What is hyponatremia, its etiology, pathogenesis, clinical manifestations, diagnosis, treatment, and potential complications, including Osmotic Demyelination Syndrome, as well as the pathogenesis and clinical features of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

Hyponatremia: Comprehensive Overview for Provider-Level Theory Preparation

Definition and Classification

Hyponatremia is defined as serum sodium concentration below 135 mmol/L, representing the most common electrolyte disorder encountered in clinical medicine 1. The condition is classified by severity: mild (126-135 mEq/L), moderate (120-125 mEq/L), and severe (<120 mEq/L) 1. Additionally, hyponatremia is categorized by volume status into three distinct types: hypovolemic (decreased extracellular fluid), euvolemic (normal volume status), and hypervolemic (increased extracellular fluid with edema/ascites) 1, 2.

The temporal classification distinguishes acute hyponatremia (<48 hours duration) from chronic hyponatremia (>48 hours), which is critical because correction rates differ dramatically between these two categories 1.

Etiology and Pathogenesis

Physiological Mechanisms

The fundamental pathophysiology involves elevated arginine vasopressin (AVP) levels despite low plasma osmolality, leading to water retention and subsequent physiologic natriuresis where fluid balance is maintained at the expense of plasma sodium 3, 4. This non-osmotic AVP release can be triggered by pain, nausea, stress, and various acute illness states 5.

Major Etiologic Categories

Euvolemic hyponatremia is most commonly caused by SIADH, characterized by inappropriately concentrated urine (>500 mOsm/kg) with elevated urinary sodium (>20-40 mEq/L) despite euvolemia 5, 6. Common SIADH causes include malignancies (particularly small cell lung cancer), CNS disorders, pulmonary diseases, postoperative states, and numerous medications including SSRIs, carbamazepine, cyclophosphamide, and vincristine 5, 4.

Hypovolemic hyponatremia results from true volume depletion with urinary sodium <30 mmol/L suggesting extrarenal losses (gastrointestinal losses, burns, dehydration), while urinary sodium >20 mmol/L indicates renal losses (diuretics, cerebral salt wasting, adrenal insufficiency, salt-losing nephropathy) 1, 6.

Hypervolemic hyponatremia occurs in edematous states including heart failure, cirrhosis, and advanced renal failure, where non-osmotic hypersecretion of vasopressin and enhanced proximal nephron sodium reabsorption lead to impaired free water clearance 1, 2. In cirrhosis, systemic vasodilation from portal hypertension decreases effective plasma volume, activating the renin-angiotensin-aldosterone system and causing excessive sodium and water reabsorption 1.

Clinical Manifestations

Symptom Severity Correlation

Clinical features are principally neuromuscular and gastrointestinal, with severity related to both the absolute serum sodium concentration and the rate of decline, particularly if exceeding 0.5 mmol/L/hour 4. Severe symptomatic hyponatremia presents with seizures, coma, confusion, and altered mental status requiring immediate intervention 1, 5.

Mild to moderate symptoms include nausea, vomiting, headache, attention deficits, and increased fall risk—hyponatremic patients present with falls in 21% of cases compared to 5% in normonatremic patients 1. Even mild hyponatremia (130-135 mmol/L) is associated with neurocognitive problems and a 60-fold increase in hospital mortality (11.2% versus 0.19%) when sodium drops below 130 mmol/L 1.

Special Population Considerations

In cirrhotic patients, hyponatremia (defined as <130 mmol/L in this population) significantly increases complications: spontaneous bacterial peritonitis (OR 3.40), hepatorenal syndrome (OR 3.45), and hepatic encephalopathy (OR 2.36) 1.

Diagnostic Approach and Evaluation

Initial Workup Algorithm

Begin with serum sodium <135 mmol/L as the threshold, but pursue comprehensive workup when sodium drops below 131 mmol/L 1, 6. The initial evaluation must include:

• Serum and urine osmolality
• Urine sodium concentration
• Urine electrolytes
• Serum uric acid
• Assessment of extracellular fluid volume status
• Thyroid-stimulating hormone (to exclude hypothyroidism)
• Serum cortisol (to exclude adrenal insufficiency)
• Serum creatinine and blood urea nitrogen 1, 6

Obtaining ADH and natriuretic peptide levels is not supported by evidence and should not delay treatment 1, 6.

Volume Status Assessment

Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) for determining volume status 1, 6. Look for specific findings:

• Hypovolemic signs: orthostatic hypotension, dry mucous membranes, decreased skin turgor, flat neck veins, tachycardia 1, 6
• 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, 6

Urine Studies Interpretation

Urine osmolality <100 mOsm/kg indicates appropriate ADH suppression, while >100 mOsm/kg suggests impaired water excretion 6. For hypovolemic hyponatremia, urine sodium <30 mmol/L (with positive predictive value 71-100% for saline responsiveness) indicates extrarenal losses, while >20 mmol/L suggests renal losses 1, 6.

For euvolemic hyponatremia, urine sodium >20-40 mmol/L with urine osmolality >300 mOsm/kg strongly supports SIADH 5, 6. Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH, though this may also occur in cerebral salt wasting 1, 6.

Critical Distinction: SIADH versus Cerebral Salt Wasting

In neurosurgical patients, distinguishing SIADH from cerebral salt wasting (CSW) is absolutely critical because treatments are opposite 1, 5:

• SIADH: euvolemic, CVP 6-10 cm H₂O, urine sodium >20-40 mmol/L, urine osmolality >500 mOsm/kg, treated with fluid restriction 1, 5
• CSW: hypovolemic, CVP <6 cm H₂O, urine sodium >20 mmol/L despite volume depletion, evidence of extracellular volume depletion, treated with volume and sodium replacement 1, 5

Treatment and Monitoring

Treatment Based on Symptom Severity

For severe symptomatic hyponatremia (seizures, coma, altered mental status), immediately administer 3% hypertonic saline with a target correction of 6 mmol/L over 6 hours or until severe symptoms resolve 1, 5. The initial bolus approach involves 100 mL of 3% saline over 10 minutes, which can be repeated up to three times at 10-minute intervals until symptoms improve 1.

For mild symptomatic or asymptomatic hyponatremia, treatment is based on volume status and etiology 1, 5:

• SIADH (euvolemic): Fluid restriction to 1 L/day is the cornerstone of treatment 1, 5. If no response, add oral sodium chloride 100 mEq three times daily 1. For resistant cases, consider vasopressin receptor antagonists (tolvaptan 15 mg once daily, titrated to 30-60 mg) 1, 7.

• Hypovolemic hyponatremia: Discontinue diuretics immediately if sodium <125 mmol/L and administer isotonic saline (0.9% NaCl) for volume repletion, with initial infusion rate 15-20 mL/kg/hour, then 4-14 mL/kg/hour based on response 1.

• Hypervolemic hyponatremia (cirrhosis, heart failure): Implement fluid restriction to 1-1.5 L/day for sodium <125 mmol/L 1. In cirrhotic patients, consider albumin infusion alongside fluid restriction 1. Avoid hypertonic saline unless life-threatening symptoms are present, as it worsens ascites and edema 1.

Critical Correction Rate Guidelines

The single most important safety principle: never exceed 8 mmol/L correction in 24 hours to prevent osmotic demyelination syndrome 1, 5, 7. For severe symptoms, correct by 6 mmol/L in the first 6 hours or until symptoms resolve, then limit additional correction to only 2 mmol/L in the remaining 18 hours 1.

High-risk patients (advanced liver disease, alcoholism, malnutrition, prior encephalopathy) require even more cautious correction at 4-6 mmol/L per day, maximum 8 mmol/L in 24 hours 1, 5. The FDA label for tolvaptan explicitly warns that correction rates >12 mEq/L/24 hours can cause osmotic demyelination 7.

Monitoring Protocols

For severe symptoms: Monitor serum sodium every 2 hours during initial correction phase 1, 5. After resolution of severe symptoms, monitor every 4 hours 1. For mild symptoms or asymptomatic patients, monitor daily initially, then adjust frequency based on response 1.

Pharmacological Options

Tolvaptan (vasopressin V2 receptor antagonist) is FDA-approved for clinically significant euvolemic and hypervolemic hyponatremia (serum sodium <125 mEq/L or symptomatic hyponatremia resistant to fluid restriction) 7. In the SALT-1 and SALT-2 trials, tolvaptan increased serum sodium by 3.7 mEq/L at Day 4 and 4.6 mEq/L at Day 30 compared to placebo (p<0.0001) 7.

Critical tolvaptan considerations: Must be initiated and re-initiated only in hospital with close sodium monitoring 7. Starting dose is 15 mg once daily, titrated to 30-60 mg as needed 7. Avoid fluid restriction during the first 24 hours of tolvaptan therapy to prevent overly rapid correction 7. Do not use for more than 30 days due to hepatotoxicity risk 7. In cirrhotic patients, tolvaptan carries higher risk of gastrointestinal bleeding (10% vs 2% placebo) 1.

Alternative pharmacological agents for SIADH include demeclocycline (induces nephrogenic diabetes insipidus), urea (very effective and safe), lithium, and loop diuretics, though these are less commonly used 1, 5.

Osmotic Demyelination Syndrome

Pathophysiology and Risk Factors

Osmotic demyelination syndrome (also called central pontine myelinolysis) results from overly rapid correction of chronic hyponatremia, typically when correction exceeds 8-12 mmol/L in 24 hours 1, 7, 3. The syndrome occurs in 0.5-1.5% of liver transplant recipients 1.

High-risk populations include patients with severe malnutrition, alcoholism, advanced liver disease, hypophosphatemia, hypokalemia, hypoglycemia, low cholesterol, or prior encephalopathy 1, 7.

Clinical Manifestations

Symptoms typically appear 2-7 days after rapid correction and include dysarthria, mutism, dysphagia, lethargy, affective changes, oculomotor dysfunction, spastic quadriparesis, seizures, coma, and death 1, 7, 3.

Prevention and Management

Prevention is paramount: Limit correction to 8 mmol/L in 24 hours for average-risk patients, and 4-6 mmol/L per day for high-risk patients 1. If overcorrection occurs, immediately discontinue current fluids, switch to D5W (5% dextrose in water), and consider administering desmopressin to relower sodium levels 1.

SIADH: Detailed Pathogenesis and Clinical Features

Diagnostic Criteria

SIADH diagnosis requires five cardinal criteria 5, 4:

1. Hypotonic hyponatremia (serum sodium <134 mEq/L, plasma osmolality <275 mOsm/kg)
2. Inappropriately elevated urinary osmolality (>500 mOsm/kg)
3. Elevated urinary sodium (>20-40 mEq/L)
4. Euvolemia (absence of edema, orthostatic hypotension, normal skin turgor, moist mucous membranes)
5. Normal renal, adrenal, and thyroid function 5, 4

Pathophysiologic Subtypes

Four categories of osmoregulated AVP secretion exist in SIADH 4:

1. Type A: Erratic AVP release
2. Type B: Reset osmostat (AVP secretion at lower osmotic threshold)
3. Type C: Persistent AVP release at low plasma osmolality
4. Type D: Normal osmoregulated AVP secretion with maintained aquaporin-2 channel permeability (activating mutations of V2 receptor identified) 5

Common Etiologies

Malignancy: Small cell lung cancer is the classic association, with SIADH affecting 1-5% of lung cancer patients 5. Paraneoplastic SIADH improves with successful cancer treatment 5.

Medications: The most frequent cause of SIADH is drug-induced secretion, including SSRIs, carbamazepine, cyclophosphamide, vincristine, cisplatin, NSAIDs, and opioids 5, 4.

Postoperative states: Hospital-acquired hyponatremia from hypotonic IV fluids in the setting of elevated AVP affects 15-30% of hospitalized patients and is entirely preventable by using isotonic maintenance fluids 5.

CNS disorders: Meningitis, encephalitis, subarachnoid hemorrhage, traumatic brain injury 5, 4.

Pulmonary diseases: Pneumonia, tuberculosis, positive pressure ventilation 4.

Treatment Algorithm

For severe symptomatic SIADH: Transfer to ICU, administer 3% hypertonic saline targeting 6 mmol/L correction over 6 hours or until symptoms resolve, monitor sodium every 2 hours, never exceed 8 mmol/L total correction in 24 hours 5.

For mild symptomatic or asymptomatic SIADH: Fluid restriction to 1 L/day is first-line 5. If ineffective after 24-48 hours, add oral sodium chloride supplementation 5. For chronic resistant SIADH, consider demeclocycline, urea, or tolvaptan 5.

Critical pitfall: Never use fluid restriction in subarachnoid hemorrhage patients at risk for vasospasm, as this worsens outcomes 5. In these patients, consider fludrocortisone or hydrocortisone to prevent natriuresis 1, 5.

Common Pitfalls to Avoid

• Overly rapid correction exceeding 8 mmol/L in 24 hours leading to osmotic demyelination syndrome 1, 5
• Inadequate monitoring during active correction 1
• Using fluid restriction in cerebral salt wasting instead of volume replacement, which worsens outcomes 1, 5
• Failing to recognize and treat the underlying cause 1, 5
• Using hypertonic saline in hypervolemic hyponatremia without life-threatening symptoms, which worsens edema and ascites 1
• Ignoring mild hyponatremia (130-135 mmol/L) as clinically insignificant, when it increases fall risk and mortality 1
• Relying solely on physical examination to determine volume status (sensitivity only 41.1%) 1, 6
• Administering hypotonic fluids (including lactated Ringer's) in SIADH, which worsens hyponatremia 1