What are the diagnostic criteria and classes for the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)?

Diagnostic Criteria and Classification of SIADH

Essential Diagnostic Criteria

SIADH is diagnosed when five cardinal criteria are met: hypotonic hyponatremia (serum sodium <134 mEq/L), plasma osmolality <275 mosm/kg, inappropriately concentrated urine (osmolality >500 mosm/kg), urinary sodium >20 mEq/L, and clinical euvolemia in the absence of hypothyroidism, adrenal insufficiency, or volume depletion. 1, 2

The diagnosis requires simultaneous demonstration of:

• Hyponatremia with hypo-osmolality: Serum sodium <134-135 mEq/L with plasma osmolality <275 mosm/kg 1, 2, 3
• Inappropriately concentrated urine: Urine osmolality >100 mosm/kg (typically >500 mosm/kg) despite low plasma osmolality 1, 2, 3
• Elevated urinary sodium: Urine sodium concentration >20-40 mEq/L, indicating continued natriuresis 1, 2, 3
• Clinical euvolemia: Absence of edema, orthostatic hypotension, dry mucous membranes, or signs of volume overload 1, 2, 4
• Normal organ function: Normal renal, adrenal, and thyroid function must be confirmed 1, 2, 3

Critical Distinguishing Features

Volume status assessment is paramount—SIADH patients are euvolemic, not hypovolemic or hypervolemic. 1, 2 Look specifically for:

• No orthostatic hypotension or tachycardia (rules out hypovolemia) 1
• No peripheral edema, ascites, or jugular venous distention (rules out hypervolemia) 1
• Normal skin turgor and moist mucous membranes 1

A serum uric acid <4 mg/dL has a 73-100% positive predictive value for SIADH, though this may include some cerebral salt wasting cases. 1, 5

Classification by Osmoregulatory Pattern

SIADH can be categorized into four distinct patterns based on AVP secretion dynamics:

Type A: Erratic AVP Release

Characterized by random, unpredictable AVP secretion independent of plasma osmolality. 2 This pattern shows no relationship between osmolality changes and AVP levels.

Type B: Reset Osmostat

AVP secretion maintains normal osmoregulation but at a lower osmotic threshold. 2 The osmostat is "reset" to defend a lower serum sodium level, typically 125-135 mEq/L.

Type C: Persistent AVP Release

Continuous AVP secretion despite low plasma osmolality, with no suppression even at very low osmolality levels. 2 This represents the classic SIADH pattern with complete loss of osmotic regulation.

Type D: Normal Osmoregulated AVP Secretion

Paradoxically normal AVP regulation patterns despite meeting SIADH criteria, suggesting enhanced renal sensitivity to AVP. 2 This may represent a form of nephrogenic SIADH.

Common Etiologies by Category

Malignancy

Small cell lung cancer is the most common malignant cause, with SIADH occurring in 1-5% of cases. 6, 1 Other malignancies include head and neck cancers, lymphomas, and various carcinomas. 2, 7

Neurological Disorders

CNS infections (meningitis, encephalitis), space-occupying lesions (abscesses, tumors), subarachnoid hemorrhage, and head trauma all disrupt hypothalamic-pituitary function. 8, 2, 4 In pediatrics, meningitis is the most common neurological cause. 4

Pulmonary Diseases

Pneumonia, tuberculosis, aspergillosis, and other pulmonary infections can trigger SIADH. 2, 7 Pulmonary carcinoids rarely cause SIADH compared to small cell lung cancer. 6

Medications

High-risk drugs include SSRIs, carbamazepine, oxcarbazepine, chlorpropamide, cyclophosphamide, vincristine, cisplatin, NSAIDs, and tramadol. 1, 7 The 2019 AGS Beers Criteria specifically warns about these medications in older adults. 1

Postoperative State

Inappropriate administration of hypotonic fluids postoperatively remains a common iatrogenic cause, particularly when combined with pain, nausea, and stress—all nonosmotic stimuli for AVP release. 1, 2

Pathophysiology

The core mechanism involves persistent or elevated plasma AVP despite hyponatremia and low plasma osmolality, leading to water retention and physiologic natriuresis where fluid balance is maintained at the expense of plasma sodium. 1, 2

Nonosmotic stimuli (pain, nausea, stress, acute illness) override normal osmotic regulation, causing AVP excess that impairs free-water excretion. 1 When electrolyte-free water is supplied in this setting, hyponatremia develops rapidly. 1

The concentrated urine with high sodium content results from the kidney's inability to suppress AVP secretion appropriately, forcing continued water reabsorption and compensatory sodium excretion. 1

Critical Diagnostic Pitfalls

The most dangerous error is confusing SIADH with cerebral salt wasting (CSW) in neurosurgical patients, as they require opposite treatments. 1, 5, 8

Key differences:

• SIADH: Euvolemic, CVP 6-10 cm H₂O, treat with fluid restriction 1, 5
• CSW: Hypovolemic, CVP <6 cm H₂O, treat with volume and sodium replacement 1, 5

Physical examination alone has poor accuracy (sensitivity 41%, specificity 80%) for volume assessment—use CVP when available in neurosurgical patients. 1, 5

Failing to exclude hypothyroidism and adrenal insufficiency before diagnosing SIADH can lead to catastrophic outcomes, as these conditions mimic SIADH but require hormone replacement. 1, 2, 3

Obtaining ADH and natriuretic peptide levels is not supported by evidence and should not delay treatment. 1, 5

Clinical Severity Assessment

Symptoms correlate with both the absolute sodium level and the rate of decline, particularly when falling faster than 0.5 mmol/L/hour. 2

• Mild (130-135 mEq/L): Often asymptomatic but increases fall risk and mortality 1
• Moderate (120-129 mEq/L): Nausea, vomiting, headache, confusion 2, 7
• Severe (<120 mEq/L): Seizures, coma, respiratory arrest, death 2, 7, 4

Acute hyponatremia (<48 hours) produces more severe symptoms at higher sodium levels than chronic hyponatremia due to inadequate cerebral adaptation. 1, 3

Laboratory Confirmation Algorithm

1. Initial screening: Serum sodium, plasma osmolality, urine osmolality, urine sodium simultaneously 1, 8
2. Exclude pseudohyponatremia: Check serum glucose (add 1.6 mEq/L to sodium for each 100 mg/dL glucose >100) 5
3. Assess organ function: TSH, cortisol, serum creatinine to exclude other causes 1, 5
4. Volume status: Physical exam supplemented by CVP if available 1, 5
5. Identify etiology: Chest imaging, neuroimaging, medication review based on clinical context 1, 8, 2

Never delay treatment while awaiting confirmatory tests in severely symptomatic patients—begin 3% hypertonic saline immediately if seizures, altered mental status, or coma are present. 1, 4, 3