correction at 4-6 mmol/L per day due to higher risk of osmotic demyelination syndrome. 1, 2

• Slower correction rates (4-6 mmol/L per day) are mandatory in patients with severe malnutrition, alcoholism, or advanced liver disease 1, 2
• If overcorrection occurs, immediately discontinue current fluids, switch to D5W, and consider desmopressin to relower sodium levels 1

Neurosurgical Patients

In neurosurgical patients, distinguishing SIADH from cerebral salt wasting is critical because treatments are opposite. 1

• SIADH: euvolemic (CVP 6-10 cm H₂O), treat with fluid restriction 1
• CSW: hypovolemic (CVP <6 cm H₂O), treat with volume and sodium replacement, NOT fluid restriction 1
• In subarachnoid hemorrhage patients at risk for vasospasm, avoid fluid restriction and consider fludrocortisone 0.1-0.2 mg daily 1

Cancer Patients

In SCLC patients with paraneoplastic SIADH, treatment of the underlying malignancy is important alongside hyponatremia management. 1

• Chemotherapeutic agents (cisplatin, vincristine, vinblastine, cyclophosphamide) can induce or worsen SIADH 1
• Hyponatremia usually improves after successful treatment of the underlying cancer 1

Common Medications That Cause SIADH

High-risk medications include SSRIs, SNRIs, carbamazepine, oxcarbazepine, NSAIDs, tramadol, and certain antipsychotics. 1

• Discontinuing the offending medication is essential if symptomatic hyponatremia is present 1
• The combination of thiazide diuretics with SSRIs or other SIADH-inducing medications substantially increases risk 1
• Older patients, especially women, are at higher risk for medication-associated hyponatremia 1

Critical Pitfalls to Avoid

Never exceed 8 mmol/L correction in 24 hours—this causes osmotic demyelination syndrome with dysarthria, dysphagia, quadriparesis, seizures, coma, or death. 1, 2

• Inadequate monitoring during active correction leads to overcorrection 1
• Using fluid restriction in cerebral salt wasting worsens outcomes 1
• Failing to recognize and treat the underlying cause perpetuates the problem 1
• Ignoring mild hyponatremia (130-135 mmol/L) is dangerous—it increases fall risk (21% vs 5%) and mortality (60-fold increase with sodium <130 mmol/L) 1

Monitoring During Treatment

For severe symptoms, monitor serum sodium every 2 hours initially; for mild symptoms, every 4 hours; once stable, every 24 hours. 1

• Watch for signs of osmotic demyelination syndrome (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 1
• After discontinuing tolvaptan, resume fluid restriction and monitor for hyponatremic relapse 3
• It may be necessary to taper the vaptan dose or restrict fluid intake or both when discontinuing therapy 3