What are the causes, work‑up, and treatment of chronic hyponatremia?

Chronic Hyponatremia: Causes, Work-up, and Treatment

Primary Causes of Chronic Hyponatremia

Chronic hyponatremia (>48 hours duration) most commonly results from non-osmotic vasopressin release causing water retention rather than true sodium depletion. 1

Euvolemic Causes (Most Common)

• Syndrome of Inappropriate Antidiuretic Hormone (SIADH) is the most frequent cause of euvolemic hyponatremia, characterized by inappropriate ADH secretion despite low plasma osmolality 1, 2
• Common triggers include malignancies (especially small cell lung cancer affecting 1-5% of patients), CNS disorders, pulmonary diseases, and medications such as SSRIs, carbamazepine, NSAIDs, and chemotherapy agents 1, 3
• Hospital-acquired hyponatremia from hypotonic IV fluids affects 15-30% of hospitalized patients and is entirely preventable by using isotonic maintenance fluids 1

Hypervolemic Causes

• Advanced liver cirrhosis with portal hypertension causes hypervolemic hyponatremia in approximately 60% of cirrhotic patients, with 21.6% having sodium ≤130 mmol/L 1
• Systemic vasodilation from portal hypertension leads to decreased effective plasma volume, triggering non-osmotic vasopressin hypersecretion and activation of the renin-angiotensin-aldosterone system 1
• Congestive heart failure produces similar pathophysiology with increased ADH release due to perceived arterial underfilling despite total body fluid overload 1

Hypovolemic Causes

• Excessive diuretic use, particularly thiazides, causes renal sodium losses with urine sodium >20 mmol/L 1
• Gastrointestinal losses (vomiting, diarrhea) and burns produce extrarenal losses with urine sodium <30 mmol/L 1, 4
• Cerebral salt wasting (CSW) in neurosurgical patients results from excessive natriuretic peptide secretion, more common with poor clinical grade and ruptured anterior communicating artery aneurysms 1

Endocrine and Medication-Related

• Hypothyroidism and adrenal insufficiency must be excluded before confirming SIADH 1
• Antidepressants including trazodone place patients at particularly high risk for developing hyponatremia 1
• Beer potomania from excessive alcohol consumption with very low solute intake represents a unique cause requiring thiamine 500 mg IV three times daily before any glucose-containing fluids 1

Diagnostic Work-up Algorithm

Initial Laboratory Assessment

Begin with serum sodium <135 mmol/L, but pursue full work-up when sodium drops below 131 mmol/L. 1

• Serum osmolality to exclude pseudohyponatremia (normal 275-290 mOsm/kg) and hypertonic hyponatremia from hyperglycemia (add 1.6 mEq/L to sodium for each 100 mg/dL glucose >100 mg/dL) 1, 4
• Urine osmolality and urine sodium concentration are essential: urine osmolality <100 mOsm/kg indicates appropriate ADH suppression, while >100 mOsm/kg suggests impaired water excretion 1, 2
• Serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH 1, 2

Volume Status Assessment

Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%), so supplement with laboratory findings 1:

• Hypovolemic signs: orthostatic hypotension, dry mucous membranes, decreased skin turgor, flat neck veins, with urine sodium <30 mmol/L predicting 71-100% response to saline 1
• Euvolemic signs: no edema, no orthostatic hypotension, normal skin turgor, moist mucous membranes 1
• Hypervolemic signs: peripheral edema, ascites, jugular venous distention, pulmonary congestion 1, 4

Distinguishing SIADH from Cerebral Salt Wasting (Critical in Neurosurgical Patients)

• SIADH: euvolemic state, urine sodium >20-40 mmol/L, urine osmolality >300 mOsm/kg, normal to slightly elevated CVP 1, 2
• CSW: true hypovolemia with CVP <6 cm H₂O, urine sodium >20 mmol/L despite volume depletion, clinical signs of extracellular volume depletion 1

Additional Testing

• TSH and cortisol levels to exclude hypothyroidism and adrenal insufficiency 1
• Comprehensive medication review, particularly SSRIs, carbamazepine, NSAIDs, opioids, and chemotherapy agents 1
• Liver function tests and BNP for suspected cirrhosis or heart failure 1
• Chest X-ray to identify pulmonary causes of SIADH 1

Treatment Approach Based on Etiology and Volume Status

Critical Safety Principle

The maximum correction rate must never exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome, with high-risk patients (advanced liver disease, alcoholism, malnutrition) limited to 4-6 mmol/L per day. 1

Euvolemic Hyponatremia (SIADH)

Fluid restriction to 1 L/day is the cornerstone of treatment for chronic SIADH. 1, 2

• For mild/asymptomatic cases: implement strict fluid restriction <1 L/day and monitor sodium every 24-48 hours initially 1
• If no response to fluid restriction: add oral sodium chloride 100 mEq three times daily (approximately 7 grams sodium/day) 1
• For resistant cases: consider vasopressin receptor antagonists (tolvaptan 15 mg once daily, titrate to 30-60 mg) with careful monitoring to avoid overly rapid correction 1, 2
• Alternative pharmacological options include urea (40 g in 100-150 mL normal saline every 8 hours), demeclocycline, or lithium, though these have more side effects 1

Hypervolemic Hyponatremia (Cirrhosis, Heart Failure)

Fluid restriction to 1-1.5 L/day is first-line for serum sodium <125 mmol/L, with sodium restriction (not fluid restriction) being more important for weight loss as fluid passively follows sodium. 1

• Discontinue diuretics temporarily if sodium <125 mmol/L 1
• For cirrhotic patients: consider albumin infusion (8 g per liter of ascites removed) alongside fluid restriction 1
• Avoid hypertonic saline unless life-threatening symptoms are present, as it worsens ascites and edema 1
• Vaptans may be considered for persistent severe hyponatremia despite fluid restriction and maximization of guideline-directed medical therapy, but use with extreme caution in cirrhosis due to 10% gastrointestinal bleeding risk (vs. 2% placebo) and hepatotoxicity (4.4% with ALT >3× ULN) 1
• Limit tolvaptan use to ≤30 days with monthly liver function monitoring 1

Hypovolemic Hyponatremia

Discontinue diuretics and administer isotonic saline (0.9% NaCl) for volume repletion, with initial infusion rate 15-20 mL/kg/h, then 4-14 mL/kg/h based on response. 1

• Urine sodium <30 mmol/L predicts good response to saline infusion 1
• For cirrhotic patients with hypovolemic hyponatremia: use cautious correction rates of 4-6 mmol/L per day maximum and consider albumin infusion alongside isotonic saline 1
• Once euvolemic, switch to maintenance isotonic fluids at 30 mL/kg/day 1

Cerebral Salt Wasting (Neurosurgical Patients)

Treatment focuses on volume and sodium replacement with isotonic or hypertonic saline—never use fluid restriction as this worsens outcomes. 1

• For severe symptoms: administer 3% hypertonic saline plus fludrocortisone 0.1-0.2 mg daily in ICU setting 1
• Aggressive volume resuscitation with normal saline 50-100 mL/kg/day or hypertonic saline for severe cases 1
• Hydrocortisone may be used to prevent natriuresis in subarachnoid hemorrhage patients 1
• Never use fluid restriction in subarachnoid hemorrhage patients at risk of vasospasm 1

Monitoring During Correction

• For severe symptoms: check serum sodium every 2 hours during initial correction 1
• For mild symptoms: check every 4 hours after resolution of severe symptoms 1
• Watch for signs of osmotic demyelination syndrome (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 1

Management of Overcorrection

If sodium correction exceeds 8 mmol/L in 24 hours, immediately discontinue current fluids and switch to D5W (5% dextrose in water), and consider administering desmopressin to slow or reverse the rapid rise. 1

The target is to bring the total 24-hour correction back to ≤8 mmol/L from baseline 1

Common Pitfalls to Avoid

• Ignoring mild hyponatremia (130-135 mmol/L) as clinically insignificant—even mild hyponatremia increases fall risk (21% vs. 5%) and mortality (60-fold increase with sodium <130 mmol/L) 1
• Using fluid restriction in cerebral salt wasting, which worsens outcomes 1
• Failing to distinguish SIADH from CSW in neurosurgical patients, as they require opposite treatments 1
• Inadequate monitoring during active correction 1
• Using hypertonic saline in hypervolemic hyponatremia without life-threatening symptoms 1
• Overly rapid correction exceeding 8 mmol/L in 24 hours, leading to osmotic demyelination syndrome 1