How do I diagnose syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a clinically euvolaemic patient with hyponatremia?

Diagnosing SIADH in a Clinically Euvolemic Patient with Hyponatremia

The diagnosis of SIADH requires five cardinal criteria: hypotonic hyponatremia (serum sodium <135 mmol/L), inappropriately concentrated urine (urine osmolality >100 mOsm/kg, typically >300-500 mOsm/kg), elevated urinary sodium (>20-40 mEq/L), clinical euvolemia (absence of edema, orthostatic hypotension, or signs of volume depletion), and normal thyroid, adrenal, and renal function. 1, 2, 3

Essential Diagnostic Criteria

Serum Studies

• Measure serum sodium, serum osmolality, and serum uric acid. Hyponatremia is defined as serum sodium <135 mmol/L, with values <131 mmol/L warranting full diagnostic workup. 1, 4

• Serum osmolality must be low (<275 mOsm/kg) to confirm true hypotonic hyponatremia and exclude pseudohyponatremia from hyperglycemia or hyperlipidemia. 2, 4, 3

• Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH, though it may also occur in cerebral salt wasting. 1, 4

Urine Studies

• Obtain urine osmolality and urine sodium concentration. A spot urine sample is sufficient and correlates well with 24-hour collection for diagnostic purposes. 5

• Urine osmolality >100 mOsm/kg (typically >300-500 mOsm/kg) despite low serum osmolality indicates inappropriate ADH activity. This represents the hallmark finding—the kidneys are concentrating urine when they should be maximally diluting it. 2, 4, 3

• Urine sodium >20-40 mEq/L confirms renal sodium wasting due to volume expansion and physiologic natriuresis. In SIADH, persistent ADH causes water retention, leading to compensatory sodium excretion to maintain fluid balance at the expense of serum sodium. 1, 2, 4

• A urine sodium value ≥50 mEq/L has 89% sensitivity and 69% specificity for distinguishing SIADH from hypovolemic hyponatremia. Values between 20-50 mEq/L require careful clinical correlation with volume status. 6

Volume Status Assessment

• Clinical euvolemia is the decisive discriminating feature separating SIADH from hypovolemic (cerebral salt wasting, diuretic use) and hypervolemic (heart failure, cirrhosis) causes of hyponatremia. 1, 2, 4

• Euvolemia is characterized by absence of orthostatic hypotension, normal skin turgor, moist mucous membranes, no peripheral edema, no ascites, and no jugular venous distention. However, physical examination alone has poor accuracy (sensitivity 41%, specificity 80%), so integrate clinical findings with laboratory data. 1, 4

• In neurosurgical patients or when volume status is uncertain, central venous pressure can help: CVP 6-10 cm H₂O suggests euvolemia (SIADH), while CVP <6 cm H₂O indicates hypovolemia (cerebral salt wasting). 2, 4

Mandatory Exclusions

Rule Out Alternative Causes

• Measure TSH to exclude hypothyroidism and cortisol/ACTH to exclude adrenal insufficiency, as both can mimic SIADH with euvolemic hyponatremia. 1, 2, 4

• Assess renal function (creatinine, BUN) to exclude advanced kidney disease, which can cause hypervolemic hyponatremia with elevated urine sodium. 1, 4

• Review all medications for SIADH-inducing drugs: SSRIs, carbamazepine, oxcarbazepine, NSAIDs, opioids, chemotherapy (cisplatin, vincristine, cyclophosphamide), and chlorpropamide. 2, 7

Tests NOT Recommended

• Do not routinely measure plasma ADH levels or natriuretic peptides (ANP, BNP) for SIADH diagnosis—these tests are not supported by evidence, delay diagnosis, and do not change management. 1, 4

Diagnostic Algorithm

1. Confirm true hyponatremia: Serum sodium <135 mmol/L with serum osmolality <275 mOsm/kg 1, 4

2. Assess volume status clinically: Look for signs of hypovolemia (orthostatic hypotension, dry mucous membranes) or hypervolemia (edema, ascites, JVD). Euvolemia = absence of both. 1, 4

3. Obtain spot urine osmolality and sodium:

   • Urine osmolality >100 mOsm/kg (typically >300-500 mOsm/kg) = inappropriate concentration 2, 4, 5
   • Urine sodium >20-40 mEq/L = renal sodium wasting 1, 4

4. Exclude alternative diagnoses:

   • TSH (hypothyroidism) 2, 4
   • Cortisol/ACTH (adrenal insufficiency) 1, 2
   • Creatinine/BUN (renal failure) 1, 4
   • Medication review 2, 7

5. If all five cardinal criteria are met, diagnose SIADH and search for underlying cause (malignancy, CNS disorder, pulmonary disease, drugs). 1, 2, 3

Common Diagnostic Pitfalls

• Misclassifying volume status leads to incorrect diagnosis and treatment. SIADH requires euvolemia; if the patient is truly hypovolemic, consider cerebral salt wasting (especially in neurosurgical patients) or diuretic use. If hypervolemic, consider heart failure or cirrhosis. 1, 4

• Relying solely on physical examination for volume assessment is inadequate given its poor sensitivity (41%) and specificity (80%). Integrate clinical findings with urine sodium, response to fluid challenge, and CVP when available. 1, 4

• Administering isotonic saline to confirm SIADH can worsen hyponatremia because SIADH patients cannot excrete free water—the sodium is excreted while water is retained. This is a diagnostic clue: hyponatremia that fails to improve or worsens with normal saline suggests SIADH. 8

• In neurosurgical patients, failing to distinguish SIADH from cerebral salt wasting is critical because they require opposite treatments (fluid restriction vs. volume expansion). Both have elevated urine sodium, but CSW presents with true hypovolemia (CVP <6 cm H₂O, orthostatic hypotension). 2, 4

• Urine sodium values between 20-50 mEq/L create diagnostic uncertainty. Values ≥50 mEq/L strongly suggest SIADH, while values <30 mEq/L favor hypovolemia. In the intermediate range, clinical context and response to therapy guide diagnosis. 6