Pathophysiology
Hypernatremia is ALWAYS a water deficit state. Serum [Na+] reflects the ratio of total body sodium to total body water. Elevated [Na+] indicates loss of water in excess of sodium, not sodium excess. Treatment fundamentally involves restoring water balance.
Free Water Deficit Calculation
Free Water Deficit = TBW × ([current Na] - 140) / 140
TBW ≈ 0.6 × weight (kg) in males; 0.5 × weight in females
Volume Status Classification
- Pure water loss: Hypernatremic hypovolemia (most common)
- Hypotonic fluid loss: Loss of both water and electrolytes with water > sodium
- Hypernatremic hypervolemia: Rare; excessive hypertonic saline or sodium gain
Etiology Classification
Renal Water Loss (Polyuric Hypernatremia)
Central Diabetes Insipidus (CDI)
- Pathophysiology: ADH deficiency from hypothalamic-pituitary insufficiency
- Causes: Idiopathic (30%), traumatic brain injury, neurosurgery, pituitary tumors, infiltrative diseases (sarcoidosis, histiocytosis), granulomatous meningitis
- Features: Abrupt onset if traumatic; polyuria (3–20 L/day), polydipsia; partial CDI exists
Nephrogenic Diabetes Insipidus (NDI)
- Pathophysiology: Kidney resistance to ADH; collecting duct cannot concentrate urine
- Genetic: X-linked (V2 receptor/AVPR2 mutations, >50%); autosomal recessive (AQP2 mutations, rare)
- Acquired (common):
- Medications: Lithium (most common; chronic use), amphotericin B, cisplatin, ifosfamide
- Electrolytes: Hypercalcemia, hypokalemia
- Renal disease: Pyelonephritis, reflux nephropathy, post-obstructive polyuria
- Features: Large volumes of dilute urine; poor response to desmopressin
Osmotic Diuresis
- Causes: Hyperglycemia/DKA (glucose >180 mg/dL), high protein/urea (tube feeding), mannitol/sorbitol, contrast agents
- Feature: Large urine volume; urine osmolality may be >300 if solute present
Extrarenal Water Loss
- GI losses: Diarrhea (most common cause in elderly), vomiting, NG suctioning
- Insensible losses: Mechanical ventilation, tachypnea, hyperthermia, burns, excessive sweating
Iatrogenic (Hospital/ICU Acquired)
- Hypertonic saline administration
- Tube feeding formulas with inadequate free water supplementation
- Normal saline in setting of ongoing insensible losses
Clinical Presentation
Neurologic manifestations result from osmotic stress on brain cells. Cells shrink as extracellular osmolarity rises; traction on meningeal vessels creates intracranial bleeding risk (especially elderly).
| Onset | Symptoms |
|---|---|
| Acute (<48h) | Thirst, irritability, restlessness, lethargy, muscle weakness, tremors, seizures (>160 mEq/L), altered mental status |
| Chronic (slow onset) | Often asymptomatic (brain adapts via osmolyte accumulation); mild confusion, lethargy; may present with complication (subdural hematoma) |
| Pediatric | Irritability, high-pitched cry, poor feeding; higher risk of CNS injury |
Diagnostic Approach
Step 1: Confirm and Assess Acuity
Serum [Na+] >145 mEq/L (mild 145–150; moderate 150–160; severe >160). Assess acute (<48h) vs chronic onset.
Step 2: Assess Volume Status
| Volume Status | Findings | Differential |
|---|---|---|
| Hypovolemic | Low JVP, orthostatic changes | GI losses, insensible losses, osmotic diuresis |
| Euvolemic | Normal vitals and exam | DI (central or nephrogenic), insensible only |
| Hypervolemic | Edema, elevated JVP, HTN | Hypertonic saline infusion, Na+ gain |
Step 3: Urine Osmolality (Key Diagnostic Test)
| Urine Osm | Interpretation | Likely Diagnosis |
|---|---|---|
| >800 mOsm/kg | Kidney concentrating appropriately | GI losses, insensible losses (extrarenal) |
| 400–800 | Partial renal response | Partial CDI, early osmotic diuresis, partial NDI |
| <300 mOsm/kg | Dilute urine; cannot concentrate | Complete CDI, NDI, osmotic diuresis |
Step 4: Desmopressin Challenge (Polyuric Cases)
Give desmopressin 10 mcg IV/SC or 20 mcg intranasal. Measure urine osmolality at 30–60 minutes.
| Response | Diagnosis |
|---|---|
| Urine osm increases >50% | Central DI (responds to ADH) |
| Urine osm increases 10–50% | Partial CDI or nephrogenic DI |
| Urine osm unchanged | Nephrogenic DI (resistant to ADH) |
Treatment
Acute hypernatremia (<48h) with symptoms: Target decrease 10–12 mEq/L in 24 hours.
Chronic hypernatremia: Slow correction MANDATORY. Target decrease 8–10 mEq/L per 24 hours.
NEVER lower [Na+] >12 mEq/L in 24 hours—rapid correction of chronic hypernatremia causes cerebral edema (brain has accumulated protective osmolytes; removing osmotic stress too fast causes water influx → herniation risk).
Hypovolemic Hypernatremia
- Initial: 0.9% NaCl bolus 500–1000 mL if hypotensive (restore intravascular volume first)
- Transition: Once stable, switch to hypotonic fluids (D5W or 0.45% NaCl)
- Calculate: Free water deficit + ongoing losses (insensible ~500–1000 mL/day); infuse over 48–72 hours
Example Calculation
70 kg male; [Na+] 155 mEq/L
TBW = 0.6 × 70 = 42 L
Free water deficit = 42 × (155 - 140) / 140 = 4.5 L
Add 500–1000 mL insensible losses → infuse ~5.5 L D5W over 48–72 hours (~100–120 mL/hr)
Euvolemic Hypernatremia (Diabetes Insipidus)
Central DI
- Desmopressin (DDAVP): Intranasal 5–10 mcg BID–TID; oral 0.1–0.2 mg TID; IV/SC 2–4 mcg daily
- Adjust dose to achieve urine output 2–3 L/day
- Patient drinks to thirst; desmopressin provides background DI suppression
Nephrogenic DI
- Desmopressin ineffective—do NOT give
- Thiazide diuretics (paradoxically helpful): HCTZ 25 mg BID → volume depletion → proximal reabsorption increases → less fluid reaches collecting duct
- NSAIDs (indomethacin): Inhibit prostaglandins → decrease solute delivery to medulla
- Amiloride (for lithium-induced NDI): Blocks lithium entry into collecting duct cells; 5–10 mg daily
- Low sodium diet; adequate free water (often need 2–3 L additional daily)
Specific Clinical Scenarios
Post-Operative/ICU Hypernatremia
- Common iatrogenic; from normal saline, tube feeding, insensible losses
- Prevention: Regular free water (IV dextrose, enteral water flushes)
- Correct slowly (typically chronic, develops over days)
Lithium-Induced NDI
- Chronic use; 15–50% incidence
- Partially reversible if lithium discontinued
- Amiloride most effective pharmacologic option
- Monitor [Na+] and renal function closely if continuing lithium
Neonatal Hypernatremia
- Causes: Inadequate breastfeeding, insensible losses, diarrhea
- Higher risk of CNS injury (brain more susceptible to osmotic changes)
- Correct slowly; target decrease 10–15 mEq/L over 48 hours
Clinical Pearls
- Hypernatremia = water deficit, not sodium excess—frame therapy as water replacement
- Urine osmolality is the key diagnostic test—high urine osm = extrarenal cause; low = DI
- Desmopressin challenge effectively distinguishes CDI (responds) from NDI (does not)
- Correct slowly in chronic hypernatremia (8–10 mEq/L/24h); faster acceptable in acute + symptomatic
- Partial CDI exists—intermediate response to desmopressin
- Thiazides paradoxically help NDI by creating mild volume depletion
- Amiloride is specific for lithium-NDI; blocks lithium entry into collecting duct cells
- Always address the underlying cause—DI management is futile if active osmotic diuresis continues
References
- Adrogué HJ, Madias NE. Hypernatremia. N Engl J Med. 2000;342(20):1493-1499. PubMed
- Sterns RH. Disorders of plasma sodium—causes, consequences, and correction. N Engl J Med. 2015;372(1):55-65. PubMed
- Zerbe RL, Stropes L, Robertson GL. Vasopressin function in SIADH. Annu Rev Med. 1980;31:315-327. PubMed
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