Hyponatremia: Comprehensive Clinical Overview
Definition and Classification
Hyponatremia is defined as serum sodium <135 mmol/L and represents the most common electrolyte disorder in clinical practice 1, 2. The condition is classified by severity: mild (130-135 mmol/L), moderate (120-129 mmol/L), and severe (<120 mmol/L) 1, 3.
Classification by Volume Status
The diagnostic approach requires categorizing patients by extracellular fluid volume status 1:
Hypovolemic hyponatremia: ECF contraction with clinical signs including orthostatic hypotension, dry mucous membranes, decreased skin turgor, and flat neck veins 1. Urine sodium <30 mmol/L suggests extrarenal losses (GI losses, burns, dehydration), while >20 mmol/L indicates renal losses (diuretics, salt-wasting nephropathy) 1.
Euvolemic hyponatremia: Normal volume status without edema or signs of dehydration 1. Most commonly caused by SIADH, characterized by urine sodium >20-40 mmol/L and urine osmolality >300 mOsm/kg 1.
Hypervolemic hyponatremia: Excess total body water with peripheral edema, ascites, and jugular venous distention 1. Seen in heart failure, cirrhosis, and nephrotic syndrome 1.
Classification by Acuity
This distinction is critical because acute hyponatremia can be corrected more rapidly without risk of osmotic demyelination syndrome, while chronic hyponatremia requires cautious correction 1.
Causes and Pathophysiology
Hypovolemic Causes
Renal sodium losses occur from diuretic use (especially thiazides), salt-wasting nephropathy, cerebral salt wasting, and adrenal insufficiency 1. Extrarenal losses result from vomiting, diarrhea, burns, and third-spacing 1.
Euvolemic Causes (SIADH)
SIADH results from inappropriate ADH activity despite low plasma osmolality and normal volume status 1. Common causes include malignancies (especially small cell lung cancer affecting 1-5% of patients), CNS disorders (meningitis, encephalitis, subarachnoid hemorrhage), pulmonary diseases (pneumonia, tuberculosis), and medications (SSRIs, carbamazepine, cyclophosphamide, NSAIDs, opioids) 1, 2.
The pathophysiology involves nonosmotic stimuli (pain, nausea, stress, acute illness) triggering AVP excess, impairing free-water excretion 1. Water retention is followed by physiologic natriuresis to maintain fluid balance at the expense of plasma sodium 1.
Hypervolemic Causes
In cirrhosis, systemic vasodilation from portal hypertension leads to decreased effective plasma volume and activation of the renin-angiotensin-aldosterone system, causing excessive sodium and water reabsorption 1. This creates dilutional hyponatremia affecting approximately 60% of cirrhotic patients 1. Non-osmotic hypersecretion of vasopressin and enhanced proximal nephron sodium reabsorption contribute to impaired free water clearance 1.
Heart failure causes similar mechanisms with increased ADH release due to perceived arterial underfilling despite total body volume overload 1.
Clinical Significance and Symptoms
Mortality and Morbidity
Even mild hyponatremia (130-135 mmol/L) is associated with increased mortality, with sodium levels <130 mmol/L linked to a 60-fold increase in hospital fatality (11.2% vs 0.19%) 1, 2. Hyponatremia increases fall risk dramatically—21% of hyponatremic patients present with falls compared to 5% of normonatremic patients 1, 2.
Symptom Spectrum
Symptom severity depends on the rapidity of development, duration, and severity of hyponatremia 2, 3:
- Mild symptoms: Nausea, vomiting, weakness, headache, mild neurocognitive deficits 3
- Moderate symptoms: Confusion, gait disturbances, attention deficits 1, 2
- Severe symptoms: Seizures, coma, delirium, impaired consciousness, ataxia, cardiorespiratory distress, and rarely brain herniation and death 2, 3
Chronic mild hyponatremia is associated with cognitive impairment, gait disturbances, osteoporosis, and increased rates of falls and fractures 2. In prospective studies, patients with hyponatremia had higher rates of new fractures over 7.4 years (23.3% vs 17.3%) 2.
Special Population Risks
In cirrhotic patients, hyponatremia significantly increases risk of spontaneous bacterial peritonitis (OR 3.40), hepatorenal syndrome (OR 3.45), and hepatic encephalopathy (OR 2.36) 1.
Diagnostic Approach
Initial Workup
The initial workup should include serum and urine osmolality, urine electrolytes (especially sodium), uric acid, and assessment of extracellular fluid volume status 1. Additional tests include serum creatinine, glucose, TSH (to exclude hypothyroidism), and cortisol (to exclude adrenal insufficiency) 1.
Key Diagnostic Parameters
- Serum osmolality: Normal is 275-290 mOsm/kg; calculated as 2 × Na + BUN/2.8 + glucose/18 1
- Urine osmolality: <100 mOsm/kg indicates appropriate ADH suppression; >100 mOsm/kg suggests impaired water excretion 1
- Urine sodium: <30 mmol/L predicts saline responsiveness with 71-100% positive predictive value in hypovolemic hyponatremia 1; >20-40 mmol/L with high urine osmolality suggests SIADH 1
- Serum uric acid: <4 mg/dL has 73-100% positive predictive value for SIADH 1
Volume Status Assessment
Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) for volume assessment 1. Look for specific findings:
- Hypovolemia: Orthostatic hypotension, dry mucous membranes, decreased skin turgor, flat neck veins 1
- Hypervolemia: Peripheral edema, ascites, jugular venous distention, pulmonary congestion 1
- Euvolemia: No edema, no orthostatic hypotension, normal skin turgor, moist mucous membranes 1
Critical Distinction: SIADH vs. Cerebral Salt Wasting
In neurosurgical patients, distinguishing SIADH from cerebral salt wasting (CSW) is critical because they require opposite treatments 1:
- SIADH: Euvolemic state, normal to slightly elevated CVP, urine sodium >20-40 mmol/L, urine osmolality >500 mOsm/kg; treated with fluid restriction 1
- CSW: True hypovolemia with CVP <6 cm H₂O, urine sodium >20 mmol/L despite volume depletion, clinical signs of hypovolemia; treated with volume and sodium replacement 1
Treatment Approach
Critical Correction Rate Guidelines
The single most important principle: never exceed 8 mmol/L correction in 24 hours to prevent osmotic demyelination syndrome 1, 2, 3. For high-risk patients (advanced liver disease, alcoholism, malnutrition, severe hyponatremia), limit correction to 4-6 mmol/L per day 1.
Severe Symptomatic Hyponatremia (Medical Emergency)
For severe symptoms (seizures, coma, confusion with altered mental status), immediately administer 3% hypertonic saline with a target correction of 6 mmol/L over 6 hours or until symptoms resolve 1, 2, 3. Administer as 100 mL boluses over 10 minutes, repeatable up to three times at 10-minute intervals 1.
Monitor serum sodium every 2 hours during initial correction 1. Once severe symptoms resolve, slow correction rate and do not exceed total correction of 8 mmol/L in 24 hours 1.
Treatment Based on Volume Status
Hypovolemic Hyponatremia
Discontinue diuretics immediately and administer isotonic saline (0.9% NaCl) for volume repletion 1, 3. Initial infusion rate: 15-20 mL/kg/h, then 4-14 mL/kg/h based on response 1. For cirrhotic patients, consider albumin infusion alongside isotonic saline with cautious correction rates (4-6 mmol/L per day maximum) 1.
Euvolemic Hyponatremia (SIADH)
Fluid restriction to 1 L/day is the cornerstone of treatment for mild to moderate asymptomatic SIADH 1, 2, 3. If no response to fluid restriction, add oral sodium chloride 100 mEq three times daily 1.
For severe symptoms or sodium <120 mEq/L, administer 3% hypertonic saline with careful monitoring 1. Pharmacological options for resistant cases include vasopressin receptor antagonists (tolvaptan, conivaptan) 1, 4.
Tolvaptan dosing: Start 15 mg once daily, titrate to 30-60 mg based on response 4. 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 (0.4 and 1.8 mEq/L respectively) 4. Tolvaptan must be initiated in hospital with close sodium monitoring and should not be used for more than 30 days 4.
Alternative agents include urea, demeclocycline, and lithium, though these have more adverse effects 1, 2.
Hypervolemic Hyponatremia
Implement fluid restriction to 1-1.5 L/day for serum sodium <125 mmol/L 1, 3. Temporarily discontinue diuretics if sodium <125 mmol/L 1.
For cirrhotic patients, consider albumin infusion alongside fluid restriction 1. Avoid hypertonic saline unless life-threatening symptoms are present, as it may worsen ascites and edema 1.
Sodium restriction (not fluid restriction) results in weight loss as fluid passively follows sodium in cirrhotic patients 1. Recommend salt intake of 5-6.5 g/day (sodium 2-2.5 g/day, 88-110 mmol/day) 1.
For heart failure patients with persistent severe hyponatremia despite water restriction and maximized guideline-directed medical therapy, vasopressin antagonists may be considered short-term 1.
Special Considerations: Cerebral Salt Wasting
CSW requires volume and sodium replacement, NOT fluid restriction 1. For severe symptoms, administer 3% hypertonic saline plus fludrocortisone (0.1-0.2 mg daily) in ICU setting 1. Hydrocortisone may prevent natriuresis in subarachnoid hemorrhage patients 1. Never use fluid restriction in subarachnoid hemorrhage patients at risk of vasospasm 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) 1. Consider administering desmopressin to slow or reverse the rapid rise in serum sodium 1. Target relowering to bring total 24-hour correction to no more than 8 mmol/L from starting point 1.
Common Pitfalls to Avoid
- Overly rapid correction of chronic hyponatremia leading to osmotic demyelination syndrome 1, 2
- Inadequate monitoring during active correction 1
- Using fluid restriction in cerebral salt wasting, which worsens outcomes 1
- Failing to recognize and treat the underlying cause 1
- Using hypertonic saline in hypervolemic hyponatremia without life-threatening symptoms 1
- Ignoring mild hyponatremia (130-135 mmol/L) as clinically insignificant 1
- Stopping diuretics prematurely in volume-overloaded heart failure patients due to mild hyponatremia 1
- Misdiagnosing volume status, leading to inappropriate treatment 1
Monitoring Requirements
- Severe symptoms: Check sodium every 2 hours during initial correction 1
- Mild symptoms: Check sodium every 4 hours after resolution of severe symptoms 1
- Chronic correction: Check sodium every 24-48 hours initially 1
- Watch for osmotic demyelination syndrome signs (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 1, 4